[ { "sid": "DEM2016", "title": "Lysosomal recruitment of TSC2 is a universal response to cellular stress", "authors": "Demetriades C; Teleman AA et al.", "year": 2016, "journal": "Nature communications", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/ncomms10662", "pmid": "26868506", "pmcid": "PMC4754342", "finding": "Lysosomal recruitment of TSC2 is a universal response to cellular stress that inhibits mTORC1.\n", "abstract": "mTORC1 promotes cell growth and is therefore inactivated upon unfavourable growth conditions. Signalling pathways downstream of most cellular stresses converge on TSC1/2, which serves as an integration point that inhibits mTORC1. The TSC1/2 complex was shown to translocate to lysosomes to inactivate mTORC1 in response to two stresses: amino-acid starvation and growth factor removal. Whether other stresses also regulate TSC2 localization is not known. How TSC2 localization responds to combinations of stresses and other stimuli is also unknown. We show that both amino acids and growth factors are required simultaneously to maintain TSC2 cytoplasmic; when one of the two is missing, TSC2 relocalizes to lysosomes. Furthermore, multiple different stresses that inhibit mTORC1 also drive TSC2 lysosomal accumulation. Our findings indicate that lysosomal recruitment of TSC2 is a universal response to stimuli that inactivate mTORC1, and that the presence of any single stress is sufficient to cause TSC2 lysosomal localization.", "ai_intervention": "Various cellular stresses (amino-acid/growth-factor withdrawal, etc.) – mechanistic", "ai_target": "TSC2 / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "Diverse stresses relocate TSC2 to the lysosome → inhibit mTORC1 (a universal response)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DEM2016/" }, { "sid": "INOK2003", "title": "Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling", "authors": "Inoki K; Guan KL et al.", "year": 2003, "journal": "Genes & development", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "In vitro; Drosophila", "peer_reviewed": "Yes", "doi": "10.1101/gad.1110003", "pmid": "12869586", "pmcid": "PMC196227", "finding": "TSC2 is a GAP for Rheb; loss of TSC2 raises Rheb-GTP and constitutively activates mTOR.\n", "abstract": "Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2. The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1. These functions of TSC1/TSC2 are likely mediated by mTOR. Here we report that TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase. Rheb stimulates phosphorylation of S6K and 4EBP1. This function of Rheb is blocked by rapamycin and dominant-negative mTOR. Rheb stimulates the phosphorylation of mTOR and plays an essential role in regulation of S6K and 4EBP1 in response to nutrients and cellular energy status. Our data demonstrate that Rheb acts downstream of TSC1/TSC2 and upstream of mTOR to regulate cell growth.", "ai_intervention": "Biochemical/genetic (TSC2 GAP activity toward Rheb)", "ai_target": "Rheb / TSC2 / mTOR", "ai_species": "In vitro; Drosophila", "ai_effect": "TSC2 is a GAP for Rheb; Rheb-GTP activates mTOR/S6K/4EBP1 (rapamycin-sensitive)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/INOK2003/" }, { "sid": "INO2002", "title": "TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling", "authors": "Inoki K; Guan KL et al.", "year": 2002, "journal": "Nature Cell Biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cell lines", "peer_reviewed": "Yes", "doi": "10.1038/ncb839", "pmid": "12172553", "pmcid": "", "finding": "Akt directly phosphorylates and inactivates TSC2, disrupting the TSC1-TSC2 complex and releasing its inhibition of mTOR - the link between growth-factor/insulin signaling and mTORC1 activation.\n", "abstract": "Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the formation of hamartomas in a wide range of human tissues. Mutation in either the TSC1 or TSC2 tumour suppressor gene is responsible for both the familial and sporadic forms of this disease. TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). Furthermore, TSC2 is directly phosphorylated by Akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. TSC2 is inactivated by Akt-dependent phosphorylation, which destabilizes TSC2 and disrupts its interaction with TSC1. Our data indicate a molecular mechanism for TSC2 in insulin signalling, tumour suppressor functions and in the inhibition of cell growth.", "ai_intervention": "Biochemical/genetic (Akt phosphorylation of TSC2)", "ai_target": "TSC2 / Akt / mTOR", "ai_species": "Human cell lines", "ai_effect": "Akt phosphorylates and inactivates TSC2 → relieves mTOR inhibition (links insulin/growth factors to mTORC1)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/INO2002/" }, { "sid": "YU2026", "title": "High-concentration hydrogen mitigates cognitive impairment in a murine model of Sepsis-associated encephalopathy by enhancing oligodendrocyte maturation and myelination in the mPFC", "authors": "Yu J; Qi W; Li F; Chang B; Wang Zengkun; Kan Y; Yu Yonghao; Yu Yang", "year": 2026, "journal": "Progress in Neuro-Psychopharmacology and Biological Psychiatry", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (CLP-induced SAE model)", "peer_reviewed": "Yes", "doi": "10.1016/j.pnpbp.2026.111892", "pmid": "", "pmcid": "", "finding": "In a mouse model of sepsis-associated encephalopathy (SAE), mTOR hyperactivation impairs oligodendrocyte maturation and causes cognitive deficits; hydrogen gas and rapamycin suppress mTOR, restore myelination, and improve cognition in these mice.\n", "abstract": "Sepsis-associated encephalopathy (SAE) commonly elicits long-lasting cognitive deterioration. This study investigates whether high-concentration (67%) hydrogen gas protects against SAE by promoting oligodendrocyte maturation and myelination in the medial prefrontal cortex (mPFC). mTOR hyperactivation in the mPFC of SAE mice impeded oligodendrocyte precursor cell (OPC) differentiation, triggered hypomyelination, and precipitated cognitive dysfunction. 67% hydrogen inhalation mitigated SAE-induced cognitive dysfunction by restraining mTOR overactivation to promote oligodendrocyte maturation and myelin reconstruction; rapamycin treatment exerted synergistic neuroprotective efficacy.", "ai_intervention": "67% Hydrogen gas; Rapamycin; NV-5138 (mTOR agonist)", "ai_target": "mTOR pathway; oligodendrocyte precursor cell differentiation; myelination", "ai_species": "Mouse", "ai_effect": "In mice, mTOR hyperactivation blocks OPC differentiation and myelination causing cognitive decline; hydrogen + rapamycin suppress mTOR and restore cognition", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/YU2026/" }, { "sid": "JIN2026B", "title": "Rapamycin attenuates age-related atrial remodeling and fibrillation by targeting HIF-1α-mediated metabolic dysregulation.", "authors": "Jin L; Jiang T; Gong H et al.", "year": 2026, "journal": "Biochimica et Biophysica Acta - Molecular Basis of Disease", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (D-galactose aging model)", "peer_reviewed": "Yes", "doi": "10.1016/j.bbadis.2026.168438", "pmid": "", "pmcid": "", "finding": "Dietary rapamycin reduced aging-induced atrial fibrillation susceptibility and atrial remodelling in D-galactose-aged mice, acting largely through mTOR-independent inhibition of HIF-1α plus restored mitochondrial function and insulin sensitivity.\n", "abstract": "Atrial fibrillation (AF) is an age-related disease. Although rapamycin is a foremost anti-aging therapy with proven efficacy in lifespan extension, its impact on aging-induced atrial remodeling and AF susceptibility was unknown. An aging-induced AF-susceptible mouse model was produced by D-galactose injection followed by a rapamycin diet. Rapamycin significantly reduced aging-induced AF susceptibility and ameliorated atrial electrical and structural remodeling. Metabolically, it improved systemic insulin resistance, restored mitochondrial function and morphology, and counteracted aging-induced perturbations in substrate utilization. Mechanistically, rapamycin inhibited HIF-1α transcriptional activity and suppressed CoCl2-induced HIF-1α expression and nuclear translocation; pharmacological restoration of HIF-1α attenuated rapamycin's protective effects. Molecular docking, dynamics simulations and isothermal titration calorimetry suggested rapamycin may directly interfere with HIF-1α dimerization. Restoration of mTOR activity failed to reverse rapamycin-mediated HIF-1α inhibition, suggesting an mTOR-independent regulatory mechanism.", "ai_intervention": "Rapamycin (dietary)", "ai_target": "HIF-1α (mTOR-independent); mitochondrial metabolism", "ai_species": "Mouse", "ai_effect": "Reduced AF susceptibility, improved insulin resistance, restored mitochondrial function and substrate utilisation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JIN2026B/" }, { "sid": "LOF2011", "title": "Ulk1-mediated phosphorylation of AMPK constitutes a negative regulatory feedback loop", "authors": "Löffler AS et al.", "year": 2011, "journal": "Autophagy", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells; mouse", "peer_reviewed": "Yes", "doi": "10.4161/auto.7.7.15451", "pmid": "21460634", "pmcid": "", "finding": "ULK1 phosphorylates and inhibits AMPK in return, showing autophagy signaling is a bidirectional feedback loop, not a one-way switch.\n", "abstract": "Unc-51-like kinase 1 (Ulk1) plays a central role in autophagy induction. It forms a stable complex with Atg13 and focal adhesion kinase (FAK) family interacting protein of 200 kDa (FIP 200). This complex is negatively regulated by the mammalian target of rapamycin complex 1 (mTORC1) in a nutrient-dependent way. AMP-activated protein kinase (AMPK), which is activated by LKB1/Strad/Mo25 upon high AMP levels, stimulates autophagy by inhibiting mTORC1. Recently, it has been described that AMPK and Ulk1 interact and that the latter is phosphorylated by AMPK. This phosphorylation leads to the direct activation of Ulk1 by AMPK bypassing mTOR-inhibition. Here we report that Ulk1/2 in turn phosphorylates all three subunits of AMPK and thereby negatively regulates its activity. Thus, we propose that Ulk1 is not only involved in the induction of autophagy, but also in terminating signaling events that trigger autophagy. In our model, phosphorylation of AMPK by Ulk1 represents a negative feedback circuit.", "ai_intervention": "Biochemical (ULK1–AMPK)", "ai_target": "ULK1 / AMPK / mTORC1", "ai_species": "Human cells; mouse", "ai_effect": "ULK1 phosphorylates and inhibits AMPK – a negative feedback loop in autophagy signaling", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LOF2011/" }, { "sid": "KIM2003", "title": "GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR", "authors": "Kim DH; Sarbassov DD; Ali SM; Latek RR; Guntur KVP; Erdjument-Bromage H; Tempst P; Sabatini DM", "year": 2003, "journal": "Molecular Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells (biochemistry)", "peer_reviewed": "Yes", "doi": "10.1016/s1097-2765(03)00114-x", "pmid": "12718876", "pmcid": "", "finding": "Discovered mLST8 (GbetaL), the third core subunit that clamps onto mTOR's kinase domain and stabilizes the complex. It fine-tunes how tightly Raptor holds mTOR in response to nutrients - a small but essential cog that later turned out to be especially critical for the mTORC2 complex.\n", "abstract": "mTOR and raptor are components of a signaling pathway that regulates mammalian cell growth in response to nutrients and growth factors. Here, we identify a member of this pathway, a protein named GbetaL that binds to the kinase domain of mTOR and stabilizes the interaction of raptor with mTOR. Like mTOR and raptor, GbetaL participates in nutrient- and growth factor-mediated signaling to S6K1, a downstream effector of mTOR, and in the control of cell size. The binding of GbetaL to mTOR strongly stimulates the kinase activity of mTOR toward S6K1 and 4E-BP1, an effect reversed by the stable interaction of raptor with mTOR. Interestingly, nutrients and rapamycin regulate the association between mTOR and raptor only in complexes that also contain GbetaL. Thus, we propose that the opposing effects on mTOR activity of the GbetaL- and raptor-mediated interactions regulate the mTOR pathway.", "ai_intervention": "Biochemical – identification of GβL (mLST8)", "ai_target": "mTOR / raptor / GβL (mLST8)", "ai_species": "Human cells (biochemistry)", "ai_effect": "GβL binds the mTOR kinase domain and stabilizes the raptor–mTOR interaction; stimulates nutrient-sensitive signaling to S6K1 and cell-size control", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KIM2003/" }, { "sid": "LIS2026", "title": "Notoginsenoside R1 Alleviates Acetaminophen-Induced Liver Injury via MAPK/mTOR-Mediated Autophagy.", "authors": "Li S, Liu Z, Pan G, Li Y, Lv K", "year": 2026, "journal": "The American Journal of Chinese Medicine", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1142/S0192415X26500576", "pmid": "42459050", "pmcid": "", "finding": "Notoginsenoside R1 alleviates acetaminophen-induced acute liver injury by activating protective autophagy through MAPK/mTOR pathway modulation, reducing hepatocyte death and oxidative damage.\n", "abstract": "Notoginsenoside R1 (NGR1), a bioactive saponin from Panax notoginseng, was investigated in acetaminophen-induced acute liver injury (AILI). NGR1 treatment activated autophagy via modulation of the MAPK/mTOR pathway, reducing hepatocyte apoptosis and oxidative stress, and attenuating liver injury in mouse models and hepatocyte cultures.", "ai_intervention": "Notoginsenoside R1", "ai_target": "MAPK/mTOR pathway; autophagy", "ai_species": "Mouse", "ai_effect": "NGR1 suppresses mTOR to activate autophagy, reducing APAP-induced hepatocyte apoptosis and liver injury", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LIS2026/" }, { "sid": "GWI2008", "title": "AMPK phosphorylation of raptor mediates a metabolic checkpoint", "authors": "Gwinn DM; Shackelford DB; Egan DF; Mihaylova MM; Mery A; Vasquez DS; Turk BE; Shaw RJ", "year": 2008, "journal": "Molecular Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human/mouse cells (biochemistry)", "peer_reviewed": "Yes", "doi": "10.1016/j.molcel.2008.03.003", "pmid": "18439900", "pmcid": "PMC2674027", "finding": "Found a SECOND way the energy sensor AMPK shuts mTORC1 down. Besides acting through TSC2, AMPK directly phosphorylates Raptor - the core mTORC1 subunit - to halt growth when energy runs low. This 'metabolic checkpoint' is exactly the switch that drugs like metformin and exercise tap into.\n", "abstract": "AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. We report here that AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress. These findings uncover a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.", "ai_intervention": "Biochemical/genetic (AMPK phosphorylation of raptor)", "ai_target": "raptor / mTORC1 / AMPK", "ai_species": "Human/mouse cells (biochemistry)", "ai_effect": "Under energy stress AMPK phosphorylates raptor → a metabolic checkpoint that suppresses mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GWI2008/" }, { "sid": "VITTE2026", "title": "Efficacy and safety of everolimus in heart transplant recipients: A meta-analysis", "authors": "Vitte SH; Luna AM; Pille JJ; Pinheiro BN; Souza MBL; Irudhayaraj CDJ; Munaretto GM", "year": 2026, "journal": "JHLT Open", "tier": "A - Systematic review", "pyramid": "1 - Systematic Review", "category": "Human", "model": "Human (adult and paediatric heart transplant recipients)", "peer_reviewed": "Yes", "doi": "10.1016/j.jhlto.2026.100610", "pmid": "42656203", "pmcid": "PMC13506258", "finding": "Meta-analysis of 60 studies (1786 heart transplant recipients): everolimus-based immunosuppression reduced cardiac allograft vasculopathy progression on IVUS (RR ~0.57) and preserved renal function (eGFR +10-15 mL/min) when combined with calcineurin-inhibitor minimisation, with neutral all-cause mortality (RR ~0.98) but more adverse events and treatment discontinuation.\n", "abstract": "Long-term outcomes after heart transplantation remain limited by cardiac allograft vasculopathy (CAV) and calcineurin inhibitor (CNI)-related nephrotoxicity. Everolimus has emerged as a CNI-sparing strategy, yet its net clinical benefit remains debated. To determine whether everolimus-based immunosuppression improves efficacy and safety compared with standard CNI-based therapy in heart transplant recipients. We conducted a systematic review and meta-analysis of randomized controlled trials and comparative observational studies enrolling adult and/or pediatric heart transplant recipients. MEDLINE, EMBASE, and CENTRAL were searched from inception. The primary endpoint was the composite MATE-3 (acute rejection, CAV, or chronic kidney disease). Secondary outcomes included mortality, individual efficacy components, renal function, and the broader safety composite (MATE-6). Pooled effect estimates were generated using random-effects models. Sixty studies including 1786 heart transplant recipients (mean age ~52 years) were analyzed. Everolimus-based regimens reduced cardiac allograft vasculopathy progression by intravascular ultrasound (RR ~0.57) and improved renal function when combined with CNI minimization (mean eGFR increase ~10-15 mL/min). The composite MATE-3 endpoint favored everolimus. All-cause mortality was neutral (RR ~0.98). Acute rejection varied by protocol, with higher rates mainly in strategies involving abrupt or late CNI withdrawal. The safety composite (MATE-6) showed increased adverse events and treatment discontinuation with everolimus. Everolimus-based immunosuppression provides meaningful vasculoprotection and renal preservation without increasing mortality. When used within structured CNI minimization protocols, it offers a strategy to improve long-term graft health after heart transplantation.", "ai_intervention": "Everolimus-based immunosuppression (with calcineurin-inhibitor minimisation or withdrawal) vs standard CNI-based therapy", "ai_target": "mTORC1 (everolimus)", "ai_species": "Human", "ai_effect": "Reduced cardiac allograft vasculopathy progression and better renal function; mortality neutral; more adverse events and discontinuations", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/VITTE2026/" }, { "sid": "DEOLIVEIRA2026", "title": "Transcriptional modulation of the PI3K/AKT/mTOR signaling pathway mediated by HPV16 oncogene expression in breast cancer.", "authors": "de Oliveira Isidio BE; Fontes PHB; da Silva GRP; Leao SL; de Franca Sao Marcos B; et al.", "year": 2026, "journal": "Exploration of targeted anti-tumor therapy", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human (clinical samples, FFPE tissue)", "peer_reviewed": "Yes", "doi": "10.37349/etat.2026.1002391", "pmid": "", "pmcid": "", "finding": "HPV16 oncogene expression in breast tumor tissue from 92 patients transcriptionally upregulates PI3K/AKT/mTOR pathway components, suggesting a viral mechanism contributing to mTOR pathway activation in breast cancer.\n", "abstract": "Breast cancer is the most prevalent malignant tumor among women. Human papillomavirus (HPV) has been detected in breast tumors since the 1990s, and beyond its oncogenic potential, therapy resistance driven by viral immune evasion in non-anogenital tumors highlights the need to investigate viral activity in breast tissues. Among high-risk HPV types, HPV16 is one of the most prevalent and exhibits the highest carcinogenic potential. This study aimed to evaluate the expression of HPV16 oncogenes and the modulation of the PI3K/AKT/mTOR signaling pathway associated with viral activity. A total of 92 breast cancer patients were included after Ethics Committee approval. RNA was extracted from formalin-fixed, paraffin-embedded tissues and reverse-transcribed into cDNA. Transcripts of HPV oncogenes and components of the PI3K/AKT/mTOR pathway were quantified.", "ai_intervention": "HPV16 oncogene expression", "ai_target": "PI3K/AKT/mTOR", "ai_species": "Human", "ai_effect": "Upregulates PI3K/AKT/mTOR pathway transcription in breast cancer", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DEOLIVEIRA2026/" }, { "sid": "SIL2026", "title": "Enforcing mTORC1 activity in therapeutic CD4+ T cells promotes persistence but eventual immune exhaustion", "authors": "Sillito F; Armbrecht E; O'Neill AT; McIntyre A; Nyatondo M; Holler A; Callender LA; Henson SM; Stauss H; Chakraverty R", "year": 2026, "journal": "Journal of Immunology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Mechanism", "model": "Mouse CD4+ T cells, adoptive transfer tumor model", "peer_reviewed": "Yes", "doi": "10.1093/jimmun/vkag206", "pmid": "42566506", "pmcid": "", "finding": "Enforced RHEB overexpression (mTORC1 hyperactivation) in therapeutic CD4+ T cells boosts initial proliferation/persistence after adoptive transfer, but drives cells toward an exhausted phenotype (co-inhibitory receptors, impaired re-proliferation on rechallenge) -- a double-edged sword for CAR/TCR-T cell engineering, distinct from the CD8 response to the same manipulation.\n", "abstract": "There is substantial interest in developing novel engineering strategies to promote the sustained metabolic fitness of therapeutic T cells. We previously showed that overexpression of RAS homologue enriched in brain (RHEB), a positive regulator of mammalian target of rapamycin complex 1 (mTORC1), promotes aerobic glycolysis and increases the anti-tumor functions of effector CD8+ T cells. To address whether these effects are conserved in CD4+ T cells, we have now examined how enforced activation of mTORC1 activity affects CD4+ T cell differentiation and function. Rheb overexpression induced a more balanced metabolic shift in CD4+ T cells than in CD8+ T cells, with increases in both oxidative phosphorylation and aerobic glycolysis. Although Rheb overexpression initially increased CD4+ T cell activation and proliferation in vitro, the underlying population architecture was complex, involving a shift to both more proliferative, cytotoxic-like cell states as well as more quiescent cell clusters characterised by counter-regulation of mTORC1 activity. Following adoptive transfer, tumor antigen-specific Rheb-transduced CD4+ T cells showed greater persistence but were less efficient than controls in eliminating tumor. This functional deficiency could be explained by a greater propensity of persisting Rheb-transduced CD4+ T cells to develop features of immune exhaustion, as evidenced by expression of multiple co-inhibitory receptors and impaired proliferation upon tumor rechallenge. Together, these data demonstrate the dynamic population response to tuning of T cell mTORC1 and the need to separately appraise cellular outputs of therapeutic CD4+ versus CD8+ T cells when metabolic pathways are manipulated by the same method.", "ai_intervention": "", "ai_target": "Rheb / mTORC1", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SIL2026/" }, { "sid": "BRO1996", "title": "Dwarf mice and the ageing process", "authors": "Brown-Borg HM; Bartke A et al.", "year": 1996, "journal": "Nature", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Ames dwarf mice (growth-hormone deficient)", "peer_reviewed": "Yes", "doi": "10.1038/384033a0", "pmid": "8900272", "pmcid": "", "finding": "Mice with growth hormone deficiency lived substantially longer than normal littermates - founding observation linking reduced growth-signaling to mammalian longevity.\n", "abstract": "(Brief communication; no formal abstract in PubMed — editorial summary.) This landmark report shows that Ames dwarf mice, which carry a mutation causing combined deficiency of growth hormone, prolactin and thyroid-stimulating hormone, live substantially longer than their normal littermates (both sexes). It was among the first demonstrations that genetically reduced growth hormone / IGF-1 endocrine signalling extends lifespan in a mammal, linking the somatotropic axis — upstream of PI3K-Akt-mTOR — to the ageing process and providing a foundational genetic model for the biology of ageing and longevity.", "ai_intervention": "Genetic – Ames dwarf mutation (GH/prolactin/TSH deficiency)", "ai_target": "GH/IGF-1 axis (upstream of PI3K-Akt-mTOR)", "ai_species": "Mouse (Ames dwarf)", "ai_effect": "Substantially longer lifespan vs normal littermates (both sexes) – early evidence linking reduced growth signaling to longevity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BRO1996/" }, { "sid": "HSI2012", "title": "The translational landscape of mTOR signalling steers cancer initiation and metastasis", "authors": "Hsieh AC; Liu Yi; Edlind MP; Ingolia NT; Janes MR; Sher A; et al.; Ruggero D", "year": 2012, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse models + human prostate cancer", "peer_reviewed": "Yes", "doi": "10.1038/nature10912", "pmid": "22367541", "pmcid": "PMC3663483", "finding": "Showed WHY mTOR-driven translation matters for cancer: in prostate cancer, oncogenic mTOR selectively translates a specific set of pro-invasion mRNAs that drive metastasis. An ATP-competitive mTOR inhibitor (INK128) reversed that signature - an early preclinical rationale from mouse models and cell lines, not a clinical result.\n", "abstract": "The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the 'cancerous' translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.", "ai_intervention": "Oncogenic mTOR modulation + ribosome profiling", "ai_target": "mTOR / 4E-BP–eIF4E translation", "ai_species": "Mouse models + human prostate cancer", "ai_effect": "Oncogenic mTOR reprograms translation of a specific gene set driving proliferation, metabolism and invasion/metastasis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HSI2012/" }, { "sid": "BOU2020", "title": "AIMTOR, a BRET biosensor for live imaging, reveals subcellular mTOR signaling and dysfunctions", "authors": "Bouquier N; Ollendorff V et al.", "year": 2020, "journal": "BMC Biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "HEK293 cells; primary hippocampal neurons and muscle cells (mouse); biosensor tool", "peer_reviewed": "Yes", "doi": "10.1186/s12915-020-00790-8", "pmid": "32620110", "pmcid": "PMC7334845", "finding": "AIMTOR is a genetically encoded BRET biosensor that reads out mTOR activity live in single cells and in specific subcellular compartments (cytosol, lysosome surface, nucleus, near mitochondria) -- the enabling technology that makes pulsatile/oscillatory mTOR hypotheses experimentally testable rather than purely theoretical.\n", "abstract": "mTOR signaling is an essential nutrient and energetic sensing pathway. Here we describe AIMTOR, a sensitive genetically encoded BRET (Bioluminescent Resonance Energy Transfer) biosensor to study mTOR activity in living cells. As a proof of principle, we show in both cell lines and primary cell cultures that AIMTOR BRET intensities are modified by mTOR activity changes induced by specific inhibitors and activators of mTORC1 including amino acids and insulin. We further engineered several versions of AIMTOR enabling subcellular-specific assessment of mTOR activities. We then used AIMTOR to decipher mTOR signaling in physio-pathological conditions. First, we show that mTORC1 activity increases during muscle cell differentiation and in response to leucine stimulation in different subcellular compartments such as the cytosol and at the surface of the lysosome, the nucleus, and near the mitochondria. Second, in hippocampal neurons, we found that the enhancement of neuronal activity increases mTOR signaling. AIMTOR further reveals mTOR-signaling dysfunctions in neurons from mouse models of autism spectrum disorder. Altogether, our results demonstrate that AIMTOR is a sensitive and specific tool to investigate mTOR-signaling dynamics in living cells and phenotype mTORopathies.", "ai_intervention": "Genetically encoded BRET biosensor (AIMTOR) -- tool, not a drug intervention", "ai_target": "mTOR activity (live, subcellular)", "ai_species": "Human (HEK293); mouse (neurons, muscle)", "ai_effect": "Enables real-time single-cell/subcellular measurement of mTOR activity dynamics", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BOU2020/" }, { "sid": "CHEN2026C", "title": "Impaired Chaperone-Mediated Autophagy Accelerates Intervertebral Disc Degeneration by Inducing MIDN Accumulation to Target TSC2 for Proteasomal Degradation", "authors": "Chen Xianglong; Gao H; Wu W; Shi P; Chen Yuhang; Zhang A; Cheng Z; Wu W; Yu Z; Zhang Y", "year": 2026, "journal": "Advanced Science", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Mechanism", "model": "Human nucleus pulposus cells; rat caudal needle-puncture model", "peer_reviewed": "Yes", "doi": "10.1002/advs.77428", "pmid": "42658647", "pmcid": "", "finding": "Loss of chaperone-mediated autophagy lets its substrate midnolin (MIDN) accumulate; MIDN binds TSC2 and drives its proteasomal degradation independently of ubiquitination, de-repressing mTORC1 and causing senescence, SASP and matrix loss in disc cells. MIDN knockdown, LAMP2A overexpression or rapamycin each blocked the degeneration - a new upstream route to mTORC1 hyperactivation.\n", "abstract": "Intervertebral disc degeneration (IDD) is a leading cause of low back pain with incompletely understood mechanisms. Although autophagy dysfunction is a documented contributor to IDD, the precise pathobiological role of chaperone-mediated autophagy (CMA) remains poorly understood. Here, we demonstrate that CMA activity is downregulated in nucleus pulposus cells (NPCs) from IDD patients and IL-1beta-induced rat intervertebral disc cell models, causing cytoplasmic accumulation of a novel CMA substrate, Midnolin (MIDN). Accumulated MIDN bypasses the ubiquitin-proteasome system and directly binds to Tuberous Sclerosis Complex 2 (TSC2), mediating its degradation. TSC2 loss relieves mechanistic target of rapamycin complex 1 (mTORC1) inhibition, resulting in mTORC1 hyperactivation, which drives cellular senescence, senescence-associated secretory phenotype (SASP), and extracellular matrix (ECM) degradation in NPCs. In vitro and in a rat caudal needle puncture model, MIDN knockdown (shRNA), CMA activation (LAMP2A overexpression), or mTORC1 inhibition (Rapamycin) significantly attenuated IL-1beta or MIDN overexpression-induced senescence and disc degeneration. Our findings reveal an 'Impaired CMA-MIDN accumulation-TSC2 degradation-mTORC1 activation' axis central to IDD pathogenesis, offering potential therapeutic targets.", "ai_intervention": "MIDN knockdown (shRNA), LAMP2A overexpression (CMA activation), rapamycin", "ai_target": "TSC2 / mTORC1 (via midnolin, MIDN)", "ai_species": "Human cells; rat", "ai_effect": "Impaired CMA -> MIDN accumulation -> TSC2 degradation -> mTORC1 hyperactivation -> senescence, SASP and matrix loss; blocked by MIDN knockdown, LAMP2A overexpression or rapamycin", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHEN2026C/" }, { "sid": "JAC2006", "title": "SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity", "authors": "Jacinto E; Su B et al.", "year": 2006, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2006.08.033", "pmid": "16962653", "pmcid": "", "finding": "SIN1 maintains rictor-mTOR integrity and confers mTORC2 Akt-Ser473 kinase activity and substrate specificity.\n", "abstract": "Mammalian target of rapamycin (mTOR) controls cell growth and proliferation via the raptor-mTOR (TORC1) and rictor-mTOR (TORC2) protein complexes. Recent biochemical studies suggested that TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif. Phosphorylation at Ser473, along with Thr308 of its activation loop, is deemed necessary for Akt function, although the regulatory mechanisms and physiological importance of each phosphorylation site remain to be fully understood. Here, we report that SIN1/MIP1 is an essential TORC2/PDK2 subunit. Genetic ablation of sin1 abolished Akt-Ser473 phosphorylation and disrupted rictor-mTOR interaction but maintained Thr308 phosphorylation. Surprisingly, defective Ser473 phosphorylation affected only a subset of Akt targets in vivo, including FoxO1/3a, while other Akt targets, TSC2 and GSK3, and the TORC1 effectors, S6K and 4E-BP1, were unaffected. Our findings reveal that the SIN1-rictor-mTOR function in Akt-Ser473 phosphorylation is required for TORC2 function in cell survival but is dispensable for TORC1 function.", "ai_intervention": "Biochemical/genetic (SIN1/MIP1)", "ai_target": "mTORC2 (rictor-mTOR) / Akt Ser473", "ai_species": "Mammalian cells", "ai_effect": "SIN1 maintains rictor–mTOR (mTORC2) integrity and controls Akt Ser473 phosphorylation and substrate specificity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JAC2006/" }, { "sid": "CHI2012", "title": "Regulation and function of mTOR signalling in T cell fate decisions", "authors": "Chi H", "year": 2012, "journal": "Nature reviews. Immunology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1038/nri3198", "pmid": "22517423", "pmcid": "PMC3417069", "finding": "Review of mTOR signalling in T-cell fate decisions.\n", "abstract": "The evolutionarily conserved kinase mTOR (mammalian target of rapamycin) couples cell growth and metabolism to environmental inputs in eukaryotes. T cells depend on mTOR signalling to integrate immune signals and metabolic cues for their proper maintenance and activation. Under steady-state conditions, mTOR is actively controlled by multiple inhibitory mechanisms, and this enforces normal T cell homeostasis. Antigen recognition by naive CD4(+) and CD8(+) T cells triggers mTOR activation, which in turn programmes the differentiation of these cells into functionally distinct lineages. This Review focuses on the signalling mechanisms of mTOR in T cell homeostatic and functional fates, and discusses the therapeutic implications of targeting mTOR in T cells.", "ai_intervention": "Not applicable (review)", "ai_target": "mTOR / mTORC1 & mTORC2", "ai_species": "Review", "ai_effect": "mTOR integrates immune and metabolic cues to program T-cell homeostasis, activation and differentiation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHI2012/" }, { "sid": "CHEN2026", "title": "FGF21-modified adipose stem cell-derived exosomes promote wound healing by activating fibroblast glycolysis through AMPK/mTOR signaling.", "authors": "Chen K; Chen X; Wen C; Chen W; Liao Z; et al.", "year": 2026, "journal": "Cellular signalling", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Mechanism", "model": "Mouse + Human fibroblasts", "peer_reviewed": "Yes", "doi": "10.1016/j.cellsig.2026.112742", "pmid": "", "pmcid": "", "finding": "FGF21-enriched exosomes from engineered ADSCs promote chronic wound healing by activating fibroblast glycolysis via AMPK/mTOR signaling, improving proliferation, migration, and tissue repair in a mouse model.\n", "abstract": "Chronic wound healing disorders remain a significant clinical challenge, largely due to the limited effectiveness of conventional therapeutic strategies. Emerging evidence suggests that engineered exosomes represent a promising cell-free therapeutic approach. This study aimed to elucidate the mechanisms by which FGF21-modified adipose-derived mesenchymal stem cell (ADSC) exosomes promote wound healing. ADSCs overexpressing FGF21 were established using genetic engineering, and FGF21-enriched exosomes (Exo@FGF21) were isolated and characterized. The biological effects of Exo@FGF21 on human skin fibroblasts (HSFs) were assessed through proliferation, migration, invasion, and apoptosis assays. Mechanistic studies involved pharmacological inhibition of AMPK/mTOR signaling. Exo@FGF21 activated fibroblast glycolysis through the AMPK/mTOR pathway, promoting tissue repair in a mouse wound model.", "ai_intervention": "FGF21-modified ADSC exosomes", "ai_target": "AMPK/mTOR", "ai_species": "Mouse + Human (fibroblasts in vitro)", "ai_effect": "Promotes wound healing via AMPK/mTOR-activated glycolysis in fibroblasts", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHEN2026/" }, { "sid": "KRA2018", "title": "A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort", "authors": "Kraig E; Linehan LA; Liang H; Romo TQ; Liu Q; et al.; Kellogg DL", "year": 2018, "journal": "Experimental Gerontology", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, pilot RCT (n=25, ages 70-95)", "peer_reviewed": "Yes", "doi": "10.1016/j.exger.2017.12.026", "pmid": "29408453", "pmcid": "PMC5869166", "finding": "A safety-first pilot RCT (n=25, ages 70-95) asking the basic question before any longevity trial: is daily rapamycin safe in healthy older people? Over 8+ weeks it was well tolerated with only minor red-blood-cell changes and - importantly - NO rise in blood glucose or insulin resistance in this short window. Groundwork for larger aging trials like PEARL.\n", "abstract": "Inhibition of the mechanistic target of rapamycin (mTOR) pathway by rapamycin (RAPA), an FDA-approved immunosuppressive drug used as a clinical therapy to prevent solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals, suggesting that mTOR inhibition could potentially slow the progression of aging-associated pathologies in older humans (Harrison et al., 2009; Miller et al., 2011). However, the safety and tolerability of RAPA in older human subjects have not yet been demonstrated. Towards this end, we undertook a placebo-controlled pilot study in 25 generally healthy older adults (aged 70-95 years); subjects were randomized to receive either 1 mg RAPA or placebo daily. Although three subjects withdrew, 11 RAPA and 14 controls completed at least 8 weeks of treatment and were included in the analysis. We monitored for changes that would indicate detrimental effects of RAPA treatment on metabolism, including both standard clinical laboratory assays (CBC, CMP, HbA1c) and oral glucose tolerance tests (OGTTs). We also monitored parameters typically associated with aging that could potentially be modified by RAPA; these included cognitive function which was assessed by three different tools: Executive Interview-25 (EXIT25); Saint Louis University Mental Status Exam (SLUMS); and Texas Assessment of Processing Speed (TAPS). In addition, physical performance was measured by handgrip strength and 40-foot timed walks. Lastly, changes in general parameters of healthy immune aging, including serum pro-inflammatory cytokine levels and blood cell subsets, were assessed. Five subjects reported potential adverse side effects; in the RAPA group, these were limited to facial rash (1 subject), stomatitis (1 subject) and gastrointestinal issues (2 subjects) whereas placebo treated subjects only reported stomatitis (1 subject). Although no other adverse events were reported, statistically significant decrements in several erythrocyte parameters including hemoglobin (HgB) and hematocrit (Hct) as well as in red blood cell count (RBC), red blood cell distribution width (RDW), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were observed in the RAPA-treatment group. None of these changes manifested clinically significant effects during the short duration of this study. Similarly, no changes were noted in any other clinical laboratory, cognitive, physical performance, or self-perceived health status measure over the study period. Immune parameters were largely unchanged as well, possibly due to the advanced ages of the cohort (70-93 years; mean age 80.5). RAPA-associated increases in a myeloid cell subset and in Twere detected, but changes in most other PBMC cell subsets were not statistically significant. Importantly, the OGTTs revealed no RAPA-induced change in blood glucose concentration, insulin secretion, and insulin sensitivity. Thus, based on the results of our pilot study, it appears that short-term RAPA treatment can be used safely in older persons who are otherwise healthy; a trial with a larger sample size and longer treatment duration is warranted.", "ai_intervention": "Rapamycin (oral, daily, ~8 weeks)", "ai_target": "mTOR / mTORC1", "ai_species": "Human – healthy older adults (age 70–95, n=25)", "ai_effect": "Well tolerated; NO rise in blood glucose / insulin resistance in the short window – groundwork for larger geroprotection trials", "ai_dose": "Rapamycin 1 mg daily orally (single dose tested; blood levels monitored in first 4 subjects), ~8-16 weeks; placebo-controlled.", "ai_samplesize": "Healthy older adults (ages 70-95); phase-1 subset = 8 subjects (half rapamycin / half placebo), 4-month protocol.", "ai_effectsize": "Established feasibility and safety of daily low-dose rapamycin in older adults; no serious adverse events; groundwork for larger geroprotection trials.", "ai_limitations": "Small sample -> single 1 mg dose chosen; short duration; feasibility (not efficacy) study.", "atlas_url": "https://mtor-atlas.org/study/KRA2018/" }, { "sid": "XIA2026", "title": "Nutrient-sensing pathways in adult stem cells: Orchestrating homeostasis, aging, and disease", "authors": "Xiao T; Zeng YA; Hu C et al.", "year": 2026, "journal": "Seminars in Cell & Developmental Biology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review (adult stem cells, multiple tissue systems)", "peer_reviewed": "Yes", "doi": "10.1016/j.semcdb.2026.103690", "pmid": "42546460", "pmcid": "", "finding": "Proposes an integrated framework in which mTOR, AMPK, sirtuins, and insulin/IGF-1 signaling jointly govern adult stem cell transitions between quiescence, activation, and differentiation; age-related dysregulation of this nutrient-sensing network drives stem cell exhaustion and tissue degeneration, and interventions (mTOR inhibitors, AMPK activators, NAD+ precursors, dietary strategies) can restore ASC function.\n", "abstract": "Nutrient-sensing pathways, including mTOR, AMPK, Sirtuins, and insulin/IGF-1 signaling, are central regulators orchestrating adult stem cell (ASC) fate by dynamically modulating cellular metabolism. This review proposes a framework that integrates these pathways into a cohesive network that dictates the metabolic transitions between quiescence, activation, and differentiation in ASCs. Age-related dysregulation of this network leads to metabolic imbalance and stem cell exhaustion, underpinning tissue degeneration. Interventions such as mTOR inhibitors, AMPK activators, NAD+ precursors, and dietary strategies can rejuvenate ASC function by restoring metabolic balance, underscoring their therapeutic potential for mitigating aging and associated diseases.", "ai_intervention": "N/A (review); discusses mTOR inhibitors, AMPK activators, NAD+ precursors, dietary strategies as ASC-rejuvenating interventions", "ai_target": "mTOR / AMPK / Sirtuins / IGF-1 nutrient-sensing network", "ai_species": "Review (multiple species/systems)", "ai_effect": "Integrated nutrient-sensing network governs adult stem cell quiescence/activation/differentiation; dysregulation drives stem cell exhaustion and aging", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/XIA2026/" }, { "sid": "MAX2009", "title": "Molecular mechanisms of mTOR-mediated translational control", "authors": "Ma XM; Blenis J et al.", "year": 2009, "journal": "Nature reviews. Molecular cell biology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1038/nrm2672", "pmid": "19339977", "pmcid": "", "finding": "Review of the molecular mechanisms of mTOR-mediated translational control.\n", "abstract": "The process of translation requires substantial cellular resources. Cells have therefore evolved complex mechanisms to control overall protein synthesis as well as the translation of specific mRNAs that are crucial for cell growth and proliferation. At the heart of this process is the mammalian target of rapamycin (mTOR) signalling pathway, which senses and responds to nutrient availability, energy sufficiency, stress, hormones and mitogens to modulate protein synthesis. Here, we highlight recent findings on the regulators and effectors of mTOR and discuss specific cases that serve as paradigms for the different modes of mTOR regulation and its control of translation.", "ai_intervention": "Not applicable (review)", "ai_target": "mTOR / 4E-BP / S6K translation machinery", "ai_species": "Review", "ai_effect": "Reviews how mTOR senses nutrients/energy/hormones to control protein synthesis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MAX2009/" }, { "sid": "HEI1991", "title": "Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast", "authors": "Heitman J; Movva NR; Hall MN", "year": 1991, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Yeast (Saccharomyces cerevisiae)", "peer_reviewed": "Yes", "doi": "10.1126/science.1715094", "pmid": "1715094", "pmcid": "", "finding": "Discovery of the TOR1 and TOR2 genes in yeast as the targets whose disruption causes rapamycin's cell-cycle-arresting toxicity - the original genetic identification of the TOR pathway.\n", "abstract": "FK506 and rapamycin are related immunosuppressive compounds that block helper T cell activation by interfering with signal transduction. In vitro, both drugs bind and inhibit the FK506-binding protein (FKBP) proline rotamase. Saccharomyces cerevisiae cells treated with rapamycin irreversibly arrested in the G1 phase of the cell cycle. An FKBP-rapamycin complex is concluded to be the toxic agent because (i) strains that lack FKBP proline rotamase, encoded by FPR1, were viable and fully resistant to rapamycin and (ii) FK506 antagonized rapamycin toxicity in vivo. Mutations that conferred rapamycin resistance altered conserved residues in FKBP that are critical for drug binding. Two genes other than FPR1, named TOR1 and TOR2, that participate in rapamycin toxicity were identified. Nonallelic noncomplementation between FPR1, TOR1, and TOR2 alleles suggests that the products of these genes may interact as subunits of a protein complex. Such a complex may mediate nuclear entry of signals required for progression through the cell cycle.", "ai_intervention": "Rapamycin (FKBP-rapamycin); genetic (FPR1, TOR)", "ai_target": "FKBP / TOR", "ai_species": "Yeast (S. cerevisiae)", "ai_effect": "FKBP-rapamycin complex arrests cells in G1; identified FKBP and TOR as targets – a foundational discovery", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HEI1991/" }, { "sid": "GAO2026", "title": "Astragaloside IV Mitigates Tacrolimus-Induced Chronic Nephrotoxicity by Regulating the mTOR-TFEB-GADD45alpha Pathway", "authors": "Ping Gao, Xinwei Cheng, Rui Xu, Xinyu Huang, Jianqiao Wang, Maochang Liu, Xiuxun Wu, Xinlei Guan, Yunzhou Chen, Zhenpeng Qiu", "year": 2026, "journal": "Journal of Agricultural and Food Chemistry", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "In vitro (renal cell lines)", "peer_reviewed": "Yes", "doi": "10.1021/acs.jafc.5c17921", "pmid": "42438242", "pmcid": "", "finding": "Astragaloside IV protects against tacrolimus-induced nephrotoxicity by inhibiting mTOR to activate TFEB and restore autophagy, nominating the mTOR-TFEB-GADD45alpha axis as a calcineurin-independent candidate therapeutic target (preclinical; no human data) in TICN.\n", "abstract": "Tacrolimus-induced chronic nephrotoxicity (TICN) is mediated in part through calcineurin-dependent TFEB phosphorylation. Astragaloside IV (AS-IV) significantly reactivated TFEB and restored tacrolimus-impaired renal function, autophagy flux, and DNA repair. TFEB knockdown reversed AS-IV effects. AS-IV does not affect calcineurin but inhibits mTOR (which phosphorylates TFEB Ser211), thereby activating TFEB via the mTOR-TFEB-GADD45alpha axis.", "ai_intervention": "Astragaloside IV", "ai_target": "mTOR / TFEB / GADD45alpha / autophagy", "ai_species": "In vitro (renal cells)", "ai_effect": "TFEB reactivation, restored autophagy flux, improved renal function markers, attenuation of nephrotoxicity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GAO2026/" }, { "sid": "FON2010", "title": "Extending healthy life span--from yeast to humans", "authors": "Fontana L; Partridge L; Longo VD", "year": 2010, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review (yeast to humans)", "peer_reviewed": "Yes", "doi": "10.1126/science.1172539", "pmid": "20395504", "pmcid": "PMC3607354", "finding": "The landmark synthesis showing that eating less (dietary restriction) and dialing down nutrient-sensing pathways - mTOR and growth hormone/IGF-1 - extend healthy lifespan by the SAME conserved mechanisms from yeast to monkeys to humans. This is the paper that frames why mTOR sits at the crossroads of diet and aging.\n", "abstract": "When the food intake of organisms such as yeast and rodents is reduced (dietary restriction), they live longer than organisms fed a normal diet. A similar effect is seen when the activity of nutrient-sensing pathways is reduced by mutations or chemical inhibitors. In rodents, both dietary restriction and decreased nutrient-sensing pathway activity can lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration. Dietary restriction also increases life span and protects against diabetes, cancer, and cardiovascular disease in rhesus monkeys, and in humans it causes changes that protect against these age-related pathologies. Tumors and diabetes are also uncommon in humans with mutations in the growth hormone receptor, and natural genetic variants in nutrient-sensing pathways are associated with increased human life span. Dietary restriction and reduced activity of nutrient-sensing pathways may thus slow aging by similar mechanisms, which have been conserved during evolution. We discuss these findings and their potential application to prevention of age-related disease and promotion of healthy aging in humans, and the challenge of possible negative side effects.", "ai_intervention": "Not applicable (review – dietary restriction / nutrient-sensing inhibition)", "ai_target": "Nutrient-sensing pathways (incl. TOR, insulin/IGF)", "ai_species": "Review (yeast to humans)", "ai_effect": "Dietary restriction and reduced nutrient-sensing activity extend lifespan and reduce age-related disease", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/FON2010/" }, { "sid": "CAS2009", "title": "mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging", "authors": "Castilho RM; Gutkind JS et al.", "year": 2009, "journal": "Cell stem cell", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1016/j.stem.2009.06.017", "pmid": "19733540", "pmcid": "PMC2939833", "finding": "Wnt-induced mTOR activation drives epidermal stem-cell senescence; rapamycin rescues it.\n", "abstract": "Epidermal integrity is a complex process established during embryogenesis and maintained throughout the organism lifespan by epithelial stem cells. Although Wnt regulates normal epithelial stem cell renewal, aberrant Wnt signaling can contribute to cancerous growth. Here, we explored the consequences of persistent expressing Wnt1 in an epidermal compartment that includes the epithelial stem cells. Surprisingly, Wnt caused the rapid growth of the hair follicles, but this was followed by epithelial cell senescence, disappearance of the epidermal stem cell compartment, and progressive hair loss. Although Wnt1 induced the activation of beta-catenin and the mTOR pathway, both hair follicle hyperproliferation and stem cell exhaustion were strictly dependent on mTOR function. These findings suggest that whereas activation of beta-catenin contributes to tumor growth, epithelial stem cells may be endowed with a protective mechanism that results in cell senescence upon the persistent stimulation of proliferative pathways that activate mTOR, ultimately suppressing tumor formation.", "ai_intervention": "Wnt1 overexpression; rapamycin rescue", "ai_target": "mTOR", "ai_species": "Mouse (epidermal stem cells)", "ai_effect": "Wnt→mTOR drives stem-cell senescence/exhaustion and hair loss; rapamycin reverses it", "ai_dose": "", "ai_samplesize": "n=25 mutant and wild-type littermates", "ai_effectsize": "Wnt1 expression caused terminal differentiation of HF after 90 days, leading to progressive hair loss.", "ai_limitations": "No nuclear β-catenin staining could be observed, possibly due to strong membrane signal or limited nuclear β-catenin; further investigation is warranted on the contribution of particular Wnt1 receptors.", "atlas_url": "https://mtor-atlas.org/study/CAS2009/" }, { "sid": "SAC2011", "title": "Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size", "authors": "Saci A; Carpenter CL et al.", "year": 2011, "journal": "Molecular cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.molcel.2011.03.017", "pmid": "21474067", "pmcid": "PMC3750737", "finding": "Rac1 binds and regulates both mTORC1 and mTORC2, controlling their localization and cell growth.\n", "abstract": "Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that exists in two separate complexes, mTORC1 and mTORC2, that function to control cell size and growth in response to growth factors, nutrients, and cellular energy levels. Low molecular weight GTP-binding proteins of the Rheb and Rag families are key regulators of the mTORC1 complex, but regulation of mTORC2 is poorly understood. Here, we report that Rac1, a member of the Rho family of GTPases, is a critical regulator of both mTORC1 and mTORC2 in response to growth-factor stimulation. Deletion of Rac1 in primary cells using an inducible-Cre/Lox approach inhibits basal and growth-factor activation of both mTORC1 and mTORC2. Rac1 appears to bind directly to mTOR and to mediate mTORC1 and mTORC2 localization at specific membranes. Binding of Rac1 to mTOR does not depend on the GTP-bound state of Rac1, but on the integrity of its C-terminal domain. This function of Rac1 provides a means to regulate mTORC1 and mTORC2 simultaneously.", "ai_intervention": "Genetic/biochemical (Rac1)", "ai_target": "Rac1 / mTORC1 / mTORC2", "ai_species": "Mammalian cells", "ai_effect": "Rac1 is a critical regulator of both mTORC1 and mTORC2, controlling cell size", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAC2011/" }, { "sid": "WOL2015", "title": "Sestrin2 is a leucine sensor for the mTORC1 pathway", "authors": "Wolfson RL; Sabatini DM et al.", "year": 2015, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/science.aab2674", "pmid": "26449471", "pmcid": "PMC4698017", "finding": "Sestrin2 is a direct leucine sensor whose leucine binding releases GATOR2 to activate mTORC1.\n", "abstract": "Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, aGTPase-activating protein; GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway.", "ai_intervention": "Biochemical/genetic (Sestrin2)", "ai_target": "Sestrin2 / GATOR2 / Rag / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "Sestrin2 is a leucine sensor for mTORC1; leucine (not arginine) binding relieves Sestrin2 inhibition", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WOL2015/" }, { "sid": "BO2026", "title": "Molecular and metabolic dysregulation of lung cancer in developing anti-tumor activity by gambogic acid mediated mTOR signaling: in vitro and computational study.", "authors": "Bo S, Liao Y, Chen X, Liu C, Pang J", "year": 2026, "journal": "3 Biotech", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human lung cancer cell lines", "peer_reviewed": "Yes", "doi": "10.1007/s13205-026-04938-1", "pmid": "42459409", "pmcid": "PMC13369087", "finding": "Gambogic acid exerts anti-tumor activity in lung cancer cells primarily by targeting and inhibiting mTOR signaling, supported by computational docking and in vitro experiments in cell lines; no in vivo or human data.\n", "abstract": "Gambogic acid (GA), a natural xanthonoid compound, was investigated for its anticancer activity in lung cancer via mTOR signaling inhibition using computational and in vitro approaches. GA demonstrated high lipophilicity and docking interactions with mTOR pathway components, resulting in anti-proliferative and pro-apoptotic effects in lung cancer cell lines.", "ai_intervention": "Gambogic acid", "ai_target": "mTOR signaling pathway", "ai_species": "Human (cell line)", "ai_effect": "Inhibition of mTOR signaling; anti-proliferative and pro-apoptotic effects in lung cancer cells", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BO2026/" }, { "sid": "YIN2026", "title": "Substrate recognition and transport mechanism of the human proton-coupled amino-acid transporter 1 (SLC36A1)", "authors": "Yin J; Yang M et al.", "year": 2026, "journal": "Nature Communications", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Recombinant human protein (cryo-EM)", "peer_reviewed": "Yes", "doi": "10.1038/s41467-026-75306-z", "pmid": "42414312", "pmcid": "", "finding": "Cryo-EM structures of human PAT1 (SLC36A1) in apo and substrate-bound states reveal a convergent binding mode for diverse zwitterionic amino acids; PAT1 mediates lysosomal amino acid export and mTORC1 activation.\n", "abstract": "The proton-coupled amino-acid transporter SLC36A1 (hPAT1) is an atypical H+-driven carrier and mediates the intestinal absorption of a wide array of zwitterionic amino-acid analogs, including many compounds with central nervous-system (CNS) activity, as well as the activation of the mTORC1 pathway and the export of amino acids from lysosomes, thereby maintaining cellular amino-acid homeostasis. Here, we present the cryo-EM structures of a member of the SLC36 family, hPAT1, in its apo state and in complex with three chemically distinct substrates, including the alpha-amino acid D-serine, the beta-amino acid nipecotic acid, and the heterocyclic drug D-cycloserine, at resolutions of 3.4-3.5 A. Despite their chemical diversity, all ligands adopt a spatially convergent binding mode, elucidating the structural basis for PAT1's broad substrate promiscuity. In addition, we identify E270 as a potential proton-binding site. Together, these findings provide structural insights into the molecular mechanism of proton-coupled amino acid transport.", "ai_intervention": "Structural/biochemical (cryo-EM of SLC36A1/PAT1, apo + 3 substrate-bound states)", "ai_target": "SLC36A1 (PAT1) / lysosomal amino acid efflux / mTORC1 activation", "ai_species": "Human (recombinant protein, cryo-EM; no animal/cell phenotype data)", "ai_effect": "Reveals structural basis for substrate promiscuity of PAT1; supports PAT1's role in lysosomal amino acid export and mTORC1 activation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/YIN2026/" }, { "sid": "MIAO2026", "title": "Chronic Kidney Disease Risk Posed by 1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) Benzene (EDPrB): An AOP of mTOR-Mediated Autophagy Dysregulation.", "authors": "Miao C; Zhang B; Yu W; Li Y; Cao Z", "year": 2026, "journal": "Environmental science & technology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Mechanism", "model": "Mouse (Kunming) + HK-2 human cell line", "peer_reviewed": "Yes", "doi": "10.1021/acs.est.6c06697", "pmid": "", "pmcid": "", "finding": "In mice, the environmental pollutant EDPrB accumulates in the kidney and causes CKD via mTOR hyperactivation, leading to autophagy dysregulation, inflammation and fibrosis; rapamycin rescue identified mTOR as the molecular initiating event, with corroborating data in HK-2 human kidney cells.\n", "abstract": "1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) benzene (EDPrB), a highly polluting fluorinated liquid-crystal monomer (FLCM), accumulates in the kidneys over the long term. Exposure to EDPrB can induce inflammatory responses and fibrosis in human renal cortical proximal tubule epithelial cells (HK-2), posing a risk of nephrotoxicity. Our study investigates the renal injury induced by EDPrB in male Kunming mice after 70-day exposure at 13, 130, and 1300 ug/kg bw/day. Proteomics and Western blot analysis revealed that mTOR signaling may be the mechanism by which EDPrB induces CKD in mice and causes damage to HK-2 cells. By treating EDPrB-exposed mice with rapamycin, we demonstrated that activation of the mTOR signaling is the molecular initiating event in EDPrB-induced CKD.", "ai_intervention": "EDPrB (fluorinated liquid crystal monomer) / Rapamycin", "ai_target": "mTOR-autophagy", "ai_species": "Mouse + Human cell line", "ai_effect": "In mice and HK-2 cells, mTOR hyperactivation causes autophagy dysregulation leading to CKD", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MIAO2026/" }, { "sid": "JEW2015", "title": "Metabolism. Differential regulation of mTORC1 by leucine and glutamine", "authors": "Jewell JL; Guan KL et al.", "year": 2015, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/science.1259472", "pmid": "25567907", "pmcid": "PMC4384888", "finding": "Glutamine activates mTORC1 via a Rag-independent, Arf1-dependent route distinct from leucine.\n", "abstract": "The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates environmental and intracellular signals to regulate cell growth. Amino acids stimulate mTORC1 activation at the lysosome in a manner thought to be dependent on the Rag small guanosine triphosphatases (GTPases), the Ragulator complex, and the vacuolar H(+)-adenosine triphosphatase (v-ATPase). We report that leucine and glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent mechanisms, respectively. Glutamine promoted mTORC1 translocation to the lysosome in RagA and RagB knockout cells and required the v-ATPase but not the Ragulator. Furthermore, we identified the adenosine diphosphate ribosylation factor-1 GTPase to be required for mTORC1 activation and lysosomal localization by glutamine. Our results uncover a signaling cascade to mTORC1 activation independent of the Rag GTPases and suggest that mTORC1 is differentially regulated by specific amino acids.", "ai_intervention": "Biochemical/genetic", "ai_target": "mTORC1 / Rag GTPases", "ai_species": "Mammalian cells", "ai_effect": "Leucine activates mTORC1 via the Rags; glutamine activates it Rag-independently – differential regulation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JEW2015/" }, { "sid": "BCH2026", "title": "Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERRα-dependent manner", "authors": "B'chir W; Giguère V et al.", "year": 2026, "journal": "Journal of Endocrinology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Side effect", "model": "Mouse (rapamycin-induced MASLD model; ERRα-null mice)", "peer_reviewed": "Yes", "doi": "10.1530/JOE-26-0176", "pmid": "42544714", "pmcid": "", "finding": "Chloroquine co-treatment attenuates rapamycin-induced hepatic steatosis (a known mTORC1-inhibitor side effect) in mice, and this rescue depends on the nuclear receptor ERRα; RNA-seq shows chloroquine reverses rapamycin-driven upregulation of lipid-metabolism genes, with ERRα identified as a top transcriptional regulator of the effect.\n", "abstract": "Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), remains a major health concern world-wide. Hepatic steatosis manifests by the aberrant accumulation of lipids in hepatocytes. We have previously shown that pharmacological inhibition of mTOR complex 1 (mTORC1) by rapamycin, a widely utilized potent immunosuppressant, induces MASLD under normal conditions. Notably, this phenotype was found exacerbated in mice with genetic or pharmacological inhibition of the master transcriptional regulator of energy metabolism, nuclear receptor ERRα. In this study, we show that combining antimalaria drug chloroquine with rapamycin attenuates the severity of hepatic lipid deposition observed with rapamycin monotherapy. Bulk mRNA-seq profiling showed that chloroquine co-injection reverses the upregulation of a large proportion of genes linked to lipid metabolism homeostasis found induced by rapamycin alone. Interrogation of these genes for direct transcriptional regulators identified ERRα among top candidates. Using a mouse model with genetic ERRα ablation, we demonstrate a crucial dependency on ERRα activity for the observed amelioration of rapamycin-induced hepatic steatosis by chloroquine addition. In ERRα-null liver, chloroquine failed to reverse, and in some instances aggravated the upregulation of lipid metabolism genes by rapamycin, with evidence linking the impaired management of hepatic lipid overload to underling mitochondrial dysfunction. Together, these findings underscore a critical role of ERRα in reversing MASLD.", "ai_intervention": "Chloroquine co-treatment with rapamycin", "ai_target": "ERRα (Esrra) / mTORC1", "ai_species": "Mouse", "ai_effect": "Chloroquine co-treatment attenuates rapamycin-induced hepatic steatosis in an ERRα-dependent manner", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BCH2026/" }, { "sid": "ZHO2001", "title": "Role of AMP-activated protein kinase in mechanism of metformin action", "authors": "Zhou G et al.", "year": 2001, "journal": "J Clin Invest", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Rat; hepatocytes; skeletal muscle", "peer_reviewed": "Yes", "doi": "10.1172/JCI13505", "pmid": "11602624", "pmcid": "PMC209533", "finding": "Metformin activates AMPK, suppressing hepatic gluconeogenesis and lipogenesis.\n", "abstract": "Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.", "ai_intervention": "Metformin", "ai_target": "AMPK (→ ACC; indirect mTORC1)", "ai_species": "Rat; hepatocytes; skeletal muscle", "ai_effect": "Metformin activates AMPK, explaining its glucose- and lipid-lowering effects", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZHO2001/" }, { "sid": "SZW2021", "title": "Regulation and metabolic functions of mTORC1 and mTORC2", "authors": "Szwed A; Jacinto E et al.", "year": 2021, "journal": "Physiological reviews", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1152/physrev.00026.2020", "pmid": "33599151", "pmcid": "PMC8424549", "finding": "Comprehensive review of the regulation and metabolic functions of mTORC1 and mTORC2.\n", "abstract": "Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process that involves cross talk between growth signaling and metabolic pathways. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. A central signaling molecule that integrates growth with metabolism is the mechanistic target of rapamycin (mTOR). mTOR is a protein kinase that responds to levels of nutrients and growth signals. mTOR forms two protein complexes, mTORC1, which is sensitive to rapamycin, and mTORC2, which is not directly inhibited by this drug. Rapamycin has facilitated the discovery of the various functions of mTORC1 in metabolism. Genetic models that disrupt either mTORC1 or mTORC2 have expanded our knowledge of their cellular, tissue, as well as systemic functions in metabolism. Since mTOR is an important target for cancer, aging, and other metabolism-related pathologies, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is vital for the development of more effective therapeutic strategies.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1 / mTORC2", "ai_species": "Review", "ai_effect": "Reviews how mTORC1/2 integrate growth signaling with metabolism", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SZW2021/" }, { "sid": "ARR2015", "title": "Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system", "authors": "Arriola Apelo SI; Lamming DW et al.", "year": 2015, "journal": "Aging cell", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1111/acel.12405", "pmid": "26463117", "pmcid": "PMC4717280", "finding": "Intermittent rapamycin regimens (weekly, or every 5 days) largely spared glucose tolerance, pyruvate tolerance, fasting glucose and insulin, beta-cell function and the immune system, while still inhibiting mTORC1 -- unlike daily dosing, which impaired all of them. IMPORTANT SCOPE: this study measured side effects only. It did NOT measure lifespan or any other benefit endpoint, so it shows the harm can be reduced, not that the benefit is retained. For evidence that a non-continuous schedule preserves a survival benefit, see BIT2016.\n", "abstract": "Inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway by the FDA-approved drug rapamycin has been shown to promote lifespan and delay age-related diseases in model organisms including mice. Unfortunately, rapamycin has potentially serious side effects in humans, including glucose intolerance and immunosuppression, which may preclude the long-term prophylactic use of rapamycin as a therapy for age-related diseases. While the beneficial effects of rapamycin are largely mediated by the inhibition of mTOR complex 1 (mTORC1), which is acutely sensitive to rapamycin, many of the negative side effects are mediated by the inhibition of a second mTOR-containing complex, mTORC2, which is much less sensitive to rapamycin. We hypothesized that different rapamycin dosing schedules or the use of FDA-approved rapamycin analogs with different pharmacokinetics might expand the therapeutic window of rapamycin by more specifically targeting mTORC1. Here, we identified an intermittent rapamycin dosing schedule with minimal effects on glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDA-approved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.", "ai_intervention": "Rapamycin – alternative/intermittent dosing regimens", "ai_target": "mTORC1 (vs mTORC2)", "ai_species": "Mouse", "ai_effect": "Intermittent regimens and rapalogs inhibit mTORC1 while largely sparing glucose tolerance and immune function; no survival endpoint was measured", "ai_dose": "2 mg/kg rapamycin administered daily (1x/day), weekly (1x/7 days), once every three days (1x/3 days), or once every five days (1x/5 days) to 9-week-old male C57BL/6J mice for 2-8 weeks.", "ai_samplesize": "9-11 male C57BL/6J mice per treatment group for glucose tolerance tests; 3-6 mice per group for blood rapamycin concentration; 4-9 mice per group for insulin/HOMA2 measurements; 6 mice per treatment for islet analysis.", "ai_effectsize": "Daily rapamycin treatment significantly impaired glucose tolerance (20–116% increase in blood glucose, 71% increase in AUC), while weekly (1x/7 days) or 1x/5 days rapamycin treatment did not impair glucose tolerance. Rapamycin 1x/3 days significantly impaired glucose tolerance. Daily rapamycin inhibited both mTORC1 (S6 S240/244) and mTORC2 (AKT S473) signaling, while weekly rapamycin only inhibited mTORC1.", "ai_limitations": "No lifespan or healthspan endpoint. Side-effect endpoints only; benefit retention is inferred, not tested.", "atlas_url": "https://mtor-atlas.org/study/ARR2015/" }, { "sid": "GOU2023", "title": "The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease", "authors": "Goul C; Zoncu R et al.", "year": 2023, "journal": "Nature reviews. Molecular cell biology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1038/s41580-023-00641-8", "pmid": "37612414", "pmcid": "", "finding": "Authoritative review of the molecular basis of nutrient sensing and signalling by mTORC1 in disease.\n", "abstract": "The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient-mTORC1 signalling in multiple diseases.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1 nutrient-sensing machinery", "ai_species": "Review", "ai_effect": "Reviews the molecular basis of nutrient sensing by mTORC1 and its role in metabolism and disease", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GOU2023/" }, { "sid": "EFE2012", "title": "Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival", "authors": "Efeyan A; Sabatini DM et al.", "year": 2012, "journal": "Nature", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (RagA GTP knock-in)", "peer_reviewed": "Yes", "doi": "10.1038/nature11745", "pmid": "23263183", "pmcid": "PMC4000705", "finding": "Rag-GTPase control of mTORC1 is essential for neonatal autophagy and survival to fasting.\n", "abstract": "The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates organismal growth in response to many environmental cues, including nutrients and growth factors. Cell-based studies showed that mTORC1 senses amino acids through the RagA-D family of GTPases (also known as RRAGA, B, C and D), but their importance in mammalian physiology is unknown. Here we generate knock-in mice that express a constitutively active form of RagA (RagA(GTP)) from its endogenous promoter. RagA(GTP/GTP) mice develop normally, but fail to survive postnatal day 1. When delivered by Caesarean section, fasted RagA(GTP/GTP) neonates die almost twice as rapidly as wild-type littermates. Within an hour of birth, wild-type neonates strongly inhibit mTORC1, which coincides with profound hypoglycaemia and a decrease in plasma amino-acid concentrations. In contrast, mTORC1 inhibition does not occur in RagA(GTP/GTP) neonates, despite identical reductions in blood nutrient amounts. With prolonged fasting, wild-type neonates recover their plasma glucose concentrations, but RagA(GTP/GTP) mice remain hypoglycaemic until death, despite using glycogen at a faster rate. The glucose homeostasis defect correlates with the inability of fasted RagA(GTP/GTP) neonates to trigger autophagy and produce amino acids for de novo glucose production. Because profound hypoglycaemia does not inhibit mTORC1 in RagA(GTP/GTP) neonates, we considered the possibility that the Rag pathway signals glucose as well as amino-acid sufficiency to mTORC1. Indeed, mTORC1 is resistant to glucose deprivation in RagA(GTP/GTP) fibroblasts, and glucose, like amino acids, controls its recruitment to the lysosomal surface, the site of mTORC1 activation. Thus, the Rag GTPases signal glucose and amino-acid concentrations to mTORC1, and have an unexpectedly key role in neonates in autophagy induction and thus nutrient homeostasis and viability.", "ai_intervention": "Genetic – constitutively active RagA(GTP) knock-in", "ai_target": "mTORC1 / Rag GTPases", "ai_species": "Mouse (RagA GTP knock-in)", "ai_effect": "Constitutive RagA→mTORC1 blocks fasting-induced autophagy in neonates → death on postnatal day 1 when fasted", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "Treatment of pups at birth with rapamycin significantly delayed the death of fasted RagA GTP/GTP neonates from ~14 h to ~21 h (p<0.01).", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/EFE2012/" }, { "sid": "HAR2004", "title": "The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins", "authors": "Harrington LS; Findlay GM; Lamb RF et al.", "year": 2004, "journal": "The Journal of Cell Biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells (TSC1/TSC2-null MEFs, human cells)", "peer_reviewed": "Yes", "doi": "10.1083/jcb.200403069", "pmid": "15249583", "pmcid": "", "finding": "One half of the discovery of mTORC1's main negative feedback loop. When mTORC1/S6K1 activity is left switched on, S6K1 phosphorylates IRS-1 and represses its expression, so the insulin receptor can no longer signal to PI3K. This is the textbook explanation for why blocking mTOR paradoxically RAISES Akt activity, and a major contributor to the insulin resistance seen with chronic rapalog dosing.\n", "abstract": "Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.", "ai_intervention": "Genetic loss of TSC1/TSC2; S6K1 activity manipulation", "ai_target": "S6K1 -> IRS-1 -> PI3K/Akt", "ai_species": "Mammalian cells", "ai_effect": "Sustained S6K1 activity depletes IRS-1 and uncouples the insulin receptor from PI3K", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HAR2004/" }, { "sid": "MAN2014", "title": "mTOR inhibition improves immune function in the elderly", "authors": "Mannick JB et al.", "year": 2014, "journal": "Science Translational Medicine", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, RCT, older adults", "peer_reviewed": "Yes", "doi": "10.1126/scitranslmed.3009892", "pmid": "25540326", "pmcid": "", "finding": "Low-dose everolimus improved influenza vaccine response by ~20% and reduced PD-1 expression on T lymphocytes.\n", "abstract": "Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species studied to date, and in mice delays the onset of age-related diseases and comorbidities. However, it is unknown if mTOR inhibition affects aging or its consequences in humans. To begin to assess the effects of mTOR inhibition on human aging-related conditions, we evaluated whether the mTOR inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination. RAD001 enhanced the response to the influenza vaccine by about 20% at doses that were relatively well tolerated. RAD001 also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. These results raise the possibility that mTOR inhibition may have beneficial effects on immunosenescence in the elderly.", "ai_intervention": "Everolimus (RAD001), low dose", "ai_target": "mTORC1", "ai_species": "Human – elderly adults, RCT", "ai_effect": "Improved influenza vaccine response (~20%) and reduced PD-1 expression on T cells", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MAN2014/" }, { "sid": "GUR2017", "title": "mTORC2 Promotes Tumorigenesis via Lipid Synthesis", "authors": "Guri Y; Hall MN et al.", "year": 2017, "journal": "Cancer cell", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse; cells", "peer_reviewed": "Yes", "doi": "10.1016/j.ccell.2017.11.011", "pmid": "29232555", "pmcid": "", "finding": "mTORC2 promotes tumorigenesis through control of de novo lipid synthesis.\n", "abstract": "Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis. Inhibition of fatty acid or sphingolipid synthesis prevented tumor development, indicating a causal effect in tumorigenesis. Increased levels of cardiolipin were associated with tubular mitochondria and enhanced oxidative phosphorylation. Furthermore, increased lipogenesis correlated with elevated mTORC2 activity and HCC in human patients. Thus, mTORC2 promotes cancer via formation of lipids essential for growth and energy production.", "ai_intervention": "Genetic mTOR-driven mouse model", "ai_target": "mTORC2", "ai_species": "Mouse; cells", "ai_effect": "Hepatic mTORC2 promotes de novo fatty-acid/lipid synthesis (sphingolipids, glycerophospholipids) driving steatosis → hepatocellular carcinoma", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GUR2017/" }, { "sid": "CHU1992", "title": "Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases", "authors": "Chung J; Blenis J et al.", "year": 1992, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "T cells; in vitro", "peer_reviewed": "Yes", "doi": "10.1016/0092-8674(92)90643-q", "pmid": "1377606", "pmcid": "", "finding": "Rapamycin-FKBP12 complex blocks growth-factor activation of p70 S6 kinase, linking the drug to a specific mitogenic pathway.\n", "abstract": "The macrolide rapamycin blocks cell cycle progression in yeast and various animal cells by an unknown mechanism. We demonstrate that rapamycin blocks the phosphorylation and activation of the 70 kd S6 protein kinases (pp70S6K) in a variety of animal cells. The structurally related drug FK506 had no effect on pp70S6K activation but at high concentrations reversed the rapamycin-induced block, confirming the requirement for the rapamycin and FK506 receptor, FKBP. Rapamycin also interfered with signaling by these S6 kinases, blocking serum-stimulated S6 phosphorylation and delaying entry of Swiss 3T3 cells into S phase. Neither rapamycin nor FK506 blocked activation of a distinct family of S6 kinases (RSKs) or the MAP kinases. These studies identify a rapamycin-sensitive signaling pathway, argue for a ubiquitous role for FKBPs in signal transduction, indicate that FK506-FKBP-calcineurin complexes do not interfere with pp70S6K signaling, and show that in fibroblasts pp70S6K, not RSK, is the physiological S6 kinase.", "ai_intervention": "Rapamycin (± FK506)", "ai_target": "FKBP / p70 S6 kinase", "ai_species": "T cells; in vitro", "ai_effect": "Rapamycin blocks activation of the p70 S6 kinases; FK506 reverses it (FKBP-dependent)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHU1992/" }, { "sid": "SCI2014", "title": "Mammalian target of rapamycin signaling in cardiac physiology and disease", "authors": "Sciarretta S; Sadoshima J et al.", "year": 2014, "journal": "Circulation research", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1161/CIRCRESAHA.114.302022", "pmid": "24481845", "pmcid": "PMC3995130", "finding": "Review of mTOR signalling in cardiac physiology and disease.\n", "abstract": "The protein kinase mammalian or mechanistic target of rapamycin (mTOR) is an atypical serine/threonine kinase that exerts its main cellular functions by interacting with specific adaptor proteins to form 2 different multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 regulates protein synthesis, cell growth and proliferation, autophagy, cell metabolism, and stress responses, whereas mTORC2 seems to regulate cell survival and polarity. The mTOR pathway plays a key regulatory function in cardiovascular physiology and pathology. However, the majority of information available about mTOR function in the cardiovascular system is related to the role of mTORC1 in the unstressed and stressed heart. mTORC1 is required for embryonic cardiovascular development and for postnatal maintenance of cardiac structure and function. In addition, mTORC1 is necessary for cardiac adaptation to pressure overload and development of compensatory hypertrophy. However, partial and selective pharmacological and genetic inhibition of mTORC1 was shown to extend life span in mammals, reduce pathological hypertrophy and heart failure caused by increased load or genetic cardiomyopathies, reduce myocardial damage after acute and chronic myocardial infarction, and reduce cardiac derangements caused by metabolic disorders. This article reviews the information available regarding the effects exerted by mTOR signaling in cardiovascular physiology and pathological states.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1 / mTORC2", "ai_species": "Review", "ai_effect": "Reviews mTOR roles in cardiac physiology and disease", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SCI2014/" }, { "sid": "WANG2026", "title": "Amino acid homeostasis by CORVET/HOPS: A metabolic and stress resilience checkpoint for T cells", "authors": "Wang J; Ni Z; Zhang Xinxin; He L; Cheng X; Huang L; Ye H; Li P; Zhao TJ; Du X", "year": 2026, "journal": "Proceedings of the National Academy of Sciences", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse T cells (conditional VPS18 / VPS11 knockout, in vitro and in vivo)", "peer_reviewed": "Yes", "doi": "10.1073/pnas.2601318123", "pmid": "42647134", "pmcid": "", "finding": "Identifies the CORVET and HOPS endolysosomal tethering complexes as upstream suppliers of intracellular amino acids in activated T cells, acquired via macropinocytosis. Loss of the core subunits VPS18 or VPS11 starves the cell of amino acids, switches on the integrated stress response and shuts down mTORC1; enforced mTORC1 activity rescues the proliferative defect while BIM deletion rescues survival, separating the two failure modes. Places vesicular nutrient acquisition upstream of the canonical lysosomal amino-acid-sensing arm of mTORC1.\n", "abstract": "Amino acid sufficiency is critical for T cell metabolic reprogramming, yet how T cells maintain amino acid homeostasis remains poorly defined. Here, we identify the CORVET and HOPS (CORVET/HOPS) tethering complexes as essential upstream regulators. In activated T cells, they sustain intracellular amino acid levels by promoting macropinocytosis to acquire extracellular nutrients. This function enables dual signaling outcomes: suppression of the integrated stress response (ISR) and activation of mTORC1, which together license metabolic plasticity and effector function. Genetic ablation of core subunits (VPS18 or VPS11) of CORVET/HOPS induces severe amino acid scarcity, triggers pathological ISR activation, and impairs mTORC1 signaling, leading to reduced peripheral T cell numbers and abrogating both inflammatory and protective immunity in vivo. These defects are mechanistically linked: BIM deletion or enforced mTORC1 activity rescues the survival and proliferative failures, respectively, of CORVET/HOPS-deficient T cells. Our work establishes CORVET/HOPS as fundamental couplers linking nutrient acquisition to immune signaling, revealing a targetable node for immuno-metabolic therapy.", "ai_intervention": "Genetic ablation of CORVET/HOPS subunits VPS18 or VPS11; BIM deletion; enforced mTORC1 activity", "ai_target": "CORVET/HOPS tethering complexes; mTORC1; integrated stress response", "ai_species": "Mouse (T cells, in vitro and in vivo)", "ai_effect": "CORVET/HOPS loss causes amino acid scarcity, ISR activation and mTORC1 failure, abrogating T cell immunity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WANG2026/" }, { "sid": "XIE2026", "title": "Glutamine alleviates bisphenol A-induced jejunal injury in piglets involving mitochondrial function restoration and AMPK-mTOR signaling regulation.", "authors": "Xie J; Liu Z; Liu W et al.", "year": 2026, "journal": "Ecotoxicology and Environmental Safety", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Piglet; porcine intestinal epithelial cells", "peer_reviewed": "Yes", "doi": "10.1016/j.ecoenv.2026.120698", "pmid": "", "pmcid": "", "finding": "Glutamine supplementation alleviated bisphenol A-induced jejunal injury in piglets, restoring mitochondrial energy metabolism and barrier integrity alongside modulation of AMPK-mTOR signalling.\n", "abstract": "Bisphenol A (BPA) disrupts intestinal homeostasis and promotes epithelial injury in piglets. Glutamine (Gln) is a vital energy substrate for intestinal epithelial cells. Piglet and porcine intestinal epithelial cell models were used. BPA exposure impaired intestinal morphology and barrier integrity, with reduced tight junction protein expression, decreased epithelial renewal capacity, altered JNK/MAPK signaling and disrupted mitochondrial structure and energy metabolism. Gln supplementation markedly alleviated BPA-induced jejunal injury, associated with improved mitochondrial function and altered AMPK-mTOR signaling activity.", "ai_intervention": "Dietary glutamine supplementation", "ai_target": "AMPK-mTOR; mitochondrial energy metabolism", "ai_species": "Pig", "ai_effect": "Improved tight junction expression, epithelial renewal and mitochondrial function under BPA stress", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/XIE2026/" }, { "sid": "WALTER2026", "title": "[Lu]Lu-edotreotide versus everolimus for gastroenteropancreatic neuroendocrine tumours (COMPETE): a phase 3, multicentre, randomised, open-label, superiority trial.", "authors": "Walter T; Jann H; Ansquer C; Deshayes E; Garcia-Carbonero R; Teule A et al.", "year": 2026, "journal": "Lancet", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Human RCT", "peer_reviewed": "Yes", "doi": "10.1016/S0140-6736(26)00604-5", "pmid": "", "pmcid": "", "finding": "Phase 3 RCT (COMPETE, Lancet 2026) found [177Lu]Lu-edotreotide (PRRT) had superior progression-free survival vs everolimus (mTOR inhibitor) in advanced somatostatin receptor-positive GEP-NETs, establishing PRRT as preferred over mTOR inhibition in this setting.\n", "abstract": "Peptide receptor radionuclide and targeted therapy are both approved treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs), but clinical evidence for preferred sequencing is scarce. The COMPETE trial evaluated the efficacy and harms of peptide receptor radionuclide therapy ([Lu]Lu-edotreotide) versus targeted molecular therapy (everolimus) in patients with advanced, progressive, somatostatin receptor-positive GEP NETs.", "ai_intervention": "Everolimus (mTOR inhibitor) vs [177Lu]Lu-edotreotide", "ai_target": "mTORC1", "ai_species": "Human", "ai_effect": "PRRT superior to everolimus on PFS; mTOR inhibition inferior as first-line in GEP-NETs", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WALTER2026/" }, { "sid": "YAO2026", "title": "Salvianolic Acid B Enhances Motor Function Recovery after Spinal Cord Injury in Association with AKT/mTOR/HIF-1α Pathway Activation and Angiogenesis.", "authors": "Yao J; Chen Yingfeng; Pan F; Zhang S", "year": 2026, "journal": "Biological & Pharmaceutical Bulletin", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Rat (spinal cord injury model)", "peer_reviewed": "Yes", "doi": "10.1248/bpb.b26-00280", "pmid": "", "pmcid": "", "finding": "Salvianolic acid B improved motor recovery, neuronal survival and angiogenesis after rat spinal cord injury in association with AKT/mTOR/HIF-1α activation; the effects were reversed by the AKT inhibitor capivasertib.\n", "abstract": "Spinal cord injury (SCI) is a devastating condition with limited treatment options. Salvianolic acid B (SalB), a natural compound from Salvia miltiorrhiza, shows therapeutic potential but its mechanisms in SCI remain unclear. This study combined network pharmacology, molecular docking and in vivo experiments using a rat SCI model, applying the AKT inhibitor capivasertib (AZD5363) for mechanistic verification. Network analysis identified 188 SalB-SCI common targets primarily in the AKT pathway, and molecular docking predicted strong binding between SalB and AKT1. In rats, SalB improved motor function, reduced tissue damage and enhanced neuronal survival in association with activation of the AKT/mTOR/HIF-1alpha axis and promoted angiogenesis, while these effects were reversed by AZD5363.", "ai_intervention": "Salvianolic acid B; capivasertib (AZD5363) as AKT inhibitor control", "ai_target": "AKT/mTOR/HIF-1α; AKT1; angiogenesis", "ai_species": "Rat", "ai_effect": "Improved motor function, reduced tissue damage, enhanced neuronal survival and angiogenesis; abolished by AKT inhibition", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/YAO2026/" }, { "sid": "CUI2026", "title": "Forsythoside A Alleviates Hypertensive Nephropathy by Promoting Mitophagy and Inhibiting Ferroptosis via ASCL1-CCNB1/mTOR Pathway.", "authors": "Cui X; Yang D; Zhang Z et al.", "year": 2026, "journal": "Journal of Ethnopharmacology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "C57BL/6 mouse; NRK-52E rat kidney cells", "peer_reviewed": "Yes", "doi": "10.1016/j.jep.2026.122346", "pmid": "", "pmcid": "", "finding": "Forsythoside A binds ASCL1 and blocks the downstream CCNB1/mTOR axis, promoting mitophagy and suppressing ferroptosis to protect against Ang II-induced hypertensive nephropathy in mice — without lowering blood pressure.\n", "abstract": "Forsythoside A (FTA), the primary bioactive component of Forsythiae Fructus, exhibits anti-inflammatory and antioxidant activity. Hypertensive nephropathy (HN) models were established in C57BL/6 mice and NRK-52E cells using Ang II. FTA mitigated Ang II-induced renal injury by reducing renal dysfunction markers (Cr, BUN, Alb/Cr), restoring renal tissue architecture and decreasing inflammatory markers, without exerting antihypertensive effects. RNA sequencing revealed associations with mTOR and ASCL1. FTA binds ASCL1 and inhibits its activity, blocking the downstream CCNB1/mTOR pathway, promoting mitophagy and inhibiting ferroptosis, ultimately alleviating renal injury.", "ai_intervention": "Forsythoside A", "ai_target": "ASCL1-CCNB1/mTOR; mitophagy; ferroptosis", "ai_species": "Mouse; rat kidney epithelial cells", "ai_effect": "Reduced renal dysfunction markers and inflammation; increased mitophagy, decreased ferroptosis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CUI2026/" }, { "sid": "BEN2008", "title": "Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy", "authors": "Bentzinger CF; Rueegg MA et al.", "year": 2008, "journal": "Cell metabolism", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (muscle raptor/rictor KO)", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2008.10.002", "pmid": "19046572", "pmcid": "", "finding": "In mice, muscle-specific raptor loss (not rictor) causes dystrophy, showing mTORC1 is essential for muscle homeostasis.\n", "abstract": "Mammalian target of rapamycin (mTOR) is a central controller of cell growth. mTOR assembles into two distinct multiprotein complexes called mTOR complex 1 (mTORC1) and mTORC2. Here we show that the mTORC1 component raptor is critical for muscle function and prolonged survival. In contrast, muscles lacking the mTORC2 component rictor are indistinguishable from wild-type controls. Raptor-deficient muscles become progressively dystrophic, are impaired in their oxidative capacity, and contain increased glycogen stores, but they express structural components indicative of oxidative muscle fibers. Biochemical analysis indicates that these changes are probably due to loss of activation of direct downstream targets of mTORC1, downregulation of genes involved in mitochondrial biogenesis, including PGC1alpha, and hyperactivation of PKB/Akt. Finally, we show that activation of PKB/Akt does not require mTORC2. Together, these results demonstrate that muscle mTORC1 has an unexpected role in the regulation of the metabolic properties and that its function is essential for life.", "ai_intervention": "Genetic – muscle-specific raptor KO (and rictor KO)", "ai_target": "mTORC1 (raptor) vs mTORC2 (rictor)", "ai_species": "Mouse (muscle raptor/rictor KO)", "ai_effect": "In mice, raptor loss (not rictor) causes progressive muscular dystrophy and metabolic changes – mTORC1 essential for muscle", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BEN2008/" }, { "sid": "SAB1994", "title": "RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs", "authors": "Sabatini DM et al.", "year": 1994, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cell culture", "peer_reviewed": "Yes", "doi": "10.1016/0092-8674(94)90570-3", "pmid": "7518356", "pmcid": "", "finding": "Discovery of the protein RAFT1 (today's mTOR) as the direct target of the FKBP12-rapamycin complex; founding paper of the entire mTOR field.\n", "abstract": "The immunosuppressants rapamycin and FK506 bind to the same intracellular protein, the immunophilin FKBP12. The FKB12-FK506 complex interacts with and inhibits the Ca(2+)-activated protein phosphatase calcineurin. The target of the FKBP12-rapamycin complex has not yet been identified. We report that a protein complex containing 245 kDa and 35 kDa components, designated rapamycin and FKBP12 targets 1 and 2 (RAFT1 and RAFT2), interacts with FKBP12 in a rapamycin-dependent manner. Sequences (330 amino acids total) of tryptic peptides derived from the 245 kDa RAFT1 reveal striking homologies to the yeast TOR gene products, which were originally identified by mutations that confer rapamycin resistance in yeast. A RAFT1 cDNA was obtained and found to encode a 289 kDa protein (2549 amino acids) that is 43% and 39% identical to TOR2 and TOR1, respectively. We propose that RAFT1 is the direct target of FKBP12-rapamycin and a mammalian homolog of the TOR proteins.", "ai_intervention": "Biochemical (FKBP12-rapamycin affinity purification)", "ai_target": "RAFT1 (mTOR/FRAP) / FKBP12", "ai_species": "Mammalian cell culture", "ai_effect": "Identifies RAFT1 (mammalian TOR) as the FKBP12-rapamycin target, homologous to yeast TORs", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAB1994/" }, { "sid": "UMX2004", "title": "Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity", "authors": "Um SH; Thomas G et al.", "year": 2004, "journal": "Nature", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (S6K1 KO)", "peer_reviewed": "Yes", "doi": "10.1038/nature02866", "pmid": "15306821", "pmcid": "", "finding": "S6K1 deletion protects mice from age- and diet-induced obesity and enhances insulin sensitivity.\n", "abstract": "Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced beta-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced beta-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K A(y) and ob/ob mice-two genetic models of obesity-have markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.", "ai_intervention": "Genetic – S6K1 knockout", "ai_target": "S6K1 (downstream of mTORC1)", "ai_species": "Mouse (S6K1 KO)", "ai_effect": "S6K1 loss protects against age- and diet-induced obesity and enhances insulin sensitivity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/UMX2004/" }, { "sid": "SAR2006", "title": "Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB", "authors": "Sarbassov DD; Ali SM; Sengupta S; Sheen JH; Hsu PP; Bagley AF; Markhard AL; Sabatini DM", "year": 2006, "journal": "Molecular Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Multiple human/mouse cell lines", "peer_reviewed": "Yes", "doi": "10.1016/j.molcel.2006.03.029", "pmid": "16603397", "pmcid": "", "finding": "The molecular explanation for rapamycin's dark side. Short-term rapamycin only hits mTORC1, but LONG-term treatment also strips down mTORC2 in many cells, cutting Akt signaling. This is the mechanistic root of the insulin-resistance side effect later shown in mice (see Lamming 2012) - crucial for anyone dosing rapamycin for longevity.\n", "abstract": "The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a multiprotein complex composed of mTOR, mLST8, and raptor (mTORC1). The distinct complex of mTOR, mLST8, and rictor (mTORC2) does not interact with FKBP12-rapamycin and is not thought to be rapamycin sensitive. mTORC2 phosphorylates and activates Akt/PKB, a key regulator of cell survival. Here we show that rapamycin inhibits the assembly of mTORC2 and that, in many cell types, prolonged rapamycin treatment reduces the levels of mTORC2 below those needed to maintain Akt/PKB signaling. The proapoptotic and antitumor effects of rapamycin are suppressed in cells expressing an Akt/PKB mutant that is rapamycin resistant. Our work describes an unforeseen mechanism of action for rapamycin that suggests it can be used to inhibit Akt/PKB in certain cell types.", "ai_intervention": "Rapamycin (prolonged treatment)", "ai_target": "mTORC2 / Akt", "ai_species": "Multiple human/mouse cell lines", "ai_effect": "Prolonged rapamycin inhibits mTORC2 assembly and Akt/PKB in some cells – mTORC2 is not always rapamycin-insensitive", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAR2006/" }, { "sid": "EVA2026", "title": "PTEN regulates microtubule polymerization via mTORC2, but not mTORC1, in peripheral sensory neurons", "authors": "Evans S; Reglewski J; Rose H; Lewis C; Nayak A; Minsky C; McNeil E; Knowles B; Wang W; Li M; Luikart BW; Hong J", "year": 2026, "journal": "eNeuro", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse peripheral sensory neuron cultures (Pten-KO with Raptor or Rictor co-deletion, both sexes)", "peer_reviewed": "Yes", "doi": "10.1523/ENEURO.0116-26.2026", "pmid": "42642329", "pmcid": "", "finding": "Uses Raptor (mTORC1) versus Rictor (mTORC2) co-deletion on a Pten-knockout background to ask which complex carries the growth signal to the microtubule cytoskeleton. Suppressing mTORC2 — but not mTORC1 — returns the accelerated microtubule polymerisation and neuronal hypertrophy of Pten-KO neurons to wild-type levels, and the effect is confined to the axonal growth cone rather than the proximal axon shaft. A clean genetic dissection on the comparatively thin mTORC2 side of the pathway.\n", "abstract": "Peripheral neuropathy affects over 18 million adults in the U.S., but therapeutic outcomes are poor due to a lack of regenerative treatments. Pten is a strong negative regulator of cell growth, and Pten-KO drives axonal regeneration in various neuronal subtypes potentially via downstream regulation of stability of the microtubule (MT) cytoskeleton, a vital component of axonal growth. While Pten-KO accelerates MT polymerization rates in the axonal growth cone, it remains unknown whether this action is dependent on mTORC1 or mTORC2 signaling, and whether regeneration under Pten-KO is dependent on MT activation. Here, we perform co-deletions of either Raptor (mTORC1) or Rictor (mTORC2) alongside Pten-KO in mouse peripheral sensory neuron cultures of either sex to isolate the effects of each pathway on the MT cytoskeleton. We use Pten-KO to increase MT polymerization and neuronal outgrowth, and then show that suppression of mTORC2, but not mTORC1, is sufficient to reduce the accelerated MT polymerization and neuronal hypertrophy to wild-type levels. These results are specific to the axonal growth cone, and MT dynamics in the proximal axon shaft are not impacted by Pten-KO, mTORC1 suppression, or mTORC2 suppression.", "ai_intervention": "Genetic: Pten knockout with Raptor (mTORC1) or Rictor (mTORC2) co-deletion", "ai_target": "mTORC2 (RICTOR); microtubule cytoskeleton; PTEN", "ai_species": "Mouse (peripheral sensory neuron cultures)", "ai_effect": "mTORC2, not mTORC1, mediates PTEN-dependent microtubule polymerization and neuronal hypertrophy at the growth cone", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/EVA2026/" }, { "sid": "GUR2016", "title": "mTOR Signaling Confers Resistance to Targeted Cancer Drugs", "authors": "Guri Y; Hall MN et al.", "year": 2016, "journal": "Trends in cancer", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1016/j.trecan.2016.10.006", "pmid": "28741507", "pmcid": "", "finding": "Review of how mTOR signalling confers resistance to targeted cancer therapies.\n", "abstract": "Cancer is a complex disease and a leading cause of death worldwide. Extensive research over decades has led to the development of therapies that target cancer-specific signaling pathways. However, the clinical benefits of such drugs are at best transient due to tumors displaying intrinsic or adaptive resistance. The underlying compensatory pathways that allow cancer cells to circumvent a drug blockade are poorly understood. We review here recent studies suggesting that mammalian TOR (mTOR) signaling is a major compensatory pathway conferring resistance to many cancer drugs. mTOR-mediated resistance can be cell-autonomous or non-cell-autonomous. These findings suggest that mTOR signaling should be monitored routinely in tumors and that an mTOR inhibitor should be considered as a co-therapy.", "ai_intervention": "Not applicable (review)", "ai_target": "mTOR", "ai_species": "Review", "ai_effect": "mTOR signaling is a major compensatory pathway conferring resistance to targeted cancer drugs", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GUR2016/" }, { "sid": "MOR2013", "title": "mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation", "authors": "Morita M; Sonenberg N et al.", "year": 2013, "journal": "Cell metabolism", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2013.10.001", "pmid": "24206664", "pmcid": "", "finding": "mTORC1 controls mitochondrial biogenesis and activity through 4E-BP-dependent translation.\n", "abstract": "mRNA translation is thought to be the most energy-consuming process in the cell. Translation and energy metabolism are dysregulated in a variety of diseases including cancer, diabetes, and heart disease. However, the mechanisms that coordinate translation and energy metabolism in mammals remain largely unknown. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates mRNA translation and other anabolic processes. We demonstrate that mTORC1 controls mitochondrial activity and biogenesis by selectively promoting translation of nucleus-encoded mitochondria-related mRNAs via inhibition of the eukaryotic translation initiation factor 4E (eIF4E)-binding proteins (4E-BPs). Stimulating the translation of nucleus-encoded mitochondria-related mRNAs engenders an increase in ATP production capacity, a required energy source for translation. These findings establish a feed-forward loop that links mRNA translation to oxidative phosphorylation, thereby providing a key mechanism linking aberrant mTOR signaling to conditions of abnormal cellular energy metabolism such as neoplasia and insulin resistance.", "ai_intervention": "Genetic/pharmacologic (mTORC1 / 4E-BP)", "ai_target": "mTORC1 / 4E-BP", "ai_species": "Mammalian cells", "ai_effect": "mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MOR2013/" }, { "sid": "FEL2009", "title": "Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2", "authors": "Feldman ME; Apsel B; Uotila A; Loewith R; Knight ZA; Ruggero D; Shokat KM", "year": 2009, "journal": "PLoS Biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse fibroblasts + primary cells", "peer_reviewed": "Yes", "doi": "10.1371/journal.pbio.1000038", "pmid": "19209957", "pmcid": "PMC2637922", "finding": "The parallel discovery to Thoreen 2009 (same year), from the Shokat lab. Their TORKinibs (PP242, PP30) block mTOR's active site, hitting both complexes and shutting down cap-dependent translation that rapamycin misses. Together these two papers established a whole new drug class beyond rapamycin.\n", "abstract": "The mammalian target of rapamycin (mTOR) regulates cell growth and survival by integrating nutrient and hormonal signals. These signaling functions are distributed between at least two distinct mTOR protein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to the selective inhibitor rapamycin and activated by growth factor stimulation via the canonical phosphoinositide 3-kinase (PI3K)-->Akt-->mTOR pathway. Activated mTORC1 kinase up-regulates protein synthesis by phosphorylating key regulators of mRNA translation. By contrast, mTORC2 is resistant to rapamycin. Genetic studies have suggested that mTORC2 may phosphorylate Akt at S473, one of two phosphorylation sites required for Akt activation; this has been controversial, in part because RNA interference and gene knockouts produce distinct Akt phospho-isoforms. The central role of mTOR in controlling key cellular growth and survival pathways has sparked interest in discovering mTOR inhibitors that bind to the ATP site and therefore target both mTORC2 and mTORC1. We investigated mTOR signaling in cells and animals with two novel and specific mTOR kinase domain inhibitors (TORKinibs). Unlike rapamycin, these TORKinibs (PP242 and PP30) inhibit mTORC2, and we use them to show that pharmacological inhibition of mTOR blocks the phosphorylation of Akt at S473 and prevents its full activation. Furthermore, we show that TORKinibs inhibit proliferation of primary cells more completely than rapamycin. Surprisingly, we find that mTORC2 is not the basis for this enhanced activity, and we show that the TORKinib PP242 is a more effective mTORC1 inhibitor than rapamycin. Importantly, at the molecular level, PP242 inhibits cap-dependent translation under conditions in which rapamycin has no effect. Our findings identify new functional features of mTORC1 that are resistant to rapamycin but are effectively targeted by TORKinibs. These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease.", "ai_intervention": "ATP-competitive mTOR active-site inhibitors (vs rapamycin)", "ai_target": "mTORC1 & mTORC2", "ai_species": "Mouse fibroblasts + primary cells", "ai_effect": "Active-site inhibitors block rapamycin-resistant outputs of mTORC1/2 (e.g. 4E-BP1), unlike rapamycin", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/FEL2009/" }, { "sid": "IYE2012", "title": "Genome sequencing identifies a basis for everolimus sensitivity", "authors": "Iyer G; Solit DB et al.", "year": 2012, "journal": "Science", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Human (patient) + sequencing", "peer_reviewed": "Yes", "doi": "10.1126/science.1226344", "pmid": "22923433", "pmcid": "PMC3633467", "finding": "Genome sequencing of a single exceptional everolimus responder implicates TSC1 loss as the sensitivity basis. An n-of-1 observation, hypothesis-generating rather than confirmatory.\n", "abstract": "Cancer drugs often induce dramatic responses in a small minority of patients. We used whole-genome sequencing to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations was a loss-of-function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR pathway activation. Targeted sequencing revealed TSC1 mutations in about 8% of 109 additional bladder cancers examined, and TSC1 mutation correlated with everolimus sensitivity. These results demonstrate the feasibility of using whole-genome sequencing in the clinical setting to identify previously occult biomarkers of drug sensitivity that can aid in the identification of patients most likely to respond to targeted anticancer drugs.", "ai_intervention": "Everolimus (mTOR inhibitor)", "ai_target": "mTOR / TSC1", "ai_species": "Human – metastatic bladder cancer patient + tumor sequencing", "ai_effect": "Loss-of-function TSC1 mutation explains an exceptional everolimus response; TSC1 mutated in ~8% of bladder cancers", "ai_dose": "Everolimus (mTOR inhibitor) in a phase II trial; whole-genome/targeted tumor sequencing of an exceptional responder.", "ai_samplesize": "1 exceptional responder + targeted sequencing of additional bladder tumors; 3 further TSC1-nonsense tumors identified (2 minor responders: 17% and 24% regression; 1 with 7%).", "ai_effectsize": "Loss-of-function TSC1 mutation underlies the exceptional everolimus response. TSC1-mutant tumors stayed on everolimus longer (7.7 vs 2.0 months, p=0.004) with improved time to recurrence (4.1 vs 1.8 months).", "ai_limitations": "Inference from rare responders; basis of mTOR-inhibitor sensitivity beyond TSC1/2 loss still incompletely understood.", "atlas_url": "https://mtor-atlas.org/study/IYE2012/" }, { "sid": "HOL2005", "title": "mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events", "authors": "Holz MK; Blenis J et al.", "year": 2005, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2005.10.024", "pmid": "16286006", "pmcid": "", "finding": "mTOR and S6K1 dynamically assemble the translation preinitiation complex on eIF3.\n", "abstract": "In response to nutrients, energy sufficiency, hormones, and mitogenic agents, S6K1 phosphorylates several targets linked to translation. However, the molecular mechanisms whereby S6K1 is activated, encounters substrate, and contributes to translation initiation are poorly understood. We show that mTOR and S6K1 maneuver on and off the eukaryotic initiation factor 3 (eIF3) translation initiation complex in a signal-dependent, choreographed fashion. When inactive, S6K1 associates with the eIF3 complex, while the S6K1 activator mTOR/raptor does not. Cell stimulation promotes mTOR/raptor binding to the eIF3 complex and phosphorylation of S6K1 at its hydrophobic motif. Phosphorylation results in S6K1 dissociation, activation, and subsequent phosphorylation of its translational targets, including eIF4B, which is then recruited into the complex in a phosphorylation-dependent manner. Thus, the eIF3 preinitiation complex acts as a scaffold to coordinate a dynamic sequence of events in response to stimuli that promote efficient protein synthesis.", "ai_intervention": "Biochemical", "ai_target": "mTOR / S6K1 / eIF3", "ai_species": "Mammalian cells", "ai_effect": "mTOR and S6K1 dynamically associate with eIF3 to control translation preinitiation via ordered phosphorylation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HOL2005/" }, { "sid": "EGA2010", "title": "Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy", "authors": "Egan DF; Shaw RJ et al.", "year": 2010, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/science.1196371", "pmid": "21205641", "pmcid": "PMC3030664", "finding": "AMPK directly phosphorylates ULK1 to connect energy sensing to autophagy/mitophagy, opposing mTOR.\n", "abstract": "Adenosine monophosphate-activated protein kinase (AMPK) is a conserved sensor of intracellular energy activated in response to low nutrient availability and environmental stress. In a screen for conserved substrates of AMPK, we identified ULK1 and ULK2, mammalian orthologs of the yeast protein kinase Atg1, which is required for autophagy. Genetic analysis of AMPK or ULK1 in mammalian liver and Caenorhabditis elegans revealed a requirement for these kinases in autophagy. In mammals, loss of AMPK or ULK1 resulted in aberrant accumulation of the autophagy adaptor p62 and defective mitophagy. Reconstitution of ULK1-deficient cells with a mutant ULK1 that cannot be phosphorylated by AMPK revealed that such phosphorylation is required for mitochondrial homeostasis and cell survival during starvation. These findings uncover a conserved biochemical mechanism coupling nutrient status with autophagy and cell survival.", "ai_intervention": "Genetic/biochemical (AMPK–ULK1)", "ai_target": "AMPK / ULK1 / mTORC1", "ai_species": "Mammalian cells (+ C. elegans)", "ai_effect": "AMPK phosphorylates ULK1 to connect energy sensing to autophagy/mitophagy", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/EGA2010/" }, { "sid": "SRI2026", "title": "Nutrient/TOR signaling controls adipose mitochondrial transcription factor A (TFAM) to regulate organismal growth in Drosophila", "authors": "Sriskanthadevan-Pirahas S et al.", "year": 2026, "journal": "FEBS Lett", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Drosophila (larvae, fat body)", "peer_reviewed": "Yes", "doi": "10.1002/1873-3468.70427", "pmid": "42572502", "pmcid": "", "finding": "In Drosophila larvae, nutrient/TOR signaling in the fat body (a key nutrient-sensing tissue) post-transcriptionally suppresses the mitochondrial transcription factor TFAM, and this TOR→TFAM axis in fat-body tissue controls whole-body developmental growth — a mechanistic link between nutrient sensing and interorgan growth control via mitochondrial bioenergetics.\n", "abstract": "Animals must adapt their growth to fluctuations in nutrient availability to ensure proper development. While nutrient-sensing tissues coordinate organismal growth through interorgan signaling, the metabolic changes within these tissues that mediate whole-body growth control remain poorly understood. Using Drosophila larvae, we show that TOR (target of rapamycin), a conserved nutrient-sensing kinase, controls developmental growth through regulation of the mitochondrial genome transcription factor TFAM, which controls mitochondrial bioenergetic capacity. We find that nutrient/TOR signaling post-transcriptionally suppresses TFAM protein levels. Furthermore, we find that TOR regulation of TFAM in the larval fat body, a key nutrient-sensing tissue, controls developmental growth. These findings establish a molecular mechanism linking nutrient-sensing pathways to mitochondrial metabolism, revealing how environmental nutrient availability coordinates organismal growth through tissue-specific metabolic control.", "ai_intervention": "Genetic manipulation of TOR signaling in the fat body (Drosophila)", "ai_target": "TOR → TFAM (mitochondrial transcription factor A)", "ai_species": "Drosophila melanogaster (larvae)", "ai_effect": "TOR suppresses TFAM protein levels in the fat body; this axis controls organismal developmental growth", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SRI2026/" }, { "sid": "VER2026", "title": "Testosterone propionate maintains autophagic flux and mitochondrial integrity via regulation of the LC3B/p62/Beclin-1/mTOR axis in induced liver fibrosis.", "authors": "Verma S, Vaishnav S, Yadav M, Verma A, Washimkar K", "year": 2026, "journal": "Journal of Molecular Histology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Rat", "peer_reviewed": "Yes", "doi": "10.1007/s10735-026-10905-0", "pmid": "42461311", "pmcid": "", "finding": "Testosterone propionate protects against CCl4-induced liver fibrosis by maintaining mTOR-regulated autophagic flux via the LC3B/p62/Beclin-1 axis, preserving mitochondrial integrity; castration worsens fibrosis by impairing this pathway.\n", "abstract": "In a CCl4-induced chronic liver injury rat model, testosterone propionate was found to preserve autophagic flux and mitochondrial function. Androgen deprivation worsened hepatic damage, while testosterone treatment maintained the LC3B/p62/Beclin-1/mTOR axis and protected mitochondrial quality control and reduced apoptosis.", "ai_intervention": "Testosterone propionate", "ai_target": "mTOR / LC3B / p62 / Beclin-1 autophagy axis", "ai_species": "Rat", "ai_effect": "Testosterone maintains mTOR-regulated autophagy and mitochondrial integrity; androgen deprivation impairs autophagy and worsens liver fibrosis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/VER2026/" }, { "sid": "LIU2015", "title": "PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex", "authors": "Liu P; Wei W et al.", "year": 2015, "journal": "Cancer discovery", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1158/2159-8290.CD-15-0460", "pmid": "26293922", "pmcid": "PMC4631654", "finding": "PIP3 relieves SIN1 PH-domain autoinhibition to activate the mTORC2 kinase complex.\n", "abstract": "mTOR serves as a central regulator of cell growth and metabolism by forming two distinct complexes, mTORC1 and mTORC2. Although mechanisms of mTORC1 activation by growth factors and amino acids have been extensively studied, the upstream regulatory mechanisms leading to mTORC2 activation remain largely elusive. Here, we report that the pleckstrin homology (PH) domain of SIN1, an essential and unique component of mTORC2, interacts with the mTOR kinase domain to suppress mTOR activity. More importantly, PtdIns(3,4,5)P3, but not other PtdInsPn species, interacts with SIN1-PH to release its inhibition on the mTOR kinase domain, thereby triggering mTORC2 activation. Mutating critical SIN1 residues that mediate PtdIns(3,4,5)P3 interaction inactivates mTORC2, whereas mTORC2 activity is pathologically increased by patient-derived mutations in the SIN1-PH domain, promoting cell growth and tumor formation. Together, our study unravels a PI3K-dependent mechanism for mTORC2 activation, allowing mTORC2 to activate AKT in a manner that is regulated temporally and spatially by PtdIns(3,4,5)P3.", "ai_intervention": "Biochemical/genetic (SIN1 PH domain)", "ai_target": "mTORC2 / SIN1 / PtdIns(3,4,5)P3", "ai_species": "Mammalian cells", "ai_effect": "PIP3 binds the SIN1 PH domain to relieve suppression of mTOR → activates mTORC2", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LIU2015/" }, { "sid": "MAN2021", "title": "Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials", "authors": "Mannick JB; Teo G; Bernardo P; Quinn D; Russell K; Klickstein L; Marshall W; Shergill S", "year": 2021, "journal": "Lancet Healthy Longevity", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Negative_result", "model": "Humans, phase 2b + phase 3 RCT (n=1024 phase 3)", "peer_reviewed": "Yes", "doi": "10.1016/S2666-7568(21)00062-3", "pmid": "33977284", "pmcid": "PMC8102040", "finding": "The crucial reality check. After the promising phase 2a, the large phase 3 trial (n=1024) FAILED its primary endpoint - RTB101 did not reduce clinically symptomatic respiratory illness (26% vs 25%, p=0.65). It still reliably switched on antiviral genes, so the biomarker moved but the clinical outcome did not. A textbook lesson that a promising biomarker is not a proven benefit.\n", "abstract": "The COVID-19 pandemic highlights the need for therapies that improve immune function in older adults, including interferon (IFN)-induced antiviral immunity that declines with age. In a previous phase 2a trial, RTB101 (previously known as BEZ235), an oral mechanistic target of rapamycin (mTOR) inhibitor, was observed to increase IFN-induced antiviral gene expression and decrease the incidence of respiratory tract infections (RTIs) in older adults. Therefore, we aimed to investigate whether oral RTB101 upregulated IFN-induced antiviral responses and decreased the incidence of viral RTIs when given once daily for 16 weeks during winter cold and flu season.\n\nWe did a phase 2b and a phase 3 double-blind, randomised, placebo-controlled trial in adults aged at least 65 years enrolled in New Zealand, Australia, and the USA at 54 sites. In the phase 2b trial, patients were aged 65-85 years, with asthma, type 2 diabetes, chronic obstructive pulmonary disease (COPD), congestive heart failure, were current smokers, or had an emergency room or hospitalisation for an RTI within the past 12 months. In the phase 3 trial, patients were aged at least 65 years, did not have COPD, and were not current smokers. In the phase 2b trial, patients were randomly assigned to using a validated automated randomisation system to oral RTB101 5 mg, RTB101 10 mg once daily, or placebo in part 1 and RTB101 10 mg once daily, RTB101 10 mg twice daily, RTB101 10 mg plus everolimus once daily, or matching placebo in part 2. In the phase 3 trial, patients were randomly assigned to RTB101 10mg once daily or matching placebo. The phase 2b primary outcome was the incidence of laboratory-confirmed RTIs during 16 weeks of winter cold and influenza season and the phase 3 primary outcome was the incidence of clinically symptomatic respiratory illness defined as symptoms consistent with an RTI, irrespective of whether an infection was laboratory-confirmed. Patients, investigators, and sponsor were masked to treatment assignments. All patients who received at least part of one dose of study drug were included in the primary and safety analyses. The phase 2b trial was registered with ANZCTR, ACTRN12617000468325, ClinicalTrials.gov, NCT03373903, and the phase 3 trial was registered with ANZCTR, ACTRN12619000628145.\n\nIn the phase 2b trial, we recruited 652 participants in total between May 16, 2017, and Jan 10, 2018, 179 participants to part 1 of the study (randomly assigned 1:1:1 to RTB101 5 mg once daily [61 participants], RTB101 10 mg once daily [58 participants], or matching placebo [60 participants]) and 473 patients to part 2 (randomly assigned 1:1:1:1 to RTB101 10 mg once daily [118 participants], RTB101 10 mg twice daily [120 participants], RTB101 10 mg in combination with everolimus 0·1 mg daily [115 participants] or matching placebo [120 participants]). In our first prespecified statistical analysis of the primary efficacy endpoint for part 2 of the phase 2b trial efficacy of RTB101 10 mg in combination with everolimus 0·1 mg once daily compared with placebo did not meet statistical significance but, in our second prespecified analysis, which included data from part 1 and part 2, we found a statistically significant reduction in the proportion of patients who had one or more laboratory-confirmed RTIs in the RTB101 10 mg once daily treatment group (34 [19%] of 176) compared with the pooled placebo group (50 [28%] of 180; odds ratio [OR] 0·601 [90% CI 0·391-0·922]; p=0·02). In the phase 3 trial, we enrolled 1024 patients between May 7, 2018, and July 19, 2019. 513 (50·1%) participants were randomly assigned to RTB101 10 mg once daily and 510 (49·9%) to placebo. In the full analysis set of the phase 3 trial, RTB101 did not reduce the proportion of patients with clinically symptomatic respiratory illness (134 [26%] of 511 patients in the RTB101 treatment group125 [25%] 510 patients in the placebo treatment group; OR 1·07 [90% CI 0·80-1·42]; p=0·65). In both trials, significantly more IFN-induced antiviral genes were upregulated in patients treated with RTB101 as compared with placebo. The study drug was found to be safe and well-tolerated across trials and treatment groups. Only one patient in the placebo group in the phase 3 trial had serious adverse events (nausea, fatigue, hyponatraemia, and arthralgia) which were considered related to study drug treatment. Three patients died in the phase 2b trial and one in the phase 3 trial but no deaths were considered related to study treatment.\n\nThe combined results indicate that low doses of the mTOR inhibitor RTB101 are well tolerated and upregulate IFN-induced antiviral responses in older adults. Further refinement of clinical trial endpoints and patient populations might be required to identify whether upregulation of IFN responses by mTOR inhibitors consistently decreases the incidence or severity of viral infections in older adults.\n\nresTORbio and the National Institute on Aging.", "ai_intervention": "RTB101 (BEZ235), oral mTOR inhibitor; ± everolimus", "ai_target": "mTOR (TORC1/2)", "ai_species": "Human – phase 2b + phase 3 RCT (n=1024)", "ai_effect": "Phase 3 FAILED its primary endpoint (no reduction in symptomatic respiratory infections, 26 vs 25%); antiviral genes still upregulated", "ai_dose": "RTB101 5 or 10 mg once daily (+/- everolimus in phase 2b); phase 3 used RTB101 10 mg once daily; oral, placebo-controlled.", "ai_samplesize": "Phase 2b + phase 3 across >1500 adults aged >=65 (phase 3 n=1024); antiviral-gene subset 180 placebo + 180 RTB101.", "ai_effectsize": "Phase 3 primary endpoint (proportion with >=1 clinically symptomatic respiratory illness) NOT met; RTB101 still upregulated IFN-induced antiviral gene expression. Biomarker moved, clinical outcome did not.", "ai_limitations": "FDA changed the primary endpoint between phase 2b and phase 3 (symptom-based vs lab-confirmed), complicating comparison; positive biomarker did not translate to clinical benefit.", "atlas_url": "https://mtor-atlas.org/study/MAN2021/" }, { "sid": "JOS2024", "title": "mTORC1 activity oscillates throughout the cell cycle, promoting mitotic entry and differentially influencing autophagy induction", "authors": "Joshi JN; Valvezan AJ et al.", "year": 2024, "journal": "Cell Reports", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human & mouse cell lines (live single-cell imaging)", "peer_reviewed": "Yes", "doi": "10.1016/j.celrep.2024.114543", "pmid": "39067023", "pmcid": "PMC12730006", "finding": "mTORC1 activity oscillates across the cell cycle (lowest in mitosis/G1, highest in S/G2) via the TSC complex, independent of Akt/Mek-Erk; low mTORC1 in G1 sensitizes cells to autophagy induction from the same partial inhibition or nutrient drop -- direct evidence that the TIMING/pattern of mTORC1 activity, not just its average level, shapes autophagy outcome.\n", "abstract": "Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a master metabolic regulator that is active in nearly all proliferating eukaryotic cells; however, it is unclear whether mTORC1 activity changes throughout the cell cycle. We find that mTORC1 activity oscillates from lowest in mitosis/G1 to highest in S/G2. The interphase oscillation is mediated through the TSC complex but is independent of major known regulatory inputs, including Akt and Mek/Erk signaling. By contrast, suppression of mTORC1 activity in mitosis does not require the TSC complex. mTORC1 has long been known to promote progression through G1. We find that mTORC1 also promotes progression through S and G2 and is important for satisfying the Chk1/Wee1-dependent G2/M checkpoint to allow entry into mitosis. We also find that low mTORC1 activity in G1 sensitizes cells to autophagy induction in response to partial mTORC1 inhibition or reduced nutrient levels. Together, these findings demonstrate that mTORC1 is differentially regulated throughout the cell cycle, with important phase-specific consequences for proliferating cells.", "ai_intervention": "Partial mTORC1 inhibition; nutrient reduction; cell-cycle synchronization", "ai_target": "mTORC1 / TSC complex", "ai_species": "Human & mouse cell lines", "ai_effect": "mTORC1 activity oscillates across the cell cycle (low mitosis/G1, high S/G2); low-mTORC1 G1 cells are more sensitive to autophagy induction", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JOS2024/" }, { "sid": "SAN2008", "title": "The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1", "authors": "Sancak Y; Sabatini DM et al.", "year": 2008, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cell lines", "peer_reviewed": "Yes", "doi": "10.1126/science.1157535", "pmid": "18497260", "pmcid": "PMC2475333", "finding": "Identifies the Rag GTPase family as the missing link that lets mTORC1 sense amino acids by controlling whether mTOR is positioned near its activator Rheb.\n", "abstract": "The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins--a family of four related small guanosine triphosphatases (GTPases)--interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate-bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.", "ai_intervention": "Genetic/biochemical (Rag GTPases)", "ai_target": "Rag GTPases / raptor / mTORC1", "ai_species": "Human cell lines", "ai_effect": "Rag GTPases interact with raptor in an amino-acid-sensitive way and are necessary for amino-acid activation of mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAN2008/" }, { "sid": "ORE2006", "title": "mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt", "authors": "O'Reilly KE; Rosen N et al.", "year": 2006, "journal": "Cancer research", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cancer cells", "peer_reviewed": "Yes", "doi": "10.1158/0008-5472.CAN-05-2925", "pmid": "16452206", "pmcid": "PMC3193604", "finding": "mTORC1 inhibition relieves feedback and activates upstream RTK-PI3K-Akt signalling.\n", "abstract": "Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.", "ai_intervention": "mTOR inhibition (rapamycin)", "ai_target": "mTOR / IRS-1 / Akt / RTK", "ai_species": "Cancer cells", "ai_effect": "mTOR inhibition relieves feedback and induces upstream RTK signaling → activates Akt (a resistance mechanism)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ORE2006/" }, { "sid": "LAW2019", "title": "Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex", "authors": "Lawrence RE; Zoncu R et al.", "year": 2019, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Structure; cells", "peer_reviewed": "Yes", "doi": "10.1126/science.aax0364", "pmid": "31672913", "pmcid": "PMC6945816", "finding": "Structure reveals the FLCN complex as a Rag-GTPase activation checkpoint gating mTORC1.\n", "abstract": "The tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) activating protein (GAP) activity toward the GTPase RagC. Concomitant with mTORC1 inactivation by starvation, FLCN relocalizes from the cytosol to lysosomes. To determine the lysosomal function of FLCN, we reconstituted the human lysosomal FLCN complex (LFC) containing FLCN, its partner FLCN-interacting protein 2 (FNIP2), and the RagA:RagCGTPases as they exist in the starved state with their lysosomal anchor Ragulator complex and determined its cryo-electron microscopy structure to 3.6 angstroms. The RagC-GAP activity of FLCN was inhibited within the LFC, owing to displacement of a catalytically required arginine in FLCN from the RagC nucleotide. Disassembly of the LFC and release of the RagC-GAP activity of FLCN enabled mTORC1-dependent regulation of the master regulator of lysosomal biogenesis, transcription factor E3, implicating the LFC as a checkpoint in mTORC1 signaling.", "ai_intervention": "Structural/biochemical (FLCN complex)", "ai_target": "FLCN–FNIP2 / RagC / mTORC1", "ai_species": "Structure; cells", "ai_effect": "The lysosomal folliculin complex acts as a GAP for RagC, a checkpoint in nutrient-dependent mTORC1 activation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LAW2019/" }, { "sid": "BAR2012", "title": "Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1", "authors": "Bar-Peled L; Sabatini DM et al.", "year": 2012, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2012.07.032", "pmid": "22980980", "pmcid": "PMC3517996", "finding": "Ragulator is the guanine-nucleotide exchange factor activating the Rag GTPases on the lysosome.\n", "abstract": "The mTOR Complex 1 (mTORC1) pathway regulates cell growth in response to numerous cues, including amino acids, which promote mTORC1 translocation to the lysosomal surface, its site of activation. The heterodimeric RagA/B-RagC/D GTPases, the Ragulator complex that tethers the Rags to the lysosome, and the v-ATPase form a signaling system that is necessary for amino acid sensing by mTORC1. Amino acids stimulate the binding of guanosine triphosphate to RagA and RagB but the factors that regulate Rag nucleotide loading are unknown. Here, we identify HBXIP and C7orf59 as two additional Ragulator components that are required for mTORC1 activation by amino acids. The expanded Ragulator has nucleotide exchange activity toward RagA and RagB and interacts with the Rag heterodimers in an amino acid- and v-ATPase-dependent fashion. Thus, we provide mechanistic insight into how mTORC1 senses amino acids by identifying Ragulator as a guanine nucleotide exchange factor (GEF) for the Rag GTPases.", "ai_intervention": "Biochemical/genetic (Ragulator)", "ai_target": "Ragulator / Rag GTPases / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "Ragulator is a GEF for RagA/B, activating the Rags to signal amino-acid levels to mTORC1 at the lysosome", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BAR2012/" }, { "sid": "SOL2014", "title": "The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice", "authors": "Solon-Biet SM et al.", "year": 2014, "journal": "Cell Metabolism", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse, 25 ad libitum diets", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2014.02.009", "pmid": "24606899", "pmcid": "PMC5087279", "finding": "Lifespan and cardiometabolic health were determined not by caloric intake but by the protein:carbohydrate ratio; low protein ratio suppressed hepatic mTOR.\n", "abstract": "The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.", "ai_intervention": "Dietary – 25 diets varying protein:carb:fat, ad libitum", "ai_target": "Nutrient/mTOR signaling (dietary protein)", "ai_species": "Mouse (25 ad libitum diets)", "ai_effect": "Macronutrient ratio (low protein, high carb), not calorie intake, optimizes cardiometabolic health and longevity", "ai_dose": "25 ad libitum diets differing in protein (5%–60%), fat (16%–75%), carbohydrate (16%–75%), and energy (8, 13, or 17 kJ/g of food) fed over a lifetime", "ai_samplesize": "858 mice across 25 diets", "ai_effectsize": "Median lifespan increased by approximately 30% (from 95 to 125 weeks) as the protein-to-carbohydrate ratio decreased; not influenced by total calorie intake", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SOL2014/" }, { "sid": "MOT2008", "title": "Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial", "authors": "Motzer RJ et al.", "year": 2008, "journal": "Lancet", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, phase III RCT (RECORD-1)", "peer_reviewed": "Yes", "doi": "10.1016/S0140-6736(08)61039-9", "pmid": "18653228", "pmcid": "", "finding": "Everolimus extended median progression-free survival from 1.9 to 4.0 months versus placebo in metastatic renal cell carcinoma.\n", "abstract": "Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy.\n\nPatients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00410124.\n\nAll randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22-0.40, p<0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity.\n\nTreatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.", "ai_intervention": "Everolimus (RAD001)", "ai_target": "mTORC1", "ai_species": "Human – phase III RCT (RECORD-1), metastatic renal cell carcinoma", "ai_effect": "Everolimus improved progression-free survival vs placebo after VEGF-targeted therapy failure (abstract excerpt truncated before full results)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MOT2008/" }, { "sid": "JAN2010", "title": "Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor", "authors": "Janes MR; Fruman DA et al.", "year": 2010, "journal": "Nature medicine", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Leukemia cells; mouse", "peer_reviewed": "Yes", "doi": "10.1038/nm.2091", "pmid": "20072130", "pmcid": "PMC4017764", "finding": "The ATP-competitive TORC1/2 inhibitor PP242 selectively kills leukemia cells, sparing normal cells.\n", "abstract": "Targeting the mammalian target of rapamycin (mTOR) protein is a promising strategy for cancer therapy. The mTOR kinase functions in two complexes, TORC1 (target of rapamycin complex-1) and TORC2 (target of rapamycin complex-2); however, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. We compared rapamycin with PP242, an inhibitor of the active site of mTOR in both TORC1 and TORC2 (hereafter referred to as TORC1/2), in models of acute leukemia harboring the Philadelphia chromosome (Ph) translocation. We demonstrate that PP242, but not rapamycin, causes death of mouse and human leukemia cells. In vivo, PP242 delays leukemia onset and augments the effects of the current front-line tyrosine kinase inhibitors more effectively than does rapamycin. Unexpectedly, PP242 has much weaker effects than rapamycin on the proliferation and function of normal lymphocytes. PI-103, a less selective TORC1/2 inhibitor that also targets phosphoinositide 3-kinase (PI3K), is more immunosuppressive than PP242. These findings establish that Ph(+) transformed cells are more sensitive than normal lymphocytes to selective TORC1/2 inhibitors and support the development of such inhibitors for leukemia therapy.", "ai_intervention": "PP242 (ATP-competitive TORC1/2 inhibitor) vs rapamycin", "ai_target": "mTORC1 & mTORC2", "ai_species": "Leukemia cells; mouse (Ph+ ALL)", "ai_effect": "TORC1/2 active-site inhibition selectively targets leukemia cells more effectively than rapamycin", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JAN2010/" }, { "sid": "BUR1998", "title": "RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1", "authors": "Burnett PE; Sabatini DM et al.", "year": 1998, "journal": "Proceedings of the National Academy of Sciences of the United States of America", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "In vitro", "peer_reviewed": "Yes", "doi": "10.1073/pnas.95.4.1432", "pmid": "9465032", "pmcid": "PMC19032", "finding": "RAFT1/mTOR directly phosphorylates p70 S6K (Thr389) and 4E-BP1, the two central translational effectors.\n", "abstract": "The complex of rapamycin with its intracellular receptor, FKBP12, interacts with RAFT1/FRAP/mTOR, the in vivo rapamycin-sensitive target and a member of the ataxia telangiectasia mutated (ATM)-related family of kinases that share homology with the catalytic domain of phosphatidylinositol 3-kinase. The function of RAFT1 in the rapamycin-sensitive pathway and its connection to downstream components of the pathway, such as p70 S6 kinase and 4E-BP1, are poorly understood. Here, we show that RAFT1 directly phosphorylates p70(S6k), 4E-BP1, and 4E-BP2 and that serum stimulates RAFT1 kinase activity with kinetics similar to those of p70(S6k) and 4E-BP1 phosphorylation. RAFT1 phosphorylates p70(S6k) on Thr-389, a residue whose phosphorylation is rapamycin-sensitive in vivo and necessary for S6 kinase activity. RAFT1 phosphorylation of 4E-BP1 on Thr-36 and Thr-45 blocks its association with the cap-binding protein, eIF-4E, in vitro, and phosphorylation of Thr-45 seems to be the major regulator of the 4E-BP1-eIF-4E interaction in vivo. RAFT1 phosphorylates p70(S6k) much more effectively than 4E-BP1, and the phosphorylation sites on the two proteins show little homology. This raises the possibility that, in vivo, an unidentified kinase analogous to p70(S6k) is activated by RAFT1 phosphorylation and acts at the rapamycin-sensitive phosphorylation sites of 4E-BP1.", "ai_intervention": "Biochemical (in vitro kinase assay)", "ai_target": "RAFT1/mTOR / p70 S6K / 4E-BP1", "ai_species": "In vitro", "ai_effect": "RAFT1/mTOR directly phosphorylates p70 S6K and 4E-BP1 – connects mTOR to translational regulators", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BUR1998/" }, { "sid": "SHW2004", "title": "The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress", "authors": "Shaw RJ; Kosmatka M; Bardeesy N; Cantley LC et al.", "year": 2004, "journal": "Proceedings of the National Academy of Sciences", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "LKB1-null MEFs; in vitro kinase assays", "peer_reviewed": "Yes", "doi": "10.1073/pnas.0308061100", "pmid": "14985505", "pmcid": "", "finding": "The paper that identified LKB1 as the upstream kinase for AMPK: LKB1 directly phosphorylates AMPK-alpha on Thr172, and LKB1-null cells cannot activate AMPK under energy stress. This is the canonical source for the LKB1 -> AMPK step that gates the whole energy-sensing arm upstream of mTORC1.\n", "abstract": "AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive. Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. We show that LKB1 directly phosphorylates Thr-172 of AMPKalpha in vitro and activates its kinase activity. LKB1-deficient murine embryonic fibroblasts show nearly complete loss of Thr-172 phosphorylation and downstream AMPK signaling in response to a variety of stimuli that activate AMPK. Reintroduction of WT, but not kinase-dead, LKB1 into these cells restores AMPK activity. Furthermore, we show that LKB1 plays a biologically significant role in this pathway, because LKB1-deficient cells are hypersensitive to apoptosis induced by energy stress. On the basis of these results, we propose a model to explain the apparent paradox that LKB1 is a tumor suppressor, yet cells lacking LKB1 are resistant to cell transformation by conventional oncogenes and are sensitive to killing in response to agents that elevate AMP. The role of LKB1/AMPK in the survival of a subset of genetically defined tumor cells may provide opportunities for cancer therapeutics.", "ai_intervention": "", "ai_target": "LKB1 -> AMPK (Thr172)", "ai_species": "Mouse cells", "ai_effect": "LKB1 directly phosphorylates and activates AMPK; LKB1-null cells fail to activate AMPK under energy stress", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SHW2004/" }, { "sid": "SAX2017", "title": "mTOR Signaling in Growth, Metabolism, and Disease", "authors": "Saxton RA; Sabatini DM", "year": 2017, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review article", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2017.02.004", "pmid": "28283069", "pmcid": "PMC5394987", "finding": "Comprehensive synthesis of mTORC1/mTORC2 signaling, growth regulation, metabolism, and disease relevance.\n", "abstract": "The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1 / mTORC2", "ai_species": "Review", "ai_effect": "Comprehensive review of mTOR in growth, metabolism and autophagy; deregulation in cancer, diabetes and aging", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAX2017/" }, { "sid": "SAB2017", "title": "Twenty-five years of mTOR: Uncovering the link from nutrients to growth", "authors": "Sabatini DM", "year": 2017, "journal": "Proceedings of the National Academy of Sciences of the United States of America", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1073/pnas.1716173114", "pmid": "29078414", "pmcid": "PMC5692607", "finding": "Sabatini's 25-year synthesis linking nutrient sensing to growth through mTOR.\n", "abstract": "In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ~25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work that has been particularly influential to me, as well as provide some personal reflections and stories. We now appreciate that, as part of two distinct complexes, mTORC1 and mTORC2, mTOR is the major regulator of growth (mass accumulation) in animals and is the key link between the availability of nutrients in the environment and the control of most anabolic and catabolic processes. Nutrients signal to mTORC1 through the lysosome-associated Rag GTPases and their many regulators and associated cytosolic and lysosomal nutrient sensors. mTOR signaling is deregulated in common diseases, like cancer and epilepsy, and mTORC1 is a well-validated modulator of aging in multiple model organisms. There is significant excitement around using mTORC1 inhibitors to treat cancer and neurological disease and, potentially, to improve healthspan and lifespan.", "ai_intervention": "Not applicable (historical review)", "ai_target": "mTOR", "ai_species": "Review", "ai_effect": "Personal historical account of the mTOR field from rapamycin's mechanism to discovery of the mTOR kinase", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAB2017/" }, { "sid": "STR2012", "title": "Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice", "authors": "Strong R; Miller RA; Harrison DE et al.", "year": 2012, "journal": "J Gerontol A Biol Sci Med Sci", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Negative_result", "model": "Mouse (genetically heterogeneous, ITP, 3 sites)", "peer_reviewed": "Yes", "doi": "10.1093/gerona/gls070", "pmid": "22451473", "pmcid": "PMC3598361", "finding": "None of five popular longevity compounds had a statistically significant effect on lifespan. The paper explicitly states the ITP's mission is to publish all results, positive or negative - the exact registry model this Atlas should emulate.\n", "abstract": "The National Institute on Aging Interventions Testing Program (ITP) was established to evaluate agents that are hypothesized to increase life span and/or health span in genetically heterogeneous mice. Each compound is tested in parallel at three test sites. It is the goal of the ITP to publish all results, negative or positive. We report here on the results of lifelong treatment of mice, beginning at 4 months of age, with each of five agents, that is, green tea extract (GTE), curcumin, oxaloacetic acid, medium-chain triglyceride oil, and resveratrol, on the life span of genetically heterogeneous mice. Each agent was administered beginning at 4 months of age. None of these five agents had a statistically significant effect on life span of male or female mice, by log-rank test, at the concentrations tested, although a secondary analysis suggested that GTE might diminish the risk of midlife deaths in females only.", "ai_intervention": "Resveratrol, green tea extract, curcumin, oxaloacetic acid, MCT oil (dietary)", "ai_target": "Nutrient/aging pathways (not mTOR-specific)", "ai_species": "Mouse (genetically heterogeneous, NIA ITP, 3 sites)", "ai_effect": "Lifespan test: these compounds did not robustly extend lifespan (largely negative ITP result)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/STR2012/" }, { "sid": "BRU1999", "title": "Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor", "authors": "Brunet A; Blenis J et al.", "year": 1999, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cell lines; primary neurons (in vitro)", "peer_reviewed": "Yes", "doi": "10.1016/S0092-8674(00)80595-4", "pmid": "10102273", "pmcid": "", "finding": "Akt phosphorylates the Forkhead transcription factor FKHRL1 (a FOXO family member), driving its cytoplasmic retention via 14-3-3 binding and blocking Fas-ligand-driven apoptosis — the discovery that placed FOXO transcription factors downstream of Akt/PI3K survival signalling.\n", "abstract": "Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase Akt, which then phosphorylates and inactivates components of the apoptotic machinery, including BAD and Caspase 9. In this study, we demonstrate that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors. In the presence of survival factors, Akt phosphorylates FKHRL1, leading to FKHRL1's association with 14-3-3 proteins and FKHRL1's retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation. Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.", "ai_intervention": "Akt/PKB overexpression + survival-factor withdrawal (genetic)", "ai_target": "Akt / FOXO (FKHRL1)", "ai_species": "Mammalian cell lines; primary neurons (in vitro)", "ai_effect": "Akt phosphorylates FKHRL1 (FOXO), blocking its nuclear translocation and Fas-ligand-driven apoptosis upon survival-factor withdrawal", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BRU1999/" }, { "sid": "DOR2006", "title": "S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth", "authors": "Dorrello NV; Pagano M et al.", "year": 2006, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/science.1130276", "pmid": "17053147", "pmcid": "", "finding": "S6K1 triggers betaTRCP-mediated degradation of the tumour suppressor PDCD4 to promote translation.\n", "abstract": "The tumor suppressor programmed cell death protein 4 (PDCD4) inhibits the translation initiation factor eIF4A, an RNA helicase that catalyzes the unwinding of secondary structure at the 5' untranslated region (5'UTR) of messenger RNAs (mRNAs). In response to mitogens, PDCD4 was rapidly phosphorylated on Ser67 by the protein kinase S6K1 and subsequently degraded via the ubiquitin ligase SCF(betaTRCP). Expression in cultured cells of a stable PDCD4 mutant that is unable to bind betaTRCP inhibited translation of an mRNA with a structured 5'UTR, resulted in smaller cell size, and slowed down cell cycle progression. We propose that regulated degradation of PDCD4 in response to mitogens allows efficient protein synthesis and consequently cell growth.", "ai_intervention": "Biochemical/genetic (S6K1, βTRCP, PDCD4)", "ai_target": "S6K1 / PDCD4 / eIF4A", "ai_species": "Mammalian cells", "ai_effect": "S6K1 phosphorylates PDCD4 (Ser67) triggering βTRCP-mediated degradation → promotes translation and cell growth", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DOR2006/" }, { "sid": "HAR2014", "title": "Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males", "authors": "Harrison DE; Miller RA et al.", "year": 2014, "journal": "Aging Cell", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (genetically heterogeneous, ITP, 3 sites)", "peer_reviewed": "Yes", "doi": "10.1111/acel.12170", "pmid": "24245565", "pmcid": "PMC3954939", "finding": "Beyond rapamycin, the same ITP program found acarbose extended male median lifespan by 22% - evidence that the registry surfaces real positive hits too, not only negative results.\n", "abstract": "Four agents--acarbose (ACA), 17-α-estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB)--were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. EST increased male median lifespan by 12% (P = 0.002), but did not lead to a significant effect on maximum lifespan. The benefits of EST were much stronger at one test site than at the other two and were not explained by effects on body weight. EST did not alter female lifespan. NDGA increased male median lifespan by 8-10% at three different doses, with P-values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. MB did not alter median lifespan of males or females, but did produce a small, statistically significant (6%, P = 0.004) increase in female maximum lifespan. These results provide new pharmacological models for exploring processes that regulate the timing of aging and late-life diseases, and in particular for testing hypotheses about sexual dimorphism in aging and health.", "ai_intervention": "Acarbose, 17-α-estradiol, NDGA, methylene blue (dietary/pharmacologic)", "ai_target": "Metabolic/aging pathways", "ai_species": "Mouse (genetically heterogeneous, NIA ITP, 3 sites)", "ai_effect": "Acarbose extended male median lifespan by 22% (female 5%); EST and NDGA extended lifespan preferentially in males", "ai_dose": "Acarbose at 1000 mg kg −1 diet (1000 ppm) from 4 months of age", "ai_samplesize": "", "ai_effectsize": "Male median lifespan increased by 22% (P < 0.0001); female median lifespan increased by 5% (P = 0.01) (pooled data).", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HAR2014/" }, { "sid": "MAN2018", "title": "TORC1 inhibition enhances immune function and reduces infections in the elderly", "authors": "Mannick JB; Morris M; Hockey HP; Roma G; Beibel M; et al.; Klickstein LB", "year": 2018, "journal": "Science Translational Medicine", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, phase 2a RCT (n=264, elderly)", "peer_reviewed": "Yes", "doi": "10.1126/scitranslmed.aaq1564", "pmid": "29997249", "pmcid": "", "finding": "The strongest human evidence that mTOR inhibition can rejuvenate a specific function of aging - immunity. In 264 elderly people, a low-dose combination that selectively hits TORC1 significantly reduced infections over the following year and boosted antiviral gene expression and flu-vaccine response. The follow-up to Mannick 2014.\n", "abstract": "Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant (= 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.", "ai_intervention": "Low-dose mTOR inhibitor (RAD001 + RTB101/BEZ235), 6 weeks", "ai_target": "TORC1", "ai_species": "Human – phase 2a RCT (n=264, elderly)", "ai_effect": "Combined low-dose TORC1 inhibition enhanced immune function and reduced infection rates in the elderly", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MAN2018/" }, { "sid": "ZHANG2026", "title": "Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma.", "authors": "Zhang C; Chao X; Williams SN; Wei X; DiGirolamo A; et al.", "year": 2026, "journal": "The Journal of clinical investigation", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Mechanism", "model": "Mouse + Human (HCC)", "peer_reviewed": "Yes", "doi": "10.1172/JCI206334", "pmid": "", "pmcid": "", "finding": "TSC1 loss drives non-canonical mTORC1-mediated TFEB nuclear translocation, promoting hepatocyte-to-biliary plasticity and spontaneous aggressive HCC in mice; Tsc1/Tfeb double knockout rescues the phenotype.\n", "abstract": "Hepatocellular carcinoma (HCC) is heterogeneous, and hepatocyte plasticity is linked to poorer patient outcomes. A subset of human HCC harboring Tuberous Sclerosis Complex 1 (TSC1) mutations exhibits more aggressive behavior. TFEB is a master regulator of lysosomal biogenesis and cell fate. Loss of hepatic Tsc1 led to increased phosphorylation of S6 and 4EBP1, with paradoxical increases in TFEB nuclear translocation and activation. L-Tsc1 KO mice showed increased hepatocyte plasticity, decreased HNF4alpha, increased YAP1 activation, and spontaneous HCC with increased SOX9 and CK19-positive biliary epithelial cell-like cells. L-Tsc1,Tfeb double KO rescued the phenotype.", "ai_intervention": "Tsc1 knockout (mTORC1 hyperactivation)", "ai_target": "mTORC1-TFEB", "ai_species": "Mouse + Human", "ai_effect": "Promotes hepatocyte plasticity and high-grade HCC malignancy", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZHANG2026/" }, { "sid": "CAO2026B", "title": "Dihydromyricetin attenuates fibrosis-associated features of hypertrophic scar with accompanying changes in PI3K/AKT/mTOR-related signaling.", "authors": "Cao P; Shi A; Wang Y; Hui S; Lyu G", "year": 2026, "journal": "Frontiers in Pharmacology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Rabbit ear hypertrophic scar model; human hypertrophic scar fibroblasts", "peer_reviewed": "Yes", "doi": "10.3389/fphar.2026.1862651", "pmid": "", "pmcid": "", "finding": "Dihydromyricetin reduced collagen I/III and α-SMA in hypertrophic scar fibroblasts and improved scar elevation in a rabbit ear model, with accompanying reductions in AKT and mTOR phosphorylation; causality was not established.\n", "abstract": "This study investigated whether dihydromyricetin (DHM) attenuates fibrosis-associated features in hypertrophic scar (HS) and whether these effects are accompanied by changes in PI3K/AKT/mTOR-related signalling. Network pharmacology identified overlapping targets between DHM and HS, highlighting AKT1 as a candidate hub target; molecular docking and 50-ns molecular dynamics simulation indicated a stable predicted DHM-AKT1 interaction. Hypertrophic scar tissues and fibroblasts showed increased collagen I, collagen III and alpha-SMA versus paired normal controls, and untreated HS fibroblasts had higher basal p-AKT/AKT and p-mTOR/mTOR ratios. DHM reduced CCK-8 viability signal and fibrosis-related markers with decreased AKT and mTOR phosphorylation. In a rabbit ear hypertrophic scar model, DHM improved gross scar appearance, reduced the scar elevation index and decreased collagen-positive area. The authors note the design cannot confirm a definitive causal regulatory relationship.", "ai_intervention": "Dihydromyricetin; LY294002 (PI3K inhibitor)", "ai_target": "PI3K/AKT/mTOR; AKT1", "ai_species": "Rabbit; human fibroblasts", "ai_effect": "Reduced fibrotic marker expression and scar elevation index; decreased AKT and mTOR phosphorylation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CAO2026B/" }, { "sid": "SANG2026", "title": "\"Trojan\" Methionine Probe Reveals PKM2 as a Methionine-Sensing Protein in the mTORC1 Pathway", "authors": "Sang Z; Zheng Y; Wang X; Wu C; Zhao J; Wang JJ; Sui S; Wang J", "year": 2026, "journal": "Journal of the American Chemical Society", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells (chemoproteomics / photoaffinity probe)", "peer_reviewed": "Yes", "doi": "10.1021/jacs.6c06772", "pmid": "42677553", "pmcid": "", "finding": "Identifies PKM2 as a direct methionine sensor for mTORC1. A photoaffinity methionine analogue plus chemoproteomics showed that PKM2 binds free methionine through a distinct recognition pocket — independently of its glycolytic enzyme activity — and transduces methionine availability to mTORC1 via the GATOR2 complex. Complements SAMTOR (GU2017), which reads the methionine metabolite SAM rather than methionine itself, and suggests a route to a pharmacological \"methionine pseudostarvation\" state.\n", "abstract": "Methionine (Met) plays a pivotal role in numerous cellular functions. Methionine restriction has been demonstrated to provide metabolic benefits in aging, obesity, diabetes and as an adjunct to cancer therapy. However, the methionine-sensing proteins and how cells directly sense the methionine level have remained elusive. In this study, we developed a photoaffinity analogue of methionine to capture proteins that specifically recognize and sense methionine in living cells. Using chemoproteomic profiling and biochemical validation, we found that PKM2 is a specific methionine sensor that transduces methionine availability signals through the interaction with the GATOR2 complex, which, in turn, modulates the downstream response of the mTORC1 pathway through a novel methionine-recognition pocket on PKM2. As our findings indicate that the sensing of methionine by PKM2 is independent of its enzymatic activity, we envision that disrupting the binding of methionine to PKM2 or stabilizing the PKM2-GATOR2 interaction would create a methionine pseudostarvation state in living cells, which holds promise as a novel therapeutic avenue that could emulate the physiological benefits of a methionine-restricted diet and circumvent the drawbacks of dietary methionine restriction.", "ai_intervention": "Photoaffinity methionine analogue (chemoproteomic capture); methionine restriction/repletion", "ai_target": "PKM2 / GATOR2 / mTORC1 (methionine sensing)", "ai_species": "Human cells (biochemistry / chemoproteomics)", "ai_effect": "PKM2 binds free methionine via a dedicated pocket and relays methionine availability to mTORC1 through GATOR2, independently of PKM2 enzymatic activity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SANG2026/" }, { "sid": "LIU2020", "title": "mTOR at the nexus of nutrition, growth, ageing and disease", "authors": "Liu GY; Sabatini DM", "year": 2020, "journal": "Nature Reviews Molecular Cell Biology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review (comprehensive)", "peer_reviewed": "Yes", "doi": "10.1038/s41580-019-0199-y", "pmid": "31937935", "pmcid": "PMC7102936", "finding": "The flagship modern review of the whole field, from Sabatini's own lab (Nature Reviews Molecular Cell Biology). Maps 25+ years of mTOR biology - how it senses nutrients, controls growth and autophagy, and goes wrong in cancer, neurodegeneration, metabolic disease and aging. The single best orientation document for the entire Atlas.\n", "abstract": "The mTOR pathway integrates a diverse set of environmental cues, such as growth factor signals and nutritional status, to direct eukaryotic cell growth. Over the past two and a half decades, mapping of the mTOR signalling landscape has revealed that mTOR controls biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Given the pathway's central role in maintaining cellular and physiological homeostasis, dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing. In this Review, we highlight recent advances in our understanding of the complex regulation of the mTOR pathway and discuss its function in the context of physiology, human disease and pharmacological intervention.", "ai_intervention": "Not applicable (review)", "ai_target": "mTOR", "ai_species": "Review", "ai_effect": "Reviews mTOR integrating nutrition, growth, ageing and disease via protein synthesis and autophagy", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LIU2020/" }, { "sid": "BANERJEE2026", "title": "Decoding the PI3K/Akt/mTOR-JAK/STAT signaling axis in multiple sclerosis: mechanistic crosstalk and therapeutic opportunities.", "authors": "Banerjee C; Singh RK; Choudhary D; Khan MN; Maurya PK; Khan Z et al.", "year": 2026, "journal": "Immunologic research", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1007/s12026-026-09808-9", "pmid": "", "pmcid": "", "finding": "Review mapping the mechanistic crosstalk between PI3K/Akt/mTOR and JAK/STAT pathways in MS neuroinflammation, identifying dual-pathway mTOR targeting as a therapeutic opportunity to reduce immune dysregulation and demyelination.\n", "abstract": "Multiple Sclerosis (MS) is a chronic immune-mediated neurodegenerative disorder characterized by demyelination, axonal injury, and progressive neurological dysfunction. Emerging evidence identifies PI3K/Akt/mTOR and JAK/STAT pathways as interconnected regulators of neuroinflammation and immune dysregulation in MS.", "ai_intervention": "mTOR inhibitors (proposed therapeutic)", "ai_target": "PI3K/Akt/mTOR-JAK/STAT axis", "ai_species": "N/A (review)", "ai_effect": "PI3K/Akt/mTOR-JAK/STAT crosstalk drives neuroinflammation in MS; mTOR inhibition proposed as treatment", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BANERJEE2026/" }, { "sid": "SAR2004", "title": "Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton", "authors": "Sarbassov DD; Ali SM; Kim DH; Guertin DA; Latek RR; Erdjument-Bromage H; Tempst P; Sabatini DM", "year": 2004, "journal": "Current Biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells + Drosophila", "peer_reviewed": "Yes", "doi": "10.1016/j.cub.2004.06.054", "pmid": "15268862", "pmcid": "", "finding": "Discovery of Rictor and the SECOND mTOR complex, mTORC2. Crucially showed this complex is NOT blocked by rapamycin and does not use Raptor - it controls the cytoskeleton via PKC. This is the paper that split mTOR biology into 'two faces' at the molecular level.\n", "abstract": "The mammalian TOR (mTOR) pathway integrates nutrient- and growth factor-derived signals to regulate growth, the process whereby cells accumulate mass and increase in size. mTOR is a large protein kinase and the target of rapamycin, an immunosuppressant that also blocks vessel restenosis and has potential anticancer applications. mTOR interacts with the raptor and GbetaL proteins to form a complex that is the target of rapamycin. Here, we demonstrate that mTOR is also part of a distinct complex defined by the novel protein rictor (rapamycin-insensitive companion of mTOR). Rictor shares homology with the previously described pianissimo from D. discoidieum, STE20p from S. pombe, and AVO3p from S. cerevisiae. Interestingly, AVO3p is part of a rapamycin-insensitive TOR complex that does not contain the yeast homolog of raptor and signals to the actin cytoskeleton through PKC1. Consistent with this finding, the rictor-containing mTOR complex contains GbetaL but not raptor and it neither regulates the mTOR effector S6K1 nor is it bound by FKBP12-rapamycin. We find that the rictor-mTOR complex modulates the phosphorylation of Protein Kinase C alpha (PKCalpha) and the actin cytoskeleton, suggesting that this aspect of TOR signaling is conserved between yeast and mammals.", "ai_intervention": "Biochemical/genetic (rictor)", "ai_target": "mTORC2 (rictor) / actin cytoskeleton", "ai_species": "Human cells + Drosophila", "ai_effect": "Defines rictor-mTOR (mTORC2) as a rapamycin-insensitive, raptor-independent pathway regulating the cytoskeleton", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAR2004/" }, { "sid": "LAB2015", "title": "mTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation", "authors": "Laberge RM; Sun Y; Orjalo AV; Patil CK; Freund A; et al.; Campisi J", "year": 2015, "journal": "Nature Cell Biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells + mouse xenografts", "peer_reviewed": "Yes", "doi": "10.1038/ncb3195", "pmid": "26147250", "pmcid": "PMC4691706", "finding": "Explained HOW rapamycin calms 'inflammaging'. Senescent cells spew inflammatory signals (the SASP) that damage surrounding tissue and even feed tumors. mTOR powers this by translating IL1A, the cytokine at the top of the cascade. Rapamycin selectively shuts it down - and blocked senescent cells from fueling prostate tumor growth in mice.\n", "abstract": "The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-κB transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.", "ai_intervention": "Rapamycin (mTORC1 inhibition)", "ai_target": "mTORC1 / IL1A / SASP", "ai_species": "Human cells + mouse xenografts", "ai_effect": "Rapamycin blunts the pro-tumorigenic senescence-associated secretory phenotype by suppressing IL1A translation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LAB2015/" }, { "sid": "MAR2012", "title": "MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB", "authors": "Martina JA; Chen Yong; Gucek M; Puertollano R", "year": 2012, "journal": "Autophagy", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells", "peer_reviewed": "Yes", "doi": "10.4161/auto.19653", "pmid": "22576015", "pmcid": "PMC3427256", "finding": "Pinned down the direct mTORC1-TFEB link: mTORC1 (docked at the lysosome via Ragulator) phosphorylates TFEB on Ser211, which traps it in the cytosol via 14-3-3 proteins. Inhibit mTORC1 and TFEB rushes to the nucleus to switch on autophagy - explaining how mTORC1 controls recycling at the level of gene transcription.\n", "abstract": "The mammalian target of rapamycin (MTOR) protein kinase complex is a key component of a pathway that regulates cell growth and proliferation in response to energy levels, hypoxia, nutrients and insulin. Inhibition of MTORC1 strongly induces autophagy by regulating the activity of the ULK protein kinase complex that is required for the formation of autophagosomes. However, the participation of MTORC1 in the expression of autophagy genes has not been characterized. Here we show that MTORC1 regulates nuclear localization and activity of the transcription factor EB (TFEB), a member of the bHLH leucine-zipper family of transcription factors that drives expression of autophagy and lysosomal genes. Under normal nutrient conditions, TFEB is phosphorylated in Ser211 in an MTORC1-dependent manner. This phosphorylation promotes association of TFEB with members of the YWHA (14-3-3) family of proteins and retention of the transcription factor in the cytosol. Pharmacological or genetic inhibition of MTORC1 causes dissociation of the TFEB/YWHA complex and rapid transport of TFEB to the nucleus where it increases transcription of multiple genes implicated in autophagy and lysosomal function. Active TFEB also associates with late endosomal/lysosomal membranes through interaction with the LAMTOR/RRAG/MTORC1 complex. Our results unveil a novel role for MTORC1 in the maintenance of cellular homeostasis by regulating autophagy at the transcriptional level.", "ai_intervention": "Genetic/pharmacologic (mTORC1)", "ai_target": "mTORC1 / TFEB", "ai_species": "Human cells", "ai_effect": "mTORC1 phosphorylates TFEB to block its nuclear transport → transcriptional control of autophagy genes", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MAR2012/" }, { "sid": "KNO2026", "title": "The hallmarks of protein and amino acid restriction in aging and longevity", "authors": "Knopf BA; Lamming DW", "year": 2026, "journal": "Cell Press Blue", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Cross-species review (yeast, worm, fly, rodent, human)", "peer_reviewed": "Yes", "doi": "10.1016/j.cpblue.2026.100079", "pmid": "42639474", "pmcid": "PMC13501984", "finding": "Defines the \"hallmarks\" of dietary protein restriction (PR) through the lens of aging: PR and restriction of specific essential amino acids — especially methionine, isoleucine and valine — improve metabolic health, healthspan and lifespan across organisms, with amino-acid composition (not just protein quantity) acting as a key determinant via nutrient-sensing pathways including mTORC1.\n", "abstract": "Despite widespread recommendations for higher protein intake during aging, increasing evidence suggests that dietary protein restriction (PR) promotes metabolic health, healthspan, and lifespan across diverse organisms. Mechanistic studies further demonstrate that restriction of specific amino acids, particularly methionine, isoleucine, and valine, recapitulates many of the benefits of PR, highlighting the specific amino acid composition of the diet as a key determinant of aging. Here, we define the hallmarks of PR through the lens of aging, examining how PR and restriction of specific essential amino acids impact metabolic health, nutrient sensing, senescence, mitochondrial function, and the epigenome. We also discuss the known and unknown roles of non-essential amino acids in healthy aging. Overall, this review provides a comprehensive overview of current knowledge regarding the benefits of PR and amino acid restriction for healthy aging and highlights the therapeutic potential of interventions based on these diets to promote healthspan and longevity.", "ai_intervention": "", "ai_target": "", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KNO2026/" }, { "sid": "PAR2014", "title": "Sestrins inhibit mTORC1 kinase activation through the GATOR complex", "authors": "Parmigiani A; Budanov AV et al.", "year": 2014, "journal": "Cell reports", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.celrep.2014.10.019", "pmid": "25457612", "pmcid": "PMC4303546", "finding": "Sestrins inhibit mTORC1 activation through the GATOR2 complex.\n", "abstract": "The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a sensor of different environmental conditions and regulator of cell growth, metabolism, and autophagy. mTORC1 is activated by Rag GTPases, working as RagA:RagB and RagC:RagD heterodimers. Rags control mTORC1 activity by tethering mTORC1 to the lysosomes where it is activated by Rheb GTPase. RagA:RagB, active in its GTP-bound form, is inhibited by GATOR1 complex, a GTPase-activating protein, and GATOR1 is in turn negatively regulated by GATOR2 complex. Sestrins are stress-responsive proteins that inhibit mTORC1 via activation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex. Here we report an AMPK-independent mechanism of mTORC1 inhibition by Sestrins mediated by their interaction with GATOR2. As a result of this interaction, the Sestrins suppress mTOR lysosomal localization in a Rag-dependent manner. This mechanism is potentially involved in mTORC1 regulation by amino acids, rotenone, and tunicamycin, connecting stress response with mTORC1 inhibition.", "ai_intervention": "Biochemical/genetic (Sestrins)", "ai_target": "Sestrins / GATOR / Rag / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "Sestrins inhibit mTORC1 kinase activation through the GATOR complex", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PAR2014/" }, { "sid": "KIM2019", "title": "mTOR as a central hub of nutrient signalling and cell growth", "authors": "Kim J; Guan KL et al.", "year": 2019, "journal": "Nature cell biology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1038/s41556-018-0205-1", "pmid": "30602761", "pmcid": "", "finding": "Review: mTOR as a central hub of nutrient signalling and cell growth.\n", "abstract": "The highly conserved protein kinase mechanistic target of rapamycin (mTOR; originally known as mammalian target of rapamycin) is a central cell growth regulator connecting cellular metabolism and growth with a wide range of environmental inputs as part of mTOR complex 1 (mTORC1) and mTORC2. In this Review, we introduce the landmark discoveries in the mTOR field, starting from the isolation of rapamycin to the molecular characterizations of key components of the mTORC signalling network with an emphasis on amino acid sensing, and discuss the perspectives of mTORC inhibitors in therapeutic applications.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1 / mTORC2", "ai_species": "Review", "ai_effect": "Reviews landmark mTOR discoveries and its role as a central hub of nutrient signalling and cell growth", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KIM2019/" }, { "sid": "LV2026", "title": "Age-associated decline of Lamtor5 drives immunosenescence and systemic aging via cGAS-mediated paracrine inflammation.", "authors": "Lv N, Tang Y, Zhang W, Zhang S, Zhang M", "year": 2026, "journal": "Cell Death and Differentiation", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1038/s41418-026-01823-5", "pmid": "42463581", "pmcid": "", "finding": "Age-driven loss of Lamtor5, a key lysosomal mTOR activation complex subunit, drives macrophage immunosenescence and systemic aging phenotypes in mice by unleashing cGAS-STING paracrine inflammation; Lamtor5 restoration in aged mice reverses these phenotypes.\n", "abstract": "Lamtor5 (late endosomal/lysosomal adapter, MAPK and mTOR activator 5) was identified as an age-dependent factor controlling innate immune cell function. Age-associated Lamtor5 decline impairs mTOR-dependent macrophage signaling, triggering cGAS-mediated paracrine inflammatory senescence. Restoring Lamtor5 in aged mice rescued immunosenescence and attenuated systemic aging phenotypes.", "ai_intervention": "Lamtor5 overexpression / restoration", "ai_target": "Lamtor5 / mTORC1 Ragulator complex / cGAS-STING", "ai_species": "Mouse", "ai_effect": "Decline of Lamtor5 reduces mTOR activity in aging macrophages, promoting immunosenescence; Lamtor5 restoration reverses aging phenotypes", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LV2026/" }, { "sid": "VAL2019", "title": "Molecular logic of mTORC1 signalling as a metabolic rheostat", "authors": "Valvezan AJ; Manning BD et al.", "year": 2019, "journal": "Nature metabolism", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1038/s42255-019-0038-7", "pmid": "32694720", "pmcid": "PMC12569966", "finding": "Review framing mTORC1 as a metabolic rheostat coupling growth signals to metabolism.\n", "abstract": "The protein kinase complex mechanistic target of rapamycin complex 1 (mTORC1) serves as a key conduit between growth signals and the metabolic processes underlying cell growth. The activation state of mTORC1 is controlled by intracellular nutrients and energy, as well as exogenous hormones and growth factors, thereby integrating local and systemic growth signals. Here we discuss the molecular logic of the mTORC1 signalling network and its importance in coupling growth signals to the control of cellular metabolism. After activation, mTORC1 promotes the conversion of available nutrients and energy into the major macromolecular species contributing to cellular mass, including proteins, nucleic acids and lipids, while suppressing the autophagic recycling of these macromolecules back into their nutrient constituents. Given that uncoupling of mTORC1 from its normal regulatory inputs contributes to many diseases-including cancer, genetic tumour syndromes, metabolic diseases, autoimmune diseases and neurological disorders-understanding the molecular logic of the mTORC1 network and how to modulate it may present therapeutic opportunities for treatment of a broad range of diseases and potentially even for the extension of lifespan.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1", "ai_species": "Review", "ai_effect": "Frames mTORC1 as a metabolic rheostat coupling growth signals to cellular metabolism", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/VAL2019/" }, { "sid": "FRI2006", "title": "mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s", "authors": "Frias MA; Sabatini DM et al.", "year": 2006, "journal": "Current biology : CB", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cub.2006.08.001", "pmid": "16919458", "pmcid": "", "finding": "mSin1 is required for mTORC2 assembly and Akt Ser473 phosphorylation; isoforms define distinct complexes.\n", "abstract": "The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that participates in at least two distinct multiprotein complexes, mTORC1 and mTORC2 . These complexes play important roles in the regulation of cell growth, proliferation, survival, and metabolism. mTORC2 is a hydrophobic motif kinase for the cell-survival protein Akt/PKB and, here, we identify mSin1 as a component of mTORC2 but not mTORC1. mSin1 is necessary for the assembly of mTORC2 and for its capacity to phosphorylate Akt/PKB. Alternative splicing generates at least five isoforms of the mSin1 protein , three of which assemble into mTORC2 to generate three distinct mTORC2s. Even though all mTORC2s can phosphorylate Akt/PKB in vitro, insulin regulates the activity of only two of them. Thus, we propose that cells contain several mTORC2 flavors that may phosphorylate Akt/PKB in response to different signals.", "ai_intervention": "Biochemical/genetic (mSin1)", "ai_target": "mTORC2 / mSin1 / Akt", "ai_species": "Mammalian cells", "ai_effect": "mSin1 is required for Akt/PKB phosphorylation; its isoforms define three distinct mTORC2 complexes", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/FRI2006/" }, { "sid": "YAN2006", "title": "Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity", "authors": "Yang Q; Guan KL et al.", "year": 2006, "journal": "Genes & development", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1101/gad.1461206", "pmid": "17043309", "pmcid": "PMC1619946", "finding": "Identified Sin1 as an essential TORC2 component required for Akt phosphorylation.\n", "abstract": "Target of rapamycin (TOR) is an evolutionally conserved protein kinase in eukaryotes and a central cell growth controller. TOR exists in two distinct complexes, termed TORC1 and TORC2. Mammalian TORC2 has recently been shown to possess kinase activity toward the C-terminal hydrophobic site of Akt/PKB. Here, we report that Sin1 is an essential component of TORC2 but not of TORC1, and functions similarly to Rictor, the defining member of TORC2, in complex formation and kinase activity. Knockdown of Sin1decreases Akt phosphorylation in both Drosophila and mammalian cells and diminishes Akt function in vivo. It also disrupts the interaction between Rictor and mTOR. Furthermore, Sin1 is required for TORC2 kinase activity in vitro. Disruption of the Rictor gene in mice results in embryonic lethality and ablates Akt phosphorylation. These data demonstrate that Sin1 together with Rictor are key components of mTORC2 and play an essential role in Akt phosphorylation and signaling.", "ai_intervention": "Biochemical/genetic (Sin1)", "ai_target": "TORC2 / Sin1 / Akt", "ai_species": "Mammalian cells", "ai_effect": "Sin1 is an essential TORC2 component required for complex formation and kinase activity toward Akt", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/YAN2006/" }, { "sid": "GUE2007", "title": "Defining the role of mTOR in cancer", "authors": "Guertin DA; Sabatini DM", "year": 2007, "journal": "Cancer Cell", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review article", "peer_reviewed": "Yes", "doi": "10.1016/j.ccr.2007.05.008", "pmid": "17613433", "pmcid": "", "finding": "Comprehensive review arguing mTOR signaling is commonly deregulated in human cancers, laying out the rationale for rapalog trials in oncology.\n", "abstract": "The mammalian target of rapamycin (mTOR) has emerged as a critical effector in cell-signaling pathways commonly deregulated in human cancers. This has led to the prediction that mTOR inhibitors may be useful in oncology, and derivatives of one such molecule, rapamycin (from which mTOR derives its name), are currently in clinical development. In this review, we discuss recent progress in understanding mTOR signaling, paying particular attention to its relevance in cancer. We further discuss the use of rapamycin in oncology and conclude with a discussion on the future of mTOR-targeted therapy.", "ai_intervention": "Not applicable (review)", "ai_target": "mTOR", "ai_species": "Review", "ai_effect": "Reviews the role of mTOR in cancer and the rationale for rapalog therapy", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GUE2007/" }, { "sid": "BEN2013", "title": "Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1", "authors": "Ben-Sahra I; Manning BD et al.", "year": 2013, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/science.1228792", "pmid": "23429703", "pmcid": "PMC3753690", "finding": "mTORC1-S6K1 stimulates de novo pyrimidine synthesis by phosphorylating CAD.\n", "abstract": "Cellular growth signals stimulate anabolic processes. The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase that senses growth signals to regulate anabolic growth and proliferation. Activation of mTORC1 led to the acute stimulation of metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolic pathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidine synthesis. Growth signaling through mTORC1 thus stimulates the production of new nucleotides to accommodate an increase in RNA and DNA synthesis needed for ribosome biogenesis and anabolic growth.", "ai_intervention": "Biochemical/genetic (mTORC1 / S6K1)", "ai_target": "mTORC1 / S6K1 / CAD (pyrimidine synthesis)", "ai_species": "Mammalian cells", "ai_effect": "mTORC1 via S6K1 stimulates de novo pyrimidine synthesis (CAD phosphorylation) to support growth", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BEN2013/" }, { "sid": "BAT2022", "title": "mTOR substrate phosphorylation in growth control", "authors": "Battaglioni S; Hall MN et al.", "year": 2022, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2022.04.013", "pmid": "35580586", "pmcid": "", "finding": "Review cataloguing direct mTOR substrates and how mTORC1/2 achieve substrate specificity.\n", "abstract": "The target of rapamycin (TOR), discovered 30 years ago, is a highly conserved serine/threonine protein kinase that plays a central role in regulating cell growth and metabolism. It is activated by nutrients, growth factors, and cellular energy. TOR forms two structurally and functionally distinct complexes, TORC1 and TORC2. TOR signaling activates cell growth, defined as an increase in biomass, by stimulating anabolic metabolism while inhibiting catabolic processes. With emphasis on mammalian TOR (mTOR), we comprehensively reviewed the literature and identified all reported direct substrates. In the context of recent structural information, we discuss how mTORC1 and mTORC2, despite having a common catalytic subunit, phosphorylate distinct substrates. We conclude that the two complexes recruit different substrates to phosphorylate a common, minimal motif.", "ai_intervention": "Not applicable (review)", "ai_target": "TORC1 / TORC2 substrates", "ai_species": "Review", "ai_effect": "Reviews mTOR substrate phosphorylation in the control of cell growth", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BAT2022/" }, { "sid": "BJE2010", "title": "Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster", "authors": "Bjedov I; Partridge L et al.", "year": 2010, "journal": "Cell Metabolism", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Drosophila melanogaster", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2009.11.010", "pmid": "20074526", "pmcid": "PMC2824086", "finding": "Feeding rapamycin extended fly lifespan through autophagy and reduced translation, and worked even in flies already on a lifespan-maximizing diet.\n", "abstract": "The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated, increases life span in evolutionarily diverse organisms including mammals. The central component of this pathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-described drug approved for human use. We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants. Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat. Analysis of the underlying mechanisms revealed that rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, through alterations to both autophagy and translation. Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms.", "ai_intervention": "Rapamycin (feeding)", "ai_target": "TOR", "ai_species": "Drosophila melanogaster", "ai_effect": "Feeding rapamycin extends fly lifespan via autophagy and reduced translation", "ai_dose": "Rapamycin administered by feeding from early adulthood at 50, 200, and 400 μM; 200 μM produced the largest increase in median life span. Concentration in flies fed 200 μM food was 3.3 ± 0.2 ng/mg wet weight.", "ai_samplesize": "Flies of diverse genetic (w1118, yw, ovoD mutant) and cytoplasmic (Wolbachia-free) backgrounds, and both sexes were tested.", "ai_effectsize": "Significant life span extension occurred at 50, 200, and 400 μM rapamycin, with 200 μM producing the largest increase in median life span. Rapamycin also significantly increased stress resistance (starvation, paraquat) and elevated triacylglyceride (TAG) levels, while reducing female fecundity in a dose-dependent manner.", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BJE2010/" }, { "sid": "NAP2020", "title": "A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dube syndrome", "authors": "Napolitano G; Ballabio A et al.", "year": 2020, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells; mouse", "peer_reviewed": "Yes", "doi": "10.1038/s41586-020-2444-0", "pmid": "32612235", "pmcid": "PMC7610377", "finding": "A substrate-specific mTORC1-TFEB pathway (RagC/D-dependent) drives Birt-Hogg-Dube kidney disease.\n", "abstract": "The mechanistic target of rapamycin complex 1 (mTORC1) is a key metabolic hub that controls the cellular response to environmental cues by exerting its kinase activity on multiple substrates. However, whether mTORC1 responds to diverse stimuli by differentially phosphorylating specific substrates is poorly understood. Here we show that transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is phosphorylated by mTORC1 via a substrate-specific mechanism that is mediated by Rag GTPases. Owing to this mechanism, the phosphorylation of TFEB-unlike other substrates of mTORC1, such as S6K and 4E-BP1- is strictly dependent on the amino-acid-mediated activation of RagC and RagD GTPases, but is insensitive to RHEB activity induced by growth factors. This mechanism has a crucial role in Birt-Hogg-Dube syndrome, a disorder that is caused by mutations in the RagC and RagD activator folliculin (FLCN) and is characterized by benign skin tumours, lung and kidney cysts and renal cell carcinoma. We found that constitutive activation of TFEB is the main driver of the kidney abnormalities and mTORC1 hyperactivity in a mouse model of Birt-Hogg-Dube syndrome. Accordingly, depletion of TFEB in kidneys of these mice fully rescued the disease phenotype and associated lethality, and normalized mTORC1 activity. Our findings identify a mechanism that enables differential phosphorylation of mTORC1 substrates, the dysregulation of which leads to kidney cysts and cancer.", "ai_intervention": "Genetic (FLCN / mTORC1)", "ai_target": "mTORC1 / TFEB / FLCN", "ai_species": "Human cells; mouse", "ai_effect": "A substrate-specific mTORC1 pathway phosphorylates TFEB and underlies Birt-Hogg-Dubé syndrome", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/NAP2020/" }, { "sid": "CHEN2026B", "title": "IGF2BP3-Mediated m6A Modification of OLR1 mRNA Promotes Immune Evasion in CRC via the PI3K/AKT/mTOR Pathway", "authors": "Chen W", "year": 2026, "journal": "Journal of Immunotherapy", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "CRC cell lines (human); TCGA dataset", "peer_reviewed": "Yes", "doi": "10.1097/CJI.0000000000000613", "pmid": "", "pmcid": "", "finding": "IGF2BP3 stabilizes OLR1 via m6A RNA modification, activating PI3K/AKT/mTOR signaling which suppresses CD8+ T cell anti-tumor activity and drives immune evasion in colorectal cancer.\n", "abstract": "OLR1 was upregulated in colorectal cancer (CRC) and negatively associated with CD8+ T-cell infiltration. Knockdown of OLR1 significantly enhanced the antitumor function of CD8+ T cells. Mechanistically, IGF2BP3 stabilized OLR1 mRNA in an m6A modification-dependent manner, thereby activating the PI3K/AKT/mTOR pathway to inhibit the antitumor activity of CD8+ T cells and promote immune evasion in CRC.", "ai_intervention": "OLR1 knockdown; IGF2BP3 modulation", "ai_target": "PI3K/AKT/mTOR pathway; OLR1; IGF2BP3; m6A RNA modification", "ai_species": "Human", "ai_effect": "m6A-stabilized OLR1 activates PI3K/AKT/mTOR to suppress CD8+ T cell function and enable CRC immune evasion; OLR1 knockdown restores T cell anti-tumor activity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHEN2026B/" }, { "sid": "CAC2010", "title": "Molecular interplay between mTOR, amyloid-beta, and Tau: effects on cognitive impairments", "authors": "Caccamo A; Majumder S; Richardson A; Strong R; Oddo S", "year": 2010, "journal": "Journal of Biological Chemistry", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "3xTg-AD transgenic mice", "peer_reviewed": "Yes", "doi": "10.1074/jbc.M110.100420", "pmid": "20178983", "pmcid": "PMC2857107", "finding": "Revealed a vicious cycle: amyloid-beta RAISES mTOR activity, and high mTOR in turn blocks the autophagy needed to clear amyloid and tau - so the disease feeds itself. Rapamycin broke the loop in 3xTg-AD mice, rescuing memory and lowering BOTH amyloid and tau, with autophagy shown to be required for the effect.\n", "abstract": "Accumulation of amyloid-beta (Abeta) and Tau is an invariant feature of Alzheimer disease (AD). The upstream role of Abeta accumulation in the disease pathogenesis is widely accepted, and there is strong evidence showing that Abeta accumulation causes cognitive impairments. However, the molecular mechanisms linking Abeta to cognitive decline remain to be elucidated. Here we show that the buildup of Abeta increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing mTOR signaling reduces Abeta levels, thereby highlighting an interrelation between mTOR signaling and Abeta. The mTOR pathway plays a central role in controlling protein homeostasis and hence, neuronal functions; indeed mTOR signaling regulates different forms of learning and memory. Using an animal model of AD, we show that pharmacologically restoring mTOR signaling with rapamycin rescues cognitive deficits and ameliorates Abeta and Tau pathology by increasing autophagy. Indeed, we further show that autophagy induction is necessary for the rapamycin-mediated reduction in Abeta levels. The results presented here provide a molecular basis for the Abeta-induced cognitive deficits and, moreover, show that rapamycin, an FDA approved drug, improves learning and memory and reduces Abeta and Tau pathology.", "ai_intervention": "Genetic/pharmacologic (amyloid-β; mTOR)", "ai_target": "mTOR / amyloid-β / Tau", "ai_species": "3xTg-AD transgenic mice", "ai_effect": "Amyloid-β accumulation increases mTOR signaling, linking Aβ to cognitive impairment", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CAC2010/" }, { "sid": "BIS2013", "title": "Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial", "authors": "Bissler JJ; Kingswood JC; Radzikowska E; Zonnenberg BA; Frost M; et al.; Budde K", "year": 2013, "journal": "Lancet", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, phase 3 RCT (n=118, TSC/LAM)", "peer_reviewed": "Yes", "doi": "10.1016/S0140-6736(12)61767-X", "pmid": "23312829", "pmcid": "", "finding": "The companion phase 3 RCT (n=118) to EXIST-1, targeting kidney tumors (angiomyolipomas) in tuberous sclerosis and LAM. Everolimus shrank them by >=50% in 42% of patients versus 0% on placebo. Together EXIST-1 and -2 sealed everolimus as a disease-modifying therapy across multiple TSC tumor types.\n", "abstract": "Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin (mTOR), and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis. The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function. Everolimus, a rapamycin derivative, inhibits the mTOR pathway by acting on the mTOR complex 1. We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata.\n\nIn this double-blind, placebo-controlled, phase 3 trial, patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter (defined by radiological assessment) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were randomly assigned, in a 2:1 fashion with the use of an interactive web response system, to receive oral everolimus 10 mg per day or placebo. The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50% reduction in total volume of target angiomyolipomas relative to baseline. This study is registered with ClinicalTrials.gov number NCT00790400.\n\n118 patients (median age 31·0 years; IQR 18·0–61·0) from 24 centres in 11 countries were randomly assigned to receive everolimus (n=79) or placebo (n=39). At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontination were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31–53%]) for everolimus and 0% (0 of 39 [0–9%]) for placebo (response rate difference 42% [24–58%]; one-sided Cochran-Mantel-Haenszel test p<0·0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]).\n\nEverolimus reduced angiomyolipoma volume with an acceptable safety profile, suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis.\n\nNovartis Pharmaceuticals.", "ai_intervention": "Everolimus", "ai_target": "mTORC1", "ai_species": "Human – phase 3 RCT (EXIST-2, n=118, TSC/LAM)", "ai_effect": "Everolimus reduced angiomyolipoma size vs placebo in TSC/LAM", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BIS2013/" }, { "sid": "DEMMINGS2026", "title": "ATF4 activates a transcriptional program that chronically suppresses mTOR activity and promotes neurodegeneration in Parkinson disease models", "authors": "Demmings MD; Kane EA; Tennyson EC; Hurley K; Zhao J; Cruickshanks NA; Ciz V; Krupa JM; Pasternak SH; Cregan SP", "year": 2026, "journal": "Cell Reports", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse (neurotoxin and alpha-synucleinopathy PD models) and cultured neurons", "peer_reviewed": "Yes", "doi": "10.1016/j.celrep.2026.117832", "pmid": "42599806", "pmcid": "", "finding": "Chronic integrated-stress-response signalling through ATF4 coordinately upregulates SESN2, DDIT4 and Trib3, which together suppress BOTH mTORC1 and mTORC2; this sustained mTOR inhibition drives dopaminergic neuron death via the pro-apoptotic BCL-2 family protein PUMA. Defines a maladaptive ISR/ATF4-to-mTOR axis in Parkinson disease models — a case where LESS mTOR activity is harmful, opposite to the usual longevity framing.\n", "abstract": "The integrated stress response (ISR) enables cells to adapt to diverse cellular stresses, but during chronic or unresolved stress it becomes maladaptive and is implicated in neurodegenerative diseases, including Parkinson disease (PD). The mechanisms underlying maladaptive ISR-driven neurodegeneration, however, remain poorly defined. Here, we find a critical pathway by which chronic ISR activation promotes neurodegeneration in neurotoxin and alpha-synucleinopathy models of PD in vitro and in vivo. We show that sustained activation of ATF4, the central ISR transcription factor, induces the coordinated transcriptional upregulation of SESN2, DDIT4, and Trib3, which cooperate to suppress both mTORC1 and mTORC2 activity. This ATF4-dependent inhibition of mTOR signaling promotes dopaminergic neuron death by facilitating activation of the pro apoptotic BCL 2 family protein PUMA. Together, these findings define a maladaptive ISR/ATF4-mTOR pathway with potential therapeutic relevance for neurodegenerative disorders characterized by chronic ISR activation.", "ai_intervention": "", "ai_target": "ATF4 / SESN2 / DDIT4 (REDD1) / TRIB3 / mTORC1 / mTORC2", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DEMMINGS2026/" }, { "sid": "MOS2018", "title": "mTOR signalling and cellular metabolism are mutual determinants in cancer", "authors": "Mossmann D; Hall MN et al.", "year": 2018, "journal": "Nature reviews. Cancer", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1038/s41568-018-0074-8", "pmid": "30425336", "pmcid": "", "finding": "Review of mTOR and cellular metabolism as mutual determinants in cancer.\n", "abstract": "Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. However, their efficacy as stand-alone therapies, similar to mTOR inhibitors, is limited. Here, we discuss how the interdependence of mTOR signalling and metabolism can be exploited for cancer therapy.", "ai_intervention": "Not applicable (review)", "ai_target": "mTOR", "ai_species": "Review", "ai_effect": "Reviews the reciprocal (mutual) control between mTOR signalling and cellular metabolism in cancer", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MOS2018/" }, { "sid": "BETZ2013", "title": "Where is mTOR and what is it doing there?", "authors": "Betz C; Hall MN et al.", "year": 2013, "journal": "The Journal of cell biology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1083/jcb.201306041", "pmid": "24385483", "pmcid": "PMC3840941", "finding": "Review of where mTOR localizes and its compartmentalized functions.\n", "abstract": "Target of rapamycin (TOR) forms two conserved, structurally distinct kinase complexes termed TOR complex 1 (TORC1) and TORC2. Each complex phosphorylates a different set of substrates to regulate cell growth. In mammals, mTOR is stimulated by nutrients and growth factors and inhibited by stress to ensure that cells grow only during favorable conditions. Studies in different organisms have reported localization of TOR to several distinct subcellular compartments. Notably, the finding that mTORC1 is localized to the lysosome has significantly enhanced our understanding of mTORC1 regulation. Subcellular localization may be a general principle used by TOR to enact precise spatial and temporal control of cell growth.", "ai_intervention": "Not applicable (review)", "ai_target": "TORC1 / TORC2 (subcellular localization)", "ai_species": "Review", "ai_effect": "Reviews where the mTOR complexes localize and what they do at each site", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BETZ2013/" }, { "sid": "SU2026", "title": "LncRNA DLX6-AS1 promotes necroptosis through PI3K/AKT/mTOR signaling pathway in myocardial ischemia/reperfusion injury mice", "authors": "Su Y; Mu L; Wang L; Li T; Zhang Q; Zhang Jun", "year": 2026, "journal": "Scientific Reports", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse; Rat H9c2 cells", "peer_reviewed": "Yes", "doi": "10.1038/s41598-026-50371-y", "pmid": "", "pmcid": "", "finding": "LncRNA DLX6-AS1 activates PI3K/AKT/mTOR signaling to promote necroptosis in myocardial ischemia-reperfusion injury; inhibiting DLX6-AS1 suppresses necroptosis and protects cardiomyocytes.\n", "abstract": "Myocardial ischemia/reperfusion injury (MIRI) leads to life-threatening myocardial infarction. Necroptosis is involved in MIRI. DLX6-AS1 overexpression caused cell damage and necroptosis and increased the expression of PI3K, p-PI3K, AKT, p-AKT, mTOR and p-mTOR. DLX6-AS1 inhibition suppressed necroptosis and cell damage through the PI3K/AKT/mTOR signaling pathway. Myocardial ischemia-reperfusion injury induces necroptosis, and DLX6-AS1 promotes this process through the PI3K/AKT/mTOR signaling pathway.", "ai_intervention": "DLX6-AS1 overexpression/inhibition", "ai_target": "PI3K/AKT/mTOR pathway; RIP1; RIP3; MLKL", "ai_species": "Mouse; Rat", "ai_effect": "DLX6-AS1 activates PI3K/AKT/mTOR, promoting necroptosis in cardiac I/R injury; knockdown is cardioprotective", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SU2026/" }, { "sid": "HARA2002", "title": "Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action", "authors": "Hara K; Maruki Y; Long X; Yoshino K; Oshiro N; Hidayat S; Tokunaga C; Avruch J; Yonezawa K", "year": 2002, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells + C. elegans RNAi", "peer_reviewed": "Yes", "doi": "10.1016/s0092-8674(02)00833-4", "pmid": "12150926", "pmcid": "", "finding": "Independent co-discovery of Raptor (same issue of Cell as Kim 2002). Showed Raptor is essential for mTOR to phosphorylate 4E-BP1 and S6K1, and that knocking it down in worms mimics loss of TOR - confirming Raptor as a core, conserved mediator of TOR action.\n", "abstract": "mTOR controls cell growth, in part by regulating p70 S6 kinase alpha (p70alpha) and eukaryotic initiation factor 4E binding protein 1 (4EBP1). Raptor is a 150 kDa mTOR binding protein that also binds 4EBP1 and p70alpha. The binding of raptor to mTOR is necessary for the mTOR-catalyzed phosphorylation of 4EBP1 in vitro, and it strongly enhances the mTOR kinase activity toward p70alpha. Rapamycin or amino acid withdrawal increases, whereas insulin strongly inhibits, the recovery of 4EBP1 and raptor on 7-methyl-GTP Sepharose. Partial inhibition of raptor expression by RNA interference (RNAi) reduces mTOR-catalyzed 4EBP1 phosphorylation in vitro. RNAi of C. elegans raptor yields an array of phenotypes that closely resemble those produced by inactivation of Ce-TOR. Thus, raptor is an essential scaffold for the mTOR-catalyzed phosphorylation of 4EBP1 and mediates TOR action in vivo.", "ai_intervention": "Biochemical/genetic (raptor; C. elegans RNAi)", "ai_target": "mTOR / raptor / 4EBP1 / S6K", "ai_species": "Human cells + C. elegans", "ai_effect": "Raptor binds mTOR and its substrates (4EBP1, p70S6K) and is required for mTOR-catalyzed phosphorylation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HARA2002/" }, { "sid": "ZEN2013", "title": "mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function", "authors": "Zeng H; Chi H et al.", "year": 2013, "journal": "Nature", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1038/nature12297", "pmid": "23812589", "pmcid": "PMC3759242", "finding": "mTORC1 couples immune signals and metabolism to establish regulatory T-cell function.\n", "abstract": "The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T-cell fate decisions. The activation of mTOR, which is the catalytic subunit of the mTORC1 and mTORC2 complexes, delivers an obligatory signal for the proper activation and differentiation of effector CD4(+) T cells, whereas in the regulatory T-cell (T(reg)) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of T(reg)-cell de novo differentiation and population expansion. However, whether mTOR signalling affects the homeostasis and function of T(reg) cells remains largely unexplored. Here we show that mTORC1 signalling is a pivotal positive determinant of T(reg)-cell function in mice. T(reg) cells have elevated steady-state mTORC1 activity compared to naive T cells. Signals through the T-cell antigen receptor (TCR) and interleukin-2 (IL-2) provide major inputs for mTORC1 activation, which in turn programs the suppressive function of T(reg) cells. Disruption of mTORC1 through Treg-specific deletion of the essential component raptor leads to a profound loss of T(reg)-cell suppressive activity in vivo and the development of a fatal early onset inflammatory disorder. Mechanistically, raptor/mTORC1 signalling in T(reg) cells promotes cholesterol and lipid metabolism, with the mevalonate pathway particularly important for coordinating T(reg)-cell proliferation and upregulation of the suppressive molecules CTLA4 and ICOS to establish Treg-cell functional competency. By contrast, mTORC1 does not directly affect the expression of Foxp3 or anti- and pro-inflammatory cytokines in T(reg) cells, suggesting a non-conventional mechanism for T(reg)-cell functional regulation. Finally, we provide evidence that mTORC1 maintains T(reg)-cell function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental rheostat in T(reg) cells to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of T(reg)-cell suppressive activity in immune homeostasis and tolerance.", "ai_intervention": "Genetic (mTORC1 in Treg cells)", "ai_target": "mTORC1", "ai_species": "Mouse", "ai_effect": "mTORC1 couples immune signals and metabolic programming to establish regulatory T-cell function", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "Normal health status of Cd4 cre Raptor fl/fl mice was likely due to impaired activation of conventional T cells, to be described elsewhere.", "atlas_url": "https://mtor-atlas.org/study/ZEN2013/" }, { "sid": "ROD2011", "title": "mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling", "authors": "Rodrik-Outmezguine VS; Rosen N et al.", "year": 2011, "journal": "Cancer discovery", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cancer cells", "peer_reviewed": "Yes", "doi": "10.1158/2159-8290.CD-11-0085", "pmid": "22140653", "pmcid": "PMC3227125", "finding": "mTOR kinase inhibition triggers feedback-dependent biphasic AKT reactivation, informing resistance.\n", "abstract": "mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound suppression of mTORC1 and accumulation of activated AKT phosphorylated on T308, but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in substantial cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways.", "ai_intervention": "ATP-competitive mTOR kinase inhibitors", "ai_target": "mTORC1/2 / AKT / RTK", "ai_species": "Cancer cells", "ai_effect": "In cancer cell lines, mTOR kinase inhibition causes feedback-dependent biphasic AKT regulation (transient inhibition then RTK-driven rebound)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ROD2011/" }, { "sid": "NAT2026", "title": "mTOR inhibition augments antitumor immune effector response by reprogramming the TP53-mutant, immune-cold HNSCC tumor microenvironment", "authors": "Nath P; Khandelwal A; Li C; Moore-Medlin T; Vasudevan SS; Alvarez VA; Franco OE; Gutkind JS; Nathan CO", "year": 2026, "journal": "Neoplasia", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Syngeneic mouse models of TP53-mutant HNSCC", "peer_reviewed": "Yes", "doi": "10.1016/j.neo.2026.101350", "pmid": "42570420", "pmcid": "", "finding": "In syngeneic TP53-mutant HNSCC mouse models, the mTOR inhibitor everolimus reprogrammed the immune-cold tumor microenvironment: it increased CD8+ T cell and dendritic cell infiltration, reduced Tregs and HIF-1α/VEGFA-driven MDSC recruitment, boosted TNF-α/CXCL10 chemokine signaling, and reduced PD-1/PD-L1 expression — restoring T-cell cytotoxic competence and suppressing tumor growth.\n", "abstract": "Resistance to immunotherapy remains a major clinical challenge in TP53-mutant head and neck squamous cell carcinoma (HNSCC), a disease subset characterized by immune exclusion, high recurrence, and poor outcomes. Given the constitutive activation of PI3K/AKT/mTOR signaling in TP53-mutant HNSCC and its role in disease progression, we investigated whether mTOR inhibition (mTORi) could overcome immune resistance and improve outcomes. We evaluated the effects of the mTOR inhibitor everolimus on tumor microenvironment (TME) changes, including immune cell infiltration, immune checkpoint expression, and key pathways associated with immune suppression and angiogenesis. Everolimus significantly suppressed tumor growth in syngeneic HNSCC models, increased intratumoral CD8+ T cell and dendritic cell infiltration while reducing regulatory T cell accumulation, induced a TNF-α/CXCL10 cytokine/chemokine response, inhibited the HIF-1α/VEGFA pathway, and attenuated PD-1/PD-L1 signaling. These findings demonstrate that mTORi with everolimus reverses multiple mechanisms of immune resistance and enhances anti-tumor T cell activity, supporting mTORi as a rational therapeutic strategy for TP53-mutant HNSCC.", "ai_intervention": "Everolimus (mTOR inhibitor)", "ai_target": "mTOR / PI3K-AKT-mTOR axis; downstream HIF-1α/VEGFA, PD-1/PD-L1", "ai_species": "Mouse (syngeneic TP53-mutant HNSCC models)", "ai_effect": "Reprograms immune-cold tumor microenvironment to an immune-active state; suppresses tumor growth", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/NAT2026/" }, { "sid": "VAL2017", "title": "mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability", "authors": "Valvezan AJ; Manning BD et al.", "year": 2017, "journal": "Cancer cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cancer cells; tumor", "peer_reviewed": "Yes", "doi": "10.1016/j.ccell.2017.09.013", "pmid": "29056426", "pmcid": "PMC5687294", "finding": "Hyperactive mTORC1 couples nucleotide synthesis to demand; imbalance drives replication stress in these cells.\n", "abstract": "The mechanistic target of rapamycin complex 1 (mTORC1) supports proliferation through parallel induction of key anabolic processes, including protein, lipid, and nucleotide synthesis. We hypothesized that these processes are coupled to maintain anabolic balance in cells with mTORC1 activation, a common event in human cancers. Loss of the tuberous sclerosis complex (TSC) tumor suppressors results in activation of mTORC1 and development of the tumor syndrome TSC. We find that pharmacological inhibitors of guanylate nucleotide synthesis have selective deleterious effects on TSC-deficient cells, including in mouse tumor models. This effect stems from replication stress and DNA damage caused by mTORC1-driven rRNA synthesis, which renders nucleotide pools limiting. These findings reveal a metabolic vulnerability downstream of mTORC1 triggered by anabolic imbalance.", "ai_intervention": "Genetic/pharmacologic (mTORC1; TSC loss)", "ai_target": "mTORC1 / nucleotide synthesis", "ai_species": "Cancer cells; tumor", "ai_effect": "mTORC1 couples nucleotide synthesis to demand, creating a targetable metabolic vulnerability in TSC-null cancer", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/VAL2017/" }, { "sid": "XU2026", "title": "High Responsiveness of Head and Neck Kaposiform Hemangioendothelioma Without Kasabach-Merritt Phenomenon to Sirolimus Monotherapy.", "authors": "Xu Y; Zhou J; Lan Y et al.", "year": 2026, "journal": "Pediatric Blood & Cancer", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Human (paediatric multicentre matched cohort, n=71)", "peer_reviewed": "Yes", "doi": "10.1002/1545-5017.70635", "pmid": "", "pmcid": "", "finding": "In 71 children with kaposiform haemangioendothelioma without Kasabach-Merritt phenomenon, head and neck lesions achieved a 100% 12-month radiologic response to sirolimus monotherapy versus 76% elsewhere; anatomical location was the only independent predictor of response.\n", "abstract": "Sirolimus is the cornerstone therapy for Kaposiform hemangioendothelioma (KHE). This multicentre study evaluated whether anatomical location independently predicts radiologic response to sirolimus monotherapy in KHE without Kasabach-Merritt phenomenon (KMP). 21 patients with head and neck KHE without KMP and 50 matched patients with non-head and neck KHE were treated with sirolimus monotherapy across five tertiary referral centres in China. The head and neck group achieved a 100% 12-month radiologic response rate versus 76% in the non-head and neck group (adjusted p = 0.012); near-complete involution was 81% versus 44% (adjusted p = 0.003). Head and neck location was the only independent predictor of radiologic response (OR = 12.34) and near-complete involution (OR = 5.87). No disease progression occurred in head and neck cases. Safety and quality-of-life outcomes were comparable between groups. ClinicalTrials.gov NCT04775173.", "ai_intervention": "Sirolimus monotherapy", "ai_target": "mTOR", "ai_species": "Human", "ai_effect": "100% 12-month radiologic response and 81% near-complete involution in head/neck KHE; no progression", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/XU2026/" }, { "sid": "KRISTIANSEN2026", "title": "Aging preserves mTORC1 but attenuates JNK-SMAD2L signaling sensitivity to passive stretch-induced tension development in isolated mouse skeletal muscle.", "authors": "Kristiansen JB; Andresen J; Jakobsgaard JE; Vissing K", "year": 2026, "journal": "Experimental gerontology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (ex vivo EDL muscle, adult 16-week vs old 24-month female mice)", "peer_reviewed": "Yes", "doi": "10.1016/j.exger.2026.113265", "pmid": "42551770", "pmcid": "", "finding": "Passive mechanical stretch activates mTORC1 signaling (mTOR, p70S6K, rpS6, 4E-BP1) equally in adult and old mouse skeletal muscle, but JNK-SMAD2L signaling sensitivity to the same stretch is blunted with age — suggesting age-related anabolic resistance in muscle arises alongside or downstream of mTORC1, not from a defect in mTORC1 mechanosensing itself.\n", "abstract": "Aging is associated with impaired skeletal muscle mass and function, often attributed to reduced sensitivity to anabolic stimuli. This study investigated whether aging influences the sensitivity of key anabolic signaling pathways to mechanical tension development in skeletal muscle. Using an ex vivo model, extensor digitorum longus (EDL) muscles from adult (16 weeks) and old (24 months) female mice were subjected to a standardized passive stretch protocol, with contralateral muscles serving as controls. Passive stretch significantly increased phosphorylation of mTORC1-related proteins (mTOR, p70S6K, rpS6, and 4E-BP1) in both adult and old muscles, with no significant differences between age groups, indicating preserved mTORC1 signaling sensitivity to mechanical tension with aging. In contrast, the magnitude of activation of JNK and SMAD2-L signaling was attenuated with aging.", "ai_intervention": "Passive mechanical stretch", "ai_target": "mTORC1 (p70S6K, rpS6, 4E-BP1)", "ai_species": "Mouse", "ai_effect": "mTORC1 mechanosensitivity preserved with aging; differential anabolic pathway response", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KRISTIANSEN2026/" }, { "sid": "KEN2016", "title": "The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging", "authors": "Kennedy BK; Lamming DW", "year": 2016, "journal": "Cell Metabolism", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review (metabolism/aging)", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2016.05.009", "pmid": "27304501", "pmcid": "PMC4910876", "finding": "A Cell Metabolism review framing mTOR as the 'grand conductor' that coordinates whole-body metabolism, tissue by tissue. Especially valuable for its clear-eyed section on WHY rapamycin causes metabolic side effects (the mTORC2 problem) - which is the main barrier to using it against aging. Pairs perfectly with Lamming's own 2012 mechanism paper.\n", "abstract": "Since the discovery that rapamycin, a small molecule inhibitor of the protein kinase mTOR (mechanistic target of rapamycin), can extend the lifespan of model organisms including mice, interest in understanding the physiological role and molecular targets of this pathway has surged. While mTOR was already well known as a regulator of growth and protein translation, it is now clear that mTOR functions as a central coordinator of organismal metabolism in response to both environmental and hormonal signals. This review discusses recent developments in our understanding of how mTOR signaling is regulated by nutrients and the role of the mTOR signaling pathway in key metabolic tissues. Finally, we discuss the molecular basis for the negative metabolic side effects associated with rapamycin treatment, which may serve as barriers to the adoption of rapamycin or similar compounds for the treatment of diseases of aging and metabolism.", "ai_intervention": "Not applicable (review)", "ai_target": "mTOR", "ai_species": "Review", "ai_effect": "Reviews mTOR as a central coordinator of organismal metabolism and aging", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KEN2016/" }, { "sid": "HAL2012", "title": "Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice", "authors": "Halloran J; Hussong SA; Burbank R; Podlutskaya N; Fischer KE; et al.; Galvan V", "year": 2012, "journal": "Neuroscience", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "C57BL/6 mice (lifespan behavior study)", "peer_reviewed": "Yes", "doi": "10.1016/j.neuroscience.2012.06.054", "pmid": "22750207", "pmcid": "PMC3454865", "finding": "Asked whether the lifespan-extending dose of rapamycin harms or helps the aging BRAIN. Reassuringly, it enhanced learning and memory in young mice, prevented age-related cognitive decline in old ones, and even reduced anxiety and depression-like behavior - linked to boosted brain monoamines. Cognitive benefit, not cost.\n", "abstract": "Aging is, by far, the greatest risk factor for most neurodegenerative diseases. In non-diseased conditions, normal aging can also be associated with declines in cognitive function that significantly affect quality of life in the elderly. It was recently shown that inhibition of Mammalian TOR (mTOR) activity in mice by chronic rapamycin treatment extends lifespan, possibly by delaying aging {Harrison, 2009 #4}{Miller, 2011 #168}. To explore the effect of chronic rapamycin treatment on normal brain aging we determined cognitive and non-cognitive components of behavior throughout lifespan in male and female C57BL/6 mice that were fed control- or rapamycin-supplemented chow. Our studies show that rapamycin enhances cognitive function in young adult mice and blocks age-associated cognitive decline in older animals. In addition, mice fed with rapamycin-supplemented chow showed decreased anxiety and depressive-like behavior at all ages tested. Levels of three major monoamines (norepinephrine, dopamine and 5-hydroxytryptamine) and their metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid) were significantly augmented in midbrain of rapamycin-treated mice compared to controls. Our results suggest that chronic, partial inhibition of mTOR by oral rapamycin enhances learning and memory in young adults, maintains memory in old C57BL/6J mice, and has concomitant anxiolytic and antidepressant-like effects, possibly by stimulating major monoamine pathways in brain.", "ai_intervention": "Rapamycin (chronic)", "ai_target": "mTOR", "ai_species": "C57BL/6 mice (lifespan behavior study)", "ai_effect": "Chronic rapamycin modulates cognitive and non-cognitive behavior across the lifespan in mice", "ai_dose": "2.24 mg rapamycin per kg body weight/day via rapamycin-supplemented chow (14 mg/kg food), ad libitum, for periods ranging from 8 to 40 weeks", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HAL2012/" }, { "sid": "LAP2012", "title": "mTOR signaling in growth control and disease", "authors": "Laplante M; Sabatini DM", "year": 2012, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review (comprehensive)", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2012.03.017", "pmid": "22500797", "pmcid": "PMC3331679", "finding": "The classic 2012 Cell review that became the standard reference for mTOR signaling. Comprehensive yet readable synthesis of how mTOR integrates environmental cues to control growth, and how its deregulation drives cancer, obesity, diabetes and neurodegeneration. A perfect companion to the newer 2020 review.\n", "abstract": "The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1 / mTORC2", "ai_species": "Review", "ai_effect": "Comprehensive review of mTOR signaling in growth control and disease (cancer, obesity, diabetes, neurodegeneration)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LAP2012/" }, { "sid": "MEN2023", "title": "A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer", "authors": "Meng D; Bandyopadhyay S et al.", "year": 2023, "journal": "Oncogene", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Human ER+/HER2- breast cancer cell lines; mouse patient-derived xenografts (PDX)", "peer_reviewed": "Yes", "doi": "10.1038/s41388-023-02737-z", "pmid": "37264081", "pmcid": "PMC10328828", "finding": "RMC-6272, a bi-steric molecule with >25-fold selectivity for mTORC1 over mTORC2, completely suppresses mTORC1 (hitting the rapamycin-resistant substrate 4E-BP1) and overcomes hormone- and CDK4/6-inhibitor resistance in breast cancer cell lines and PDX -- the preclinical basis for the RMC-5552 selective-inhibitor clinical program.\n", "abstract": "Activation of the PI3K-mTOR pathway is central to breast cancer pathogenesis including resistance to many targeted therapies. The mTOR kinase forms two distinct complexes, mTORC1 and mTORC2, and understanding which is required for the survival of malignant cells has been limited by tools to selectively and completely impair either subcomplex. To address this, we used RMC-6272, a bi-steric molecule with a rapamycin-like moiety linked to an mTOR active-site inhibitor that displays >25-fold selectivity for mTORC1 over mTORC2 substrates. Complete suppression of mTORC1 by RMC-6272 causes apoptosis in ER+/HER2- breast cancer cell lines, particularly in those that harbor mutations in PIK3CA or PTEN, due to inhibition of the rapamycin resistant, mTORC1 substrate 4EBP1 and reduction of the pro-survival protein MCL1. RMC-6272 reduced translation of ribosomal mRNAs, MYC target genes, and components of the CDK4/6 pathway, suggesting enhanced impairment of oncogenic pathways compared to the partial mTORC1 inhibitor everolimus. RMC-6272 maintained efficacy in hormone therapy-resistant acquired cell lines and patient-derived xenografts (PDX), showed increased efficacy in CDK4/6 inhibitor treated acquired resistant cell lines versus their parental counterparts, and was efficacious in a PDX from a patient experiencing resistance to CDK4/6 inhibition. Bi-steric mTORC1-selective inhibition may be effective in overcoming multiple forms of therapy-resistance in ER+ breast cancers.", "ai_intervention": "RMC-6272 (bi-steric mTORC1-selective inhibitor)", "ai_target": "mTORC1 (4E-BP1), >25-fold selective over mTORC2", "ai_species": "Human cell lines; mouse PDX", "ai_effect": "Overcomes hormone- and CDK4/6-inhibitor drug resistance via complete mTORC1 suppression", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MEN2023/" }, { "sid": "POL2008", "title": "Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration", "authors": "Polak P; Hall MN et al.", "year": 2008, "journal": "Cell metabolism", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (adipose raptor KO)", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2008.09.003", "pmid": "19046571", "pmcid": "", "finding": "Adipose raptor knockout yields lean, metabolically protected mice, revealing mTORC1's role in fat metabolism.\n", "abstract": "raptor is a specific and essential component of mammalian TOR complex 1 (mTORC1), a key regulator of cell growth and metabolism. To investigate a role of adipose mTORC1 in regulation of adipose and whole-body metabolism, we generated mice with an adipose-specific knockout of raptor (raptor(ad-/-)). Compared to control littermates, raptor(ad-/-) mice had substantially less adipose tissue, were protected against diet-induced obesity and hypercholesterolemia, and exhibited improved insulin sensitivity. Leanness was in spite of reduced physical activity and unaffected caloric intake, lipolysis, and absorption of lipids from the food. White adipose tissue of raptor(ad-/-) mice displayed enhanced expression of genes encoding mitochondrial uncoupling proteins characteristic of brown fat. Leanness of the raptor(ad-/-) mice was attributed to elevated energy expenditure due to mitochondrial uncoupling. These results suggest that adipose mTORC1 is a regulator of adipose metabolism and, thereby, controls whole-body energy homeostasis.", "ai_intervention": "Genetic – adipose-specific raptor knockout", "ai_target": "mTORC1 (raptor)", "ai_species": "Mouse (adipose raptor KO)", "ai_effect": "Adipose raptor loss yields lean mice protected from diet-induced obesity with enhanced mitochondrial respiration", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/POL2008/" }, { "sid": "KIM2008", "title": "Regulation of TORC1 by Rag GTPases in nutrient response", "authors": "Kim E; Guan KL et al.", "year": 2008, "journal": "Nature cell biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/ncb1753", "pmid": "18604198", "pmcid": "PMC2711503", "finding": "Rag GTPases mediate amino-acid signalling to TORC1 (parallel discovery to Sancak 2008).\n", "abstract": "TORC1 (target of rapamycin complex 1) has a crucial role in the regulation of cell growth and size. A wide range of signals, including amino acids, is known to activate TORC1. Here, we report the identification of Rag GTPases as activators of TORC1 in response to amino acid signals. Knockdown of Rag gene expression suppressed the stimulatory effect of amino acids on TORC1 in Drosophila melanogaster S2 cells. Expression of constitutively active (GTP-bound) Rag in mammalian cells activated TORC1 in the absence of amino acids, whereas expression of dominant-negative Rag blocked the stimulatory effects of amino acids on TORC1. Genetic studies in Drosophila also show that Rag GTPases regulate cell growth, autophagy and animal viability during starvation. Our studies establish a function of Rag GTPases in TORC1 activation in response to amino acid signals.", "ai_intervention": "Genetic/biochemical (Rag GTPases)", "ai_target": "TORC1 / Rag GTPases", "ai_species": "Mammalian cells (+ Drosophila S2)", "ai_effect": "Rag GTPases activate TORC1 in response to amino-acid signals", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KIM2008/" }, { "sid": "GUE2006", "title": "Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1", "authors": "Guertin DA; Stevens DM; Thoreen CC; Burds AA; Kalaany NY; Moffat J; Brown M; Fitzgerald KJ; Sabatini DM", "year": 2006, "journal": "Developmental Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Knockout mice (raptor/rictor/mLST8)", "peer_reviewed": "Yes", "doi": "10.1016/j.devcel.2006.10.007", "pmid": "17141160", "pmcid": "", "finding": "The foundational genetic 'dissection' of the two complexes in living mice. Deleting Raptor was lethal early (mTORC1 essential); deleting Rictor or mLST8 selectively knocked out mTORC2 signaling to Akt and PKCalpha but spared S6K1. This cleanly assigned jobs to each complex and showed mLST8 is an mTORC2-specific requirement in mice.\n", "abstract": "The mTOR kinase controls cell growth, proliferation, and survival through two distinct multiprotein complexes, mTORC1 and mTORC2. mTOR and mLST8 are in both complexes, while raptor and rictor are part of only mTORC1 and mTORC2, respectively. To investigate mTORC1 and mTORC2 function in vivo, we generated mice deficient for raptor, rictor, or mLST8. Like mice null for mTOR, those lacking raptor die early in development. However, mLST8 null embryos survive until e10.5 and resemble embryos missing rictor. mLST8 is necessary to maintain the rictor-mTOR, but not the raptor-mTOR, interaction, and both mLST8 and rictor are required for the hydrophobic motif phosphorylation of Akt/PKB and PKCalpha, but not S6K1. Furthermore, insulin signaling to FOXO3, but not to TSC2 or GSK3beta, requires mLST8 and rictor. Thus, mTORC1 function is essential in early development, mLST8 is required only for mTORC2 signaling, and mTORC2 is a necessary component of the Akt-FOXO and PKCalpha pathways.", "ai_intervention": "Genetic (raptor / rictor / mLST8 knockout mice)", "ai_target": "mTORC1 vs mTORC2 / Akt-FOXO / PKCα", "ai_species": "Knockout mice", "ai_effect": "mTORC2 (rictor/mLST8) is required for Akt-FOXO and PKCα signaling but not S6K1; raptor/mTOR-null mice die early", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GUE2006/" }, { "sid": "MADKOUR2026", "title": "Carvedilol attenuates PTZ-induced epileptogenesis: associations with hippocampal neuroinflammation and PI3K/AKT/mTOR-related alterations.", "authors": "Madkour AH; Abdelaziz RR; Nader MA; Elshal M", "year": 2026, "journal": "Scientific Reports", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Rat (PTZ kindling model)", "peer_reviewed": "Yes", "doi": "10.1038/s41598-026-67306-2", "pmid": "", "pmcid": "", "finding": "Prophylactic carvedilol reduced seizure scores, hippocampal damage and NLRP3-driven neuroinflammation in PTZ-kindled rats, with accompanying changes in PI3K/AKT/mTOR-related protein expression; the authors explicitly state causality was not established.\n", "abstract": "Epileptogenesis is a multifactorial process driven by persistent neuroinflammation, oxidative stress and dysregulated intracellular signalling. This study investigated prophylactic carvedilol in the PTZ-induced kindling model. Repeated PTZ administration produced progressive behavioural seizure development, impaired open-field performance, hippocampal neuronal damage, reduced GABA, increased oxidative stress and inflammatory mediators, altered hippocampal NLRP3 expression and changes in PI3K-, AKT- and mTOR-related protein expression. Carvedilol treatment was associated with lower seizure scores, improved open-field performance, preserved hippocampal architecture, restored GABA content, attenuated oxidative and inflammatory alterations, reduced NLRP3 and changes in PI3K/AKT/mTOR-related measurements. The authors note these findings demonstrate associations only and do not establish direct pathway-specific causality.", "ai_intervention": "Carvedilol (prophylactic)", "ai_target": "PI3K/AKT/mTOR; NLRP3", "ai_species": "Rat", "ai_effect": "Reduced seizure severity and hippocampal injury; associative (non-causal) changes in PI3K/AKT/mTOR signalling", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MADKOUR2026/" }, { "sid": "HE2026", "title": "An ANGPTL8-AKT2-mTOR Axis Drives Adipose Senescence and Aging-Related Functional Decline", "authors": "He Y; Pan L; Ping W et al.", "year": 2026, "journal": "Aging Cell", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Human cohort (correlation) + mouse (Angptl8-/- knockout, lifespan) + primary adipocyte/cell studies", "peer_reviewed": "Yes", "doi": "10.1111/acel.70671", "pmid": "42605193", "pmcid": "", "finding": "Identifies ANGPTL8 as an endocrine driver of adipose-tissue aging: circulating ANGPTL8 tracked with biological age and mortality risk in a large human cohort, and genetic deletion of Angptl8 in mice extended lifespan and reduced senescence markers. Mechanistically, ANGPTL8 binds AKT2 and drives the AKT-mTOR-S6K axis to promote adipocyte senescence; blocking that axis abolished the pro-senescent effect.\n", "abstract": "", "ai_intervention": "", "ai_target": "", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HE2026/" }, { "sid": "HSI2010", "title": "Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E", "authors": "Hsieh AC; Ruggero D et al.", "year": 2010, "journal": "Cancer cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cancer cells; mouse", "peer_reviewed": "Yes", "doi": "10.1016/j.ccr.2010.01.021", "pmid": "20227039", "pmcid": "PMC2901095", "finding": "Genetic dissection shows the 4E-BP1-eIF4E axis mediates oncogenic mTOR signalling and is druggable.\n", "abstract": "We genetically dissect the contribution of the most prominent downstream translational components of mTOR signaling toward Akt-driven lymphomagenesis. While phosphorylation of rpS6 is dispensable for cancer formation, 4EBP-eIF4E exerts significant control over cap-dependent translation, cell growth, cancer initiation, and progression. This effect is mediated at least in part through 4EBP-dependent control of Mcl-1 expression, a key antiapoptotic protein. By using an active site inhibitor of mTOR, PP242, we show a marked therapeutic response in rapamycin-resistant tumors. The therapeutic benefit of PP242 is mediated through inhibition of mTORC1-dependent 4EBP-eIF4E hyperactivation. Thus, the 4EBP-eIF4E axis downstream of mTOR is a druggable mediator of translational control and Akt-mediated tumorigenesis that has important implications for the treatment of human cancers.", "ai_intervention": "Genetic dissection (4EBP-eIF4E, rpS6)", "ai_target": "mTOR / 4EBP-eIF4E", "ai_species": "Cancer cells; mouse", "ai_effect": "4EBP-eIF4E (not rpS6) controls cap-dependent translation driving Akt lymphomagenesis – a druggable addiction", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HSI2010/" }, { "sid": "GIL2026", "title": "Association of rapamycin treatment with the modulation of purine metabolism, reduced microglial inflammatory responses, improved mitochondrial energy metabolism, and alleviation of fatigue symptoms in ME/CFS subjects: pilot findings from phase-II observational study", "authors": "Brooke Gile, Sarojini Bulbule, Mubaraq A Toriola, Brian T Ruan, Shabnam Marium, Anna Benko, Stephanie Grach, Michael Mueller, Lucinda Bateman, Jennifer Bell, Brayden Yellman, Jon Berner, Bela Chheda, David Kaufman, Gunnar Gottschalk, Avik Roy", "year": 2026, "journal": "Journal of Translational Medicine", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Human (ME/CFS patients)", "peer_reviewed": "Yes", "doi": "10.1186/s12967-026-08575-3", "pmid": "42432754", "pmcid": "PMC13374298", "finding": "Low-dose rapamycin in ME/CFS patients reduced fatigue symptoms, modulated purine biosynthesis via IMP dehydrogenase inhibition, reduced microglial inflammatory responses, and improved mitochondrial energy metabolism in a phase-II observational pilot study.\n", "abstract": "Phase II observational pilot trial. Low-dose rapamycin significantly reduced fatigue symptoms in ME/CFS subjects. LCMS-based quantification revealed differential regulation of purine biosynthetic intermediates (IMP to XMP and HPX pathway). Rapamycin reduces IMP dehydrogenase activity, limiting IMP to XMP conversion. Altered purine levels impair mitochondrial energy metabolism and contribute to microglial inflammation. No placebo group; results biased to responders. NCT06257420.", "ai_intervention": "Low-dose rapamycin", "ai_target": "mTORC1 / IMP dehydrogenase / purine biosynthesis / mitochondria", "ai_species": "Human", "ai_effect": "Reduced fatigue, improved mitochondrial energy metabolism, modulated purine biosynthesis, reduced microglial inflammation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GIL2026/" }, { "sid": "GAR2003", "title": "Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2", "authors": "Garami A; Thomas G et al.", "year": 2003, "journal": "Molecular cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Drosophila & mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/s1097-2765(03)00220-x", "pmid": "12820960", "pmcid": "", "finding": "Insulin activates Rheb-GTP, inhibited by TSC1/2, positioning Rheb as the direct upstream activator of TOR.\n", "abstract": "Tumor suppressor genes evolved as negative effectors of mitogen and nutrient signaling pathways, such that mutations in these genes can lead to pathological states of growth. Tuberous sclerosis (TSC) is a potentially devastating disease associated with mutations in two tumor suppressor genes, TSC1 and 2, that function as a complex to suppress signaling in the mTOR/S6K/4E-BP pathway. However, the inhibitory target of TSC1/2 and the mechanism by which it acts are unknown. Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin-mediated Rheb activation is PI3K dependent. Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation. Finally, coexpression of a human TSC2 cDNA harboring a disease-associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1.", "ai_intervention": "Genetic/biochemical (Rheb, TSC1/2)", "ai_target": "Rheb / TSC1-TSC2 / mTOR-S6K-4EBP", "ai_species": "Drosophila & mammalian cells", "ai_effect": "Insulin activates Rheb, a mediator of mTOR/S6K/4E-BP signaling, and this is inhibited by TSC1/2", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GAR2003/" }, { "sid": "SIN2013", "title": "Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation", "authors": "Sinclair LV; Cantrell DA et al.", "year": 2013, "journal": "Nature immunology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse T cells", "peer_reviewed": "Yes", "doi": "10.1038/ni.2556", "pmid": "23525088", "pmcid": "PMC3672957", "finding": "Antigen-receptor-driven System-L (SLC7A5) amino-acid transport controls mTORC1 and T-cell differentiation.\n", "abstract": "T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells.", "ai_intervention": "Genetic (Slc7a5, T-cell receptor)", "ai_target": "Slc7a5 (System L) / leucine / mTORC1", "ai_species": "Mouse T cells", "ai_effect": "Antigen-receptor-driven Slc7a5 amino-acid transport coordinates the metabolic reprogramming essential for T-cell differentiation", "ai_dose": "TCR triggering with cognate peptide for 4h or 20h; IL-2 at 20 ng/ml or 1.25 ng/ml for 20h; BCH at 10 mM or 50 mM; rapamycin at 20 nM; CsA at 100 nM; glutamine at 2 mM; leucine at 0.4 mM.", "ai_samplesize": "minimum of 3 experiments done in triplicates (Fig. 1a,c,d); 6 mice (Fig. 1b); 3 experiments (Fig. 2); 3 mice per group (Fig. 3a); 2 collated experiments (Fig. 3d-f).", "ai_effectsize": "TCR triggering increased phenylalanine transport (p=0.0147 at 4h, p<0.0001 at 20h); CsA abrogated TCR-induced system L activity (p=0.0242) and Slc7a5 mRNA expression (p=0.0070); Slc7a5 haplo-insufficient T cells showed a 50% reduction in System L transporter activity.", "ai_limitations": "Systemic deletion of Slc7a5 causes embryonic lethality, necessitating the use of haplo-insufficient mice.", "atlas_url": "https://mtor-atlas.org/study/SIN2013/" }, { "sid": "KRU2010", "title": "Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis", "authors": "Krueger DA et al.", "year": 2010, "journal": "New England Journal of Medicine", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, open-label trial (n=28)", "peer_reviewed": "Yes", "doi": "10.1056/NEJMoa1001671", "pmid": "21047224", "pmcid": "", "finding": "In patients whose TSC1/TSC2 mutations cause brain tumors, everolimus shrank tumor volume by 30%+ in three-quarters of patients. Open-label and uncontrolled (n=28); randomised confirmation came later (FRA2013).\n", "abstract": "Neurosurgical resection is the standard treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex.\n\nPatients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas were eligible for this open-label study. The primary efficacy end point was the change in volume of subependymal giant-cell astrocytomas between baseline and 6 months. We gave everolimus orally, at a dose of 3.0 mg per square meter of body-surface area, to achieve a trough concentration of 5 to 15 ng per milliliter.\n\nWe enrolled 28 patients. Everolimus therapy was associated with a clinically meaningful reduction in volume of the primary subependymal giant-cell astrocytoma, as assessed on independent central review (P<0.001 for baseline vs. 6 months), with a reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Marked reductions were seen within 3 months and were sustained. There were no new lesions, worsening hydrocephalus, evidence of increased intracranial pressure, or necessity for surgical resection or other therapy for subependymal giant-cell astrocytoma. Of the 16 patients for whom 24-hour video electroencephalography data were available, seizure frequency for the 6-month study period (vs. the previous 6-month period) decreased in 9, did not change in 6, and increased in 1 (median change, -1 seizure; P=0.02). The mean (±SD) score on the validated Quality-of-Life in Childhood Epilepsy questionnaire (on which scores can range from 0 to 100, with higher scores indicating a better quality of life) was improved at 3 months (63.4±12.4) and 6 months (62.1±14.2) over the baseline score (57.8±14.0). Single cases of grade 3 treatment-related sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia were reported.\n\nEverolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed. (Funded by Novartis; ClinicalTrials.gov number, NCT00411619.).", "ai_intervention": "Everolimus", "ai_target": "mTOR", "ai_species": "Human – open-label trial (n=28, TSC)", "ai_effect": "Everolimus reduced subependymal giant-cell astrocytoma (SEGA) volume in tuberous sclerosis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KRU2010/" }, { "sid": "SAX2016", "title": "Mechanism of arginine sensing by CASTOR1 upstream of mTORC1", "authors": "Saxton RA; Sabatini DM et al.", "year": 2016, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Structure; cells", "peer_reviewed": "Yes", "doi": "10.1038/nature19079", "pmid": "27487210", "pmcid": "PMC4988899", "finding": "CASTOR1 is a direct arginine sensor upstream of mTORC1; structure reveals the arginine-binding mechanism.\n", "abstract": "The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4, 5, 6, 7). Arginine activates mTORC1 upstream of the Rag family of GTPases, through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting Cellular Arginine Sensor for mTORC1 (CASTOR1). However, the mechanism by which the mTORC1 pathway detects and transmits this arginine signal has been elusive. Here, we present the 1.8 A crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two Aspartate kinase, Chorismate mutase, TyrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity. Together, these results establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor.", "ai_intervention": "Structural/biochemical (CASTOR1)", "ai_target": "CASTOR1 / GATOR2 / mTORC1 (arginine)", "ai_species": "Structure; cells", "ai_effect": "CASTOR1 is a direct arginine sensor upstream of mTORC1; structure reveals the arginine-binding mechanism", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAX2016/" }, { "sid": "SAU2003", "title": "Rheb promotes cell growth as a component of the insulin/TOR signalling network", "authors": "Saucedo LJ; Edgar BA et al.", "year": 2003, "journal": "Nature cell biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Drosophila", "peer_reviewed": "Yes", "doi": "10.1038/ncb996", "pmid": "12766776", "pmcid": "", "finding": "Rheb promotes cell growth as a component of the insulin/TOR network in Drosophila.\n", "abstract": "Insulin signalling is a potent stimulator of cell growth and has been proposed to function, at least in part, through the conserved protein kinase TOR (target of rapamycin). Recent studies suggest that the tuberous sclerosis complex Tsc1-Tsc2 may couple insulin signalling to Tor activity. However, the regulatory mechanism involved remains unclear, and additional components are most probably involved. In a screen for novel regulators of growth, we identified Rheb (Ras homologue enriched in brain), a member of the Ras superfamily of GTP-binding proteins. Increased levels of Rheb in Drosophila melanogaster promote cell growth and alter cell cycle kinetics in multiple tissues. In mitotic tissues, overexpression of Rheb accelerates passage through G1-S phase without affecting rates of cell division, whereas in endoreplicating tissues, Rheb increases DNA ploidy. Mutation of Rheb suspends larval growth and prevents progression from first to second instar. Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR. Levels of rheb mRNA are rapidly induced in response to protein starvation, and overexpressed Rheb can drive cell growth in starved animals, suggesting a role for Rheb in the nutritional control of cell growth.", "ai_intervention": "Genetic (Rheb screen)", "ai_target": "Rheb / TOR", "ai_species": "Drosophila", "ai_effect": "Rheb promotes cell growth as a component of the insulin/TOR signalling network", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAU2003/" }, { "sid": "ROM2016", "title": "Safety of two-year caloric restriction in non-obese healthy individuals", "authors": "Romashkan SV; Ravussin E et al.", "year": 2016, "journal": "Oncotarget", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, RCT (CALERIE trial, n=218)", "peer_reviewed": "Yes", "doi": "10.18632/oncotarget.8093", "pmid": "26992237", "pmcid": "PMC4991370", "finding": "Two years of sustained 25% caloric restriction in healthy non-obese adults was safe overall, though it lowered bone density more than controls.\n", "abstract": "The extent to which sustained caloric restriction (CR) in healthy non-obese adults is safe has not been previously investigated.\n\nAssess the safety and tolerability of sustained two-year CR intervention in healthy, non-obese adults.\n\nA multi-center, randomized controlled trial. Participants were randomized using a 2:1 allocation in favor of 25% CR vs. Ad-Libitum intake (AL). Adverse and serious adverse events (AE, SAE), safety laboratory tests, and other safety parameters were closely monitored.\n\nThree participants were withdrawn from the CR intervention because of the safety concerns. No deaths and one SAE was reported by participants in the CR group. Although the difference in AE between AL and CR groups was not significant, within the CR group, the incidence of nervous system (p = 0.02), musculoskeletal (p = 0.02) and reproductive system (p = 0.002) disorders was significantly higher in the normal-weight than in the overweight participants. At months 12 and 24, bone mineral densities at the lumbar spine, total hip, and femoral neck of participants in the CR group were significantly lower than in those in the AL group.\n\nTwo-years of CR at levels achieved in CALERIE was safe and well tolerated. Close monitoring for excessive bone loss and anemia is important.", "ai_intervention": "Caloric restriction (25%, 2 years)", "ai_target": "Nutrient-sensing / mTOR (indirect)", "ai_species": "Human – RCT (CALERIE, n=218, non-obese)", "ai_effect": "Sustained 25% caloric restriction was safe and well tolerated in healthy non-obese adults over 2 years", "ai_dose": "Caloric restriction ~25% (achieved ~480 kcal/day deficit in first 6 months) for 2 years vs ad libitum; multicenter RCT (CALERIE).", "ai_samplesize": "218 participants in safety analysis (66 male / 152 female); 30 discontinued (26 CR, 4 AL).", "ai_effectsize": "Sustained 25% CR was safe and well tolerated over 2 years; most lab abnormalities were small and not significantly different from control.", "ai_limitations": "Between-group differences mostly not statistically significant; a few treatment-resistant hematocrit decreases (2 withdrawn); healthy non-obese cohort only.", "atlas_url": "https://mtor-atlas.org/study/ROM2016/" }, { "sid": "CHU2019", "title": "Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial", "authors": "Chung CL; Lawrence I; Hoffman M; Elgindi D; Nadhan K; et al.; Sell C", "year": 2019, "journal": "GeroScience", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, RCT (skin, age >40; n=17 completed)", "peer_reviewed": "Yes", "doi": "10.1007/s11357-019-00113-y", "pmid": "31761958", "pmcid": "PMC6925069", "finding": "A small human trial testing whether rapamycin can slow aging in a tissue you can actually see and biopsy - skin. Topical rapamycin significantly lowered the senescence marker p16 and raised collagen VII, with visible improvement in skin appearance. Early but tangible human evidence for rapamycin as an anti-aging agent.\n", "abstract": "Aging is a major risk factor for the majority of human diseases, and the development of interventions to reduce the intrinsic rate of aging is expected to reduce the risk for age-related diseases including cardiovascular disease, cancer, and dementia. In the skin, aging manifests itself in photodamage and dermal atrophy, with underlying tissue reduction and impaired barrier function. To determine whether rapamycin, an FDA-approved drug targeting the mechanistic target of rapamycin (mTOR) complex, can reduce senescence and markers of aging in human skin, an exploratory, placebo-controlled, interventional trial was conducted in a clinical dermatology setting. Participants were greater than 40 years of age with evidence of age-related photoaging and dermal volume loss and no major morbidities. Thirty-six participants were enrolled in the study, and nineteen discontinued or were lost to follow-up. A significant (P = 0.008) reduction in p16protein levels and an increase in collagen VII protein levels (P = 0.0077) were observed among participants at the end of the study. Clinical improvement in skin appearance was noted in multiple participants, and immunohistochemical analysis revealed improvement in histological appearance of skin tissue. Topical rapamycin reduced the expression of the p16protein consistent with a reduction in cellular senescence. This change was accompanied by relative improvement in clinical appearance of the skin and histological markers of aging and by an increase in collagen VII, which is critical to the integrity of the basement membrane. These results indicate that rapamycin treatment is a potential anti-aging therapy with efficacy in humans.Trial registration ClinicalTrials.gov Identifier: NCT03103893.", "ai_intervention": "Topical rapamycin", "ai_target": "mTORC1", "ai_species": "Human – RCT (skin, age >40, n=17 completed)", "ai_effect": "Topical rapamycin reduced senescence markers and signs of aging in human skin", "ai_dose": "Topical rapamycin 10 microM cream vs placebo (DMSO), applied to the hands; no detectable systemic rapamycin (LC/MS LOD 1 ng/ml).", "ai_samplesize": "36 enrolled, 17 completed, 13 consented to biopsy, 8 samples analyzable (some analyses n=12).", "ai_effectsize": "Significant reduction in epidermal p16 (senescence marker; p=0.008); reduced collagen VII mRNA (p=0.025). p21/tp53 trended down but not significant.", "ai_limitations": "Small sample size and high dropout; exploratory; some markers not significant; parametric+non-parametric testing used due to small n.", "atlas_url": "https://mtor-atlas.org/study/CHU2019/" }, { "sid": "WEN2026", "title": "Role of Autophagy in Scleral Remodeling During Form-Deprivation Myopia", "authors": "Wen J; Tang S; Zhang Xiaoxiao", "year": 2026, "journal": "FASEB Journal", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Guinea pig; Human scleral fibroblasts", "peer_reviewed": "Yes", "doi": "10.1096/fj.202600954RR", "pmid": "", "pmcid": "", "finding": "Rapamycin-activated autophagy via AMPK/mTOR/P70S6K drives scleral ECM remodeling in myopia; atropine suppresses this pathway and ameliorates myopia progression.\n", "abstract": "Autophagy has been implicated in tissue remodeling, but its role in scleral remodeling during myopia development and in atropine-mediated myopia control remains unclear. Human scleral fibroblasts exposed to hypoxia were treated with rapamycin (RAPA) or 3-methyladenine (3-MA). In vivo, form-deprivation myopia (FDM) was induced in guinea pigs, followed by atropine, RAPA, or 3-MA intervention. Hypoxia induced scleral fibroblast remodeling; 3-MA attenuated these changes, whereas RAPA aggravated them. In FDM guinea pigs, atropine slowed myopia progression and suppressed autophagy-related changes. Subconjunctival RAPA exacerbated, whereas 3-MA alleviated, myopia progression and scleral remodeling. Excessive scleral autophagy links hypoxic stress to extracellular matrix remodeling in experimental myopia; atropine's anti-myopic action involves suppression of mTOR-regulated autophagy.", "ai_intervention": "Rapamycin; 3-methyladenine; Atropine", "ai_target": "AMPK/mTOR/P70S6K; Beclin-1; LC3B", "ai_species": "Guinea pig; Human", "ai_effect": "mTOR-mediated autophagy drives scleral remodeling; inhibiting autophagy (3-MA) or mTOR (atropine) reduces myopia progression", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WEN2026/" }, { "sid": "SCH2025", "title": "The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial", "authors": "Schram AM; Meyerowitz JG et al.", "year": 2025, "journal": "Clinical Cancer Research", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Human (Phase 1 dose escalation, n=57, advanced solid tumors, NCT04774952)", "peer_reviewed": "Yes", "doi": "10.1158/1078-0432.CCR-25-2112", "pmid": "41056387", "pmcid": "PMC12666311", "finding": "First-in-human, open-label dose-escalation trial (n=57, advanced solid tumors, no comparator arm) of a bi-steric mTORC1-selective inhibitor. Treatment-related hyperglycemia was low (4%) and not dose-limiting, alongside a 64% disease control rate. Because the trial was uncontrolled and made no head-to-head comparison against rapamycin or an ATP-site inhibitor, this is encouraging early clinical evidence consistent with the hypothesis that sparing mTORC2 reduces metabolic toxicity -- it does not establish mTORC2 sparing as the cause.\n", "abstract": "PI3K/mTOR pathway activation drives oncogenesis and progression of many cancers. RMC-5552 is a bi-steric, mTOR complex 1 (mTORC1)-selective inhibitor that potently inhibits phosphorylation of key mTORC1 substrates eukaryotic initiation factor 4E-binding protein-1 and S6 kinase and exhibits selectivity for mTORC1 over mTORC2. In this study, we report results from a first-in-human, dose-escalation study of RMC-5552 in patients with advanced solid tumors (NCT04774952). The safety, tolerability, pharmacokinetics, and preliminary activity of RMC-5552 (1.6-16 mg intravenous infusion weekly) were evaluated in 57 patients. The most common treatment-related adverse events were mucositis (49%), nausea (44%), and fatigue (42%). Consistent with mTORC1 selectivity, treatment-related hyperglycemia incidence was generally low (4%) and not dose limiting. Additionally, we tested potential prophylaxis with tacrolimus mouthwash (TM), which was predicted to block the mechanism of action of RMC-5552 locally and alleviate treatment-related oral mucositis. Between 8- and 12-mg dosing, mucositis was 65% without TM versus 31% with TM. In this study, the disease control rate was 64%, and one patient with PTEN- and PIK3CA-altered endometrial cancer had a complete response and treatment was ongoing for >6 months as of the June 2024 data cut. Clearance of PI3K/mTOR pathway variants among ctDNA was observed. The success of TM-mediated prophylaxis and the clearance of selected variants in ctDNA are concordant with selective, on-mechanism, antitumor activity following RMC-5552 treatment. These data show that RMC-5552, the first bi-steric mTORC1-selective inhibitor in the clinic, is active at tolerable doses and that selective inhibition of mTORC1 alleviates mTORC2-mediated hyperglycemia, overcoming a key limitation of prior mTOR inhibitors.", "ai_intervention": "RMC-5552 (bi-steric mTORC1-selective inhibitor), 1.6-16mg IV weekly", "ai_target": "mTORC1 (4E-BP1, S6K1), sparing mTORC2", "ai_species": "Human", "ai_effect": "64% disease control rate (uncontrolled); low (4%) treatment-related hyperglycemia, consistent with mTORC2 sparing", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SCH2025/" }, { "sid": "JAC2004", "title": "Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive", "authors": "Jacinto E; Hall MN et al.", "year": 2004, "journal": "Nature cell biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/ncb1183", "pmid": "15467718", "pmcid": "", "finding": "mTORC2 (rictor) controls the actin cytoskeleton and is rapamycin-insensitive, defining a second mTOR complex in mammals.\n", "abstract": "The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of cell growth. In budding yeast, TOR is found in structurally and functionally distinct protein complexes: TORC1 and TORC2. A mammalian counterpart of TORC1 (mTORC1) has been described, but it is not known whether TORC2 is conserved in mammals. Here, we report that a mammalian counterpart of TORC2 (mTORC2) also exists. mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. Like yeast TORC2, mTORC2 is rapamycin insensitive and seems to function upstream of Rho GTPases to regulate the actin cytoskeleton. mTORC2 is not upstream of the mTORC1 effector S6K. Thus, two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.", "ai_intervention": "Biochemical/genetic (mTORC2/rictor)", "ai_target": "mTORC2 / actin cytoskeleton", "ai_species": "Mammalian cells", "ai_effect": "mTORC2 (mTOR-mLST8-rictor) controls the actin cytoskeleton and is rapamycin-insensitive", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JAC2004/" }, { "sid": "ROD2016", "title": "Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor", "authors": "Rodrik-Outmezguine VS; Shokat KM et al.", "year": 2016, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cancer cells; mouse", "peer_reviewed": "Yes", "doi": "10.1038/nature17963", "pmid": "27279227", "pmcid": "PMC4902179", "finding": "RapaLink-1, a third-generation bivalent inhibitor, overcomes mTOR resistance mutations.\n", "abstract": "Precision medicines exert selective pressure on tumour cells that leads to the preferential growth of resistant subpopulations, necessitating the development of next-generation therapies to treat the evolving cancer. The PIK3CA-AKT-mTOR pathway is one of the most commonly activated pathways in human cancers, which has led to the development of small-molecule inhibitors that target various nodes in the pathway. Among these agents, first-generation mTOR inhibitors (rapalogs) have caused responses in 'N-of-1' cases, and second-generation mTOR kinase inhibitors (TORKi) are currently in clinical trials. Here we sought to delineate the likely resistance mechanisms to existing mTOR inhibitors in human cell lines, as a guide for next-generation therapies. The mechanism of resistance to the TORKi was unusual in that intrinsic kinase activity of mTOR was increased, rather than a direct active-site mutation interfering with drug binding. Indeed, identical drug-resistant mutations have been also identified in drug-naive patients, suggesting that tumours with activating MTOR mutations will be intrinsically resistant to second-generation mTOR inhibitors. We report the development of a new class of mTOR inhibitors that overcomes resistance to existing first- and second-generation inhibitors. The third-generation mTOR inhibitor exploits the unique juxtaposition of two drug-binding pockets to create a bivalent interaction that allows inhibition of these resistant mutants.", "ai_intervention": "New-generation bivalent mTOR inhibitor (RapaLink-type)", "ai_target": "mTOR (resistance mutations)", "ai_species": "Cancer cells; mouse", "ai_effect": "A bivalent next-generation inhibitor overcomes mTOR resistance mutations that defeat first- and second-generation drugs", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ROD2016/" }, { "sid": "TSU2013", "title": "The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1", "authors": "Tsun ZY; Sabatini DM et al.", "year": 2013, "journal": "Molecular cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.molcel.2013.09.016", "pmid": "24095279", "pmcid": "PMC3867817", "finding": "Folliculin is a GAP for RagC/D that signals amino-acid sufficiency, activating mTORC1 substrate binding.\n", "abstract": "The mTORC1 kinase is a master growth regulator that senses numerous environmental cues, including amino acids. The Rag GTPases interact with mTORC1 and signal amino acid sufficiency by promoting the translocation of mTORC1 to the lysosomal surface, its site of activation. The Rags are unusual GTPases in that they function as obligate heterodimers, which consist of RagA or B bound to RagC or D. While the loading of RagA/B with GTP initiates amino acid signaling to mTORC1, the role of RagC/D is unknown. Here, we show that RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP bound for the interaction to occur. We identify FLCN and its binding partners, FNIP1/2, as Rag-interacting proteins with GAP activity for RagC/D, but not RagA/B. Thus, we reveal a role for RagC/D in mTORC1 activation and a molecular function for the FLCN tumor suppressor.", "ai_intervention": "Biochemical/genetic (FLCN)", "ai_target": "FLCN / RagC-RagD / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "The folliculin tumor suppressor is a GAP for RagC/D that signals amino-acid levels to mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/TSU2013/" }, { "sid": "LEI2018", "title": "Crystal structure of arginine-bound lysosomal transporter SLC38A9 in the cytosol-open state", "authors": "Lei HT; Gonen T et al.", "year": 2018, "journal": "Nature structural & molecular biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Structure; in vitro", "peer_reviewed": "Yes", "doi": "10.1038/s41594-018-0072-2", "pmid": "29872228", "pmcid": "PMC7346717", "finding": "Crystal structure of arginine-bound SLC38A9 reveals the basis of lysosomal arginine sensing.\n", "abstract": "Recent advances in understanding intracellular amino acid transport and mechanistic target of rapamycin complex 1 (mTORC1) signaling shed light on solute carrier 38, family A member 9 (SLC38A9), a lysosomal transporter responsible for the binding and translocation of several essential amino acids. Here we present the first crystal structure of SLC38A9 from Danio rerio in complex with arginine. As captured in the cytosol-open state, the bound arginine was locked in a transitional state stabilized by transmembrane helix 1 (TM1) of drSLC38A9, which was anchored at the groove between TM5 and TM7. These anchoring interactions were mediated by the highly conserved WNTMM motif in TM1, and mutations in this motif abolished arginine transport by drSLC38A9. The underlying mechanism of substrate binding is critical for sensitizing the mTORC1 signaling pathway to amino acids and for maintenance of lysosomal amino acid homeostasis. This study offers a first glimpse into a prototypical model for SLC38 transporters.", "ai_intervention": "Structural (crystal structure of SLC38A9)", "ai_target": "SLC38A9 / arginine / mTORC1", "ai_species": "Structure; in vitro (Danio rerio)", "ai_effect": "First crystal structure of arginine-bound SLC38A9 (cytosol-open state), the lysosomal amino-acid transporter/sensor for mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LEI2018/" }, { "sid": "BAS2012", "title": "Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer (BOLERO-2)", "authors": "Baselga J; Campone M; Piccart M; Burris HA; Rugo HS; et al.; Hortobagyi GN", "year": 2012, "journal": "New England Journal of Medicine", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, phase 3 RCT (n=724)", "peer_reviewed": "Yes", "doi": "10.1056/NEJMoa1109653", "pmid": "22149876", "pmcid": "PMC5705195", "finding": "A phase 3 RCT (n=724) proving mTOR matters in a common cancer. When hormone-therapy stops working in breast cancer, it's partly because mTOR switches on. Adding everolimus more than doubled progression-free survival (10.6 vs 4.1 months by central review) - leading to FDA approval. Main toxicity was stomatitis.\n", "abstract": "Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity.\n\nIn this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed.\n\nBaseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001).\n\nEverolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).", "ai_intervention": "Everolimus + exemestane", "ai_target": "mTORC1", "ai_species": "Human – phase 3 RCT (BOLERO-2, n=724, HR+ breast cancer)", "ai_effect": "Adding everolimus to exemestane improved progression-free survival in HR+ advanced breast cancer", "ai_dose": "Everolimus 10 mg once daily + exemestane vs placebo + exemestane; oral; international double-blind phase 3, 2:1 randomization (BOLERO-2).", "ai_samplesize": "724 women, 189 centers, 24 countries (485 everolimus-combination / 239 control); PK subgroup n=80.", "ai_effectsize": "Primary endpoint progression-free survival; adding everolimus significantly improved PFS vs exemestane alone (log-rank, stratified).", "ai_limitations": "Kaplan-Meier estimates beyond week 36 to be interpreted with caution (few patients at risk, limited follow-up).", "atlas_url": "https://mtor-atlas.org/study/BAS2012/" }, { "sid": "SHE2019", "title": "Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex", "authors": "Shen K; Sabatini DM et al.", "year": 2019, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2019.10.036", "pmid": "31704029", "pmcid": "PMC7008705", "finding": "Cryo-EM structure of the human FLCN-FNIP2-Rag-Ragulator complex.\n", "abstract": "mTORC1 controls anabolic and catabolic processes in response to nutrients through the Rag GTPase heterodimer, which is regulated by multiple upstream protein complexes. One such regulator, FLCN-FNIP2, is a GTPase activating protein (GAP) for RagC/D, but despite its important role, how it activates the Rag GTPase heterodimer remains unknown. We used cryo-EM to determine the structure of FLCN-FNIP2 in a complex with the Rag GTPases and Ragulator. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains. The Longin domains heterodimerize and contact both nucleotide binding domains of the Rag heterodimer, while the DENN domains interact at the distal end of the structure. Biochemical analyses reveal a conserved arginine on FLCN as the catalytic arginine finger and lead us to interpret our structure as an on-pathway intermediate. These data reveal features of a GAP-GTPase interaction and the structure of a critical component of the nutrient-sensing mTORC1 pathway.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "FLCN-FNIP2 / Rag / Ragulator / mTORC1", "ai_species": "Cryo-EM structure", "ai_effect": "Cryo-EM structure reveals how FLCN-FNIP2 engages the Rag GTPase heterodimer and Ragulator", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SHE2019/" }, { "sid": "KAE2005", "title": "Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients", "authors": "Kaeberlein M; Kennedy BK et al.", "year": 2005, "journal": "Science", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Yeast (Saccharomyces cerevisiae)", "peer_reviewed": "Yes", "doi": "10.1126/science.1115535", "pmid": "16293764", "pmcid": "", "finding": "A systematic screen of 564 yeast gene deletions found TOR and Sch9 pathway genes as the strongest lifespan-extending hits.\n", "abstract": "Calorie restriction increases life span in many organisms, including the budding yeast Saccharomyces cerevisiae. From a large-scale analysis of 564 single-gene-deletion strains of yeast, we identified 10 gene deletions that increase replicative life span. Six of these correspond to genes encoding components of the nutrient-responsive TOR and Sch9 pathways. Calorie restriction of tor1D or sch9D cells failed to further increase life span and, like calorie restriction, deletion of either SCH9 or TOR1 increased life span independent of the Sir2 histone deacetylase. We propose that the TOR and Sch9 kinases define a primary conduit through which excess nutrient intake limits longevity in yeast.", "ai_intervention": "Genetic (tor1Δ, sch9Δ) + caloric restriction", "ai_target": "TOR / Sch9", "ai_species": "Yeast (S. cerevisiae)", "ai_effect": "Deleting TOR or Sch9 extends yeast replicative lifespan, overlapping with the caloric-restriction effect", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KAE2005/" }, { "sid": "SAX2015", "title": "Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway", "authors": "Saxton RA; Wolfson RL; Sabatini DM et al.", "year": 2015, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cell lines (crystal structure)", "peer_reviewed": "Yes", "doi": "10.1126/science.aad2087", "pmid": "26586190", "pmcid": "PMC4698039", "finding": "Solves the crystal structure of Sestrin2 bound to leucine, revealing the molecular pocket that lets it act as mTORC1's dedicated leucine sensor.\n", "abstract": "Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.", "ai_intervention": "Structural (crystal structure of Sestrin2-leucine)", "ai_target": "Sestrin2 / leucine / GATOR2 / mTORC1", "ai_species": "Human cell lines (crystal structure)", "ai_effect": "Structure of Sestrin2 bound to leucine reveals the leucine-sensing mechanism for the mTORC1 pathway", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAX2015/" }, { "sid": "SHIMADA2026", "title": "Sexual Dimorphism in Placental mTORC1 Signaling, Amino Acid Transport, and Mitochondrial Respiration at Term.", "authors": "Shimada H; Sakuragi T; Zaegel V et al.", "year": 2026, "journal": "Antioxidants", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Human placenta at term (n=46)", "peer_reviewed": "Yes", "doi": "10.3390/antiox15080977", "pmid": "", "pmcid": "", "finding": "In 46 term placentas, male placentas showed higher mTORC1 signalling (increased S6RP phosphorylation, reduced 4E-BP1), greater System A amino acid transport and higher mitochondrial respiratory capacity than female placentas, correlating with a higher birth-weight-to-placental-weight ratio.\n", "abstract": "Male fetuses generally grow faster in utero and are heavier at birth than females, whereas perinatal mortality and morbidity are often higher in boys. Placentas were collected from 46 women with uncomplicated pregnancies delivering appropriate-for-gestational-age infants (23 female, 23 male). In homogenates of male placentas, phosphorylation of S6RP (Ser235/236) was increased and total 4E-BP1 protein expression reduced compared with female placentas, indicating enhanced mTORC1 signalling. In vitro System A amino acid transport activity was greater in microvillous plasma membranes from male placentas. Male placentas exhibited greater maximal oxidative phosphorylation capacity, enhanced complex II-linked respiration and higher maximal electron transport system capacity under both carbohydrate- and lipid-supported conditions. Although placental weight did not differ between sexes, the birth weight-to-placental weight ratio was significantly higher in male pregnancies.", "ai_intervention": "None (observational comparison by fetal sex)", "ai_target": "mTORC1; S6RP; 4E-BP1; System A amino acid transport", "ai_species": "Human", "ai_effect": "Higher mTORC1 activity, amino acid transport and mitochondrial respiratory capacity in male placentas; higher birth-weight-to-placental-weight ratio", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SHIMADA2026/" }, { "sid": "LEE2010", "title": "Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies", "authors": "Lee JH; Budanov AV; Bodmer R; Bier E; Karin M et al.", "year": 2010, "journal": "Science", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Drosophila melanogaster (dSesn loss-of-function)", "peer_reviewed": "Yes", "doi": "10.1126/science.1182228", "pmid": "20203043", "pmcid": "", "finding": "The one study that connects an amino-acid sensor to an organismal ageing phenotype. Loss of Drosophila Sestrin produced triglyceride accumulation, mitochondrial dysfunction, muscle degeneration and cardiac malfunction - all prevented by inhibiting TOR or activating AMPK. Sestrin sits in a negative feedback loop: TOR activity drives Sestrin expression, and Sestrin inhibits TOR back.\n", "abstract": "Sestrins are conserved proteins that accumulate in cells exposed to stress, potentiate adenosine monophosphate-activated protein kinase (AMPK), and inhibit activation of target of rapamycin (TOR). We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO). Loss of dSesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.", "ai_intervention": "dSesn loss of function; rapamycin; AMPK activation", "ai_target": "Sestrin -> AMPK/TOR feedback loop", "ai_species": "Drosophila", "ai_effect": "Sestrin loss causes age-related muscle, cardiac and metabolic pathology in flies; rescued by TOR inhibition or AMPK activation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LEE2010/" }, { "sid": "CHA2014", "title": "The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1", "authors": "Chantranupong L; Sabatini DM et al.", "year": 2014, "journal": "Cell reports", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.celrep.2014.09.014", "pmid": "25263562", "pmcid": "PMC4223866", "finding": "Sestrins bind GATOR2 to negatively regulate amino-acid signalling upstream of mTORC1.\n", "abstract": "The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. GATOR2 is a complex of unknown function that positively regulates mTORC1 signaling by acting upstream of or in parallel to GATOR1, which is a GTPase-activating protein (GAP) for RagA or RagB and an inhibitor of the amino-acid-sensing pathway. Here, we find that the Sestrins, a family of poorly understood growth regulators (Sestrin1-Sestrin3), interact with GATOR2 in an amino-acid-sensitive fashion. Sestrin2-mediated inhibition of mTORC1 signaling requires GATOR1 and the Rag GTPases, and the Sestrins regulate the localization of mTORC1 in response to amino acids. Thus, we identify the Sestrins as GATOR2-interacting proteins that regulate the amino-acid-sensing branch of the mTORC1 pathway.", "ai_intervention": "Biochemical/genetic (Sestrins)", "ai_target": "Sestrins / GATOR2 / Rag / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "Sestrins bind GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHA2014/" }, { "sid": "EHN2008", "title": "Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis", "authors": "Ehninger D; Silva AJ et al.", "year": 2008, "journal": "Nature medicine", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (Tsc2+/-)", "peer_reviewed": "Yes", "doi": "10.1038/nm1788", "pmid": "18568033", "pmcid": "PMC2664098", "finding": "Rapamycin reverses learning and memory deficits in a Tsc2+/- tuberous sclerosis model.\n", "abstract": "Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.", "ai_intervention": "Rapamycin (in Tsc2+/- mice)", "ai_target": "mTORC1 / TSC2", "ai_species": "Mouse (Tsc2+/-)", "ai_effect": "mTOR inhibition reverses learning and memory deficits in a tuberous sclerosis mouse model", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/EHN2008/" }, { "sid": "KUO1992", "title": "Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase", "authors": "Kuo CJ; Crabtree GR et al.", "year": 1992, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "T cells; in vitro", "peer_reviewed": "Yes", "doi": "10.1038/358070a0", "pmid": "1614535", "pmcid": "", "finding": "Rapamycin selectively inhibits IL-2-driven activation of p70 S6 kinase during T-cell proliferation.\n", "abstract": "The macrolide rapamycin induces cell cycle G1 arrest in yeast and in mammalian cells, which suggests that an evolutionarily conserved, rapamycin-sensitive pathway may regulate entry into S phase. In mammals, rapamycin inhibits interleukin-2 receptor-induced S phase entry and subsequent T-cell proliferation, resulting in immunosuppression. Here we show that interleukin-2 selectively stimulates the phosphorylation and activation of p70 S6 kinase but not the erk-encoded MAP kinases and rsk-encoded S6 kinases. Rapamycin completely and rapidly inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase at concentrations comparable to those blocking S phase entry of T cells (0.05-0.2 nM). The structurally related macrolide FK506 competitively antagonizes the actions of rapamycin, indicating that these effects are mediated by FKBP, which binds the transition-state mimic structure common to both rapamycin and FK506 (refs 4, 6, 9-11). The selective blockade of the p70 S6 kinase activation cascade by the rapamycin-FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase.", "ai_intervention": "Rapamycin", "ai_target": "p70 S6 kinase (IL-2 signaling)", "ai_species": "T cells; in vitro", "ai_effect": "Rapamycin selectively inhibits IL-2-induced activation of p70 S6 kinase (basis of immunosuppression)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KUO1992/" }, { "sid": "GUE2009", "title": "mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice", "authors": "Guertin DA; Sabatini DM et al.", "year": 2009, "journal": "Cancer cell", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (prostate)", "peer_reviewed": "Yes", "doi": "10.1016/j.ccr.2008.12.017", "pmid": "19185849", "pmcid": "PMC2701381", "finding": "mTORC2 is required for prostate cancer driven by Pten loss in mice.\n", "abstract": "mTOR complex 2 (mTORC2) contains the mammalian target of rapamycin (mTOR) kinase and the Rictor regulatory protein and phosphorylates Akt. Whether this function of mTORC2 is critical for cancer progression is unknown. Here, we show that transformed human prostate epithelial cells lacking PTEN require mTORC2 to form tumors when injected into nude mice. Furthermore, we find that Rictor is a haploinsufficient gene and that deleting one copy protects Pten heterozygous mice from prostate cancer. Finally, we show that the development of prostate cancer caused by Pten deletion specifically in prostate epithelium requires mTORC2, but that for normal prostate epithelial cells, mTORC2 activity is nonessential. The selective requirement for mTORC2 in tumor development suggests that mTORC2 inhibitors may be of substantial clinical utility.", "ai_intervention": "Genetic (Rictor/mTORC2 deletion; Pten loss)", "ai_target": "mTORC2 (Rictor) / Akt", "ai_species": "Mouse (prostate)", "ai_effect": "mTORC2 is required for prostate cancer driven by Pten loss; Rictor is haploinsufficient", "ai_dose": "", "ai_samplesize": "Pten +/- mice (n=9), Pten +/- Rictor +/- mice (n=10), wild-type controls (n=10) for prostate cancer analysis.", "ai_effectsize": "PC-3 xenografts: shLuc-expressing cells formed tumors of 312 mm 3; shRictor 1 and shRictor 2 cells formed tumors of 10.1 mm 3 (p=0.01) and 39.6 mm 3 (p=0.01). Ki67 positive cells: 2.3% in Pten +/- Rictor +/- vs 10.7% in Pten +/- (p < 0.001).", "ai_limitations": "Specific inhibitors of mTORC2 are unavailable, precluding pharmacological testing. Differences in genetic background between Rictor +/- mice and mtor/Raptor/mlst8 heterozygous mice precluded prostate cancer analysis in some cohorts.", "atlas_url": "https://mtor-atlas.org/study/GUE2009/" }, { "sid": "INO2006", "title": "TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth", "authors": "Inoki K; Guan KL et al.", "year": 2006, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2006.06.055", "pmid": "16959574", "pmcid": "", "finding": "TSC2 integrates Wnt and energy signals through coordinated AMPK and GSK3 phosphorylation.\n", "abstract": "Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.", "ai_intervention": "Biochemical/genetic (AMPK, GSK3, TSC2)", "ai_target": "TSC2 / AMPK / GSK3 / mTOR", "ai_species": "Mammalian cells", "ai_effect": "AMPK and GSK3 coordinately phosphorylate TSC2 to integrate Wnt and energy signals controlling growth", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/INO2006/" }, { "sid": "CAN2002", "title": "The phosphoinositide 3-kinase pathway", "authors": "Cantley LC", "year": 2002, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review article", "peer_reviewed": "Yes", "doi": "10.1126/science.296.5573.1655", "pmid": "12040186", "pmcid": "", "finding": "Review establishing PI3K as a central signaling hub controlling cell survival, metabolism, and growth downstream of growth-factor receptors and upstream of Akt and mTOR.\n", "abstract": "Phosphorylated lipids are produced at cellular membranes during signaling events and contribute to the recruitment and activation of various signaling components. The role of phosphoinositide 3-kinase (PI3K), which catalyzes the production of phosphatidylinositol-3,4,5-trisphosphate, in cell survival pathways; the regulation of gene expression and cell metabolism; and cytoskeletal rearrangements are highlighted. The PI3K pathway is implicated in human diseases including diabetes and cancer, and understanding the intricacies of this pathway may provide new avenues for therapuetic intervention.", "ai_intervention": "Not applicable (review)", "ai_target": "PI3K / PIP3 (upstream of Akt-mTOR)", "ai_species": "Review", "ai_effect": "Reviews the PI3K pathway in cell survival, metabolism, gene expression and cytoskeletal control", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CAN2002/" }, { "sid": "CUN2007", "title": "mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex", "authors": "Cunningham JT; Rodgers JT; Arlow DH; Vazquez F; Mootha VK; Puigserver P", "year": 2007, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Skeletal muscle cells + tissue", "peer_reviewed": "Yes", "doi": "10.1038/nature06322", "pmid": "18046414", "pmcid": "", "finding": "Showed mTOR isn't just about building proteins - it also runs the cell's POWER plants. mTORC1 drives mitochondrial gene expression and oxygen consumption through a YY1-PGC-1alpha transcriptional program; block mTOR with rapamycin and mitochondrial output falls. Explains part of why mTOR inhibition reshapes metabolism.\n", "abstract": "Transcriptional complexes that contain peroxisome-proliferator-activated receptor coactivator (PGC)-1alpha control mitochondrial oxidative function to maintain energy homeostasis in response to nutrient and hormonal signals. An important component in the energy and nutrient pathways is mammalian target of rapamycin (mTOR), a kinase that regulates cell growth, size and survival. However, it is unknown whether and how mTOR controls mitochondrial oxidative activities. Here we show that mTOR is necessary for the maintenance of mitochondrial oxidative function. In skeletal muscle tissues and cells, the mTOR inhibitor rapamycin decreased the gene expression of the mitochondrial transcriptional regulators PGC-1alpha, oestrogen-related receptor alpha and nuclear respiratory factors, resulting in a decrease in mitochondrial gene expression and oxygen consumption. Using computational genomics, we identified the transcription factor yin-yang 1 (YY1) as a common target of mTOR and PGC-1alpha. Knockdown of YY1 caused a significant decrease in mitochondrial gene expression and in respiration, and YY1 was required for rapamycin-dependent repression of those genes. Moreover, mTOR and raptor interacted with YY1, and inhibition of mTOR resulted in a failure of YY1 to interact with and be coactivated by PGC-1alpha. We have therefore identified a mechanism by which a nutrient sensor (mTOR) balances energy metabolism by means of the transcriptional control of mitochondrial oxidative function. These results have important implications for our understanding of how these pathways might be altered in metabolic diseases and cancer.", "ai_intervention": "Genetic/pharmacologic (mTOR; rapamycin)", "ai_target": "mTOR / YY1 / PGC-1α", "ai_species": "Skeletal muscle cells + tissue", "ai_effect": "mTOR controls mitochondrial oxidative function through a YY1-PGC-1α transcriptional complex", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CUN2007/" }, { "sid": "YUX2010", "title": "Termination of autophagy and reformation of lysosomes regulated by mTOR", "authors": "Yu L; Lenardo MJ et al.", "year": 2010, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/nature09076", "pmid": "20526321", "pmcid": "PMC2920749", "finding": "Reactivation of mTOR terminates autophagy and drives autophagic lysosome reformation (ALR).\n", "abstract": "Autophagy is an evolutionarily conserved process by which cytoplasmic proteins and organelles are catabolized. During starvation, the protein TOR (target of rapamycin), a nutrient-responsive kinase, is inhibited, and this induces autophagy. In autophagy, double-membrane autophagosomes envelop and sequester intracellular components and then fuse with lysosomes to form autolysosomes, which degrade their contents to regenerate nutrients. Current models of autophagy terminate with the degradation of the autophagosome cargo in autolysosomes, but the regulation of autophagy in response to nutrients and the subsequent fate of the autolysosome are poorly understood. Here we show that mTOR signalling in rat kidney cells is inhibited during initiation of autophagy, but reactivated by prolonged starvation. Reactivation of mTOR is autophagy-dependent and requires the degradation of autolysosomal products. Increased mTOR activity attenuates autophagy and generates proto-lysosomal tubules and vesicles that extrude from autolysosomes and ultimately mature into functional lysosomes, thereby restoring the full complement of lysosomes in the cell-a process we identify in multiple animal species. Thus, an evolutionarily conserved cycle in autophagy governs nutrient sensing and lysosome homeostasis during starvation.", "ai_intervention": "Genetic/pharmacologic (mTOR reactivation)", "ai_target": "mTOR / autophagic lysosome reformation", "ai_species": "Mammalian cells", "ai_effect": "Reactivation of mTOR terminates autophagy and drives reformation of lysosomes (ALR)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/YUX2010/" }, { "sid": "GOR2026", "title": "A Systems Pharmacology Model of Aging Identifies Optimal Combination Therapies With Secondary Benefits on Weight Loss and Metabolic Health", "authors": "Goryanin I et al.", "year": 2026, "journal": "CPT Pharmacometrics Syst Pharmacol", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Quantitative systems pharmacology (QSP) model calibrated to human trial data (semaglutide STEP trials)", "peer_reviewed": "Yes", "doi": "10.1002/psp4.70322", "pmid": "42572918", "pmcid": "", "finding": "A calibrated systems-pharmacology model of aging finds that optimal drug combinations diverge by objective: GLP-1 receptor agonist + SGLT2 inhibitor + metformin is best for metabolic (weight/HbA1c) improvement, while GLP-1 receptor agonist + SGLT2 inhibitor + rapamycin is predicted best for aging-related (frailty/biological-age-gap) benefit — the two goals do not converge on the same regimen. Authors flag the aging predictions as hypothesis-generating, pending external validation.\n", "abstract": "Aging is a systems-level process linking metabolic dysfunction, inflammation, impaired repair, frailty, and multimorbidity, whereas existing pharmacological strategies usually optimize disease-specific endpoints such as weight loss or HbA1c rather than aging-related trajectories. We developed an SBML-compliant quantitative systems pharmacology (QSP) model in which aging is represented as a dynamic, pharmacologically modifiable endpoint. The model integrates four coupled layers: metabolic/pharmacodynamic responses to GLP-1 receptor agonism, SGLT2 inhibition, metformin and rapamycin; adverse-event dynamics; aging states including damage accumulation, repair capacity, frailty and biological age gap; and biomarker outputs including GDF15, cystatin C, leptin, adiponectin and estimated glucose disposal rate. The semaglutide submodel was calibrated against published STEP trial endpoints, and Bayesian hierarchical meta-analysis, global sensitivity analysis, practical identifiability analysis and internal consistency checks were used to assess model behavior. The calibrated model reproduced semaglutide-associated weight loss, HbA1c reduction and transient nausea within pre-specified error benchmarks. Bayesian meta-analysis confirmed strong metabolic effects for semaglutide, moderate glycaemic effects for SGLT2 inhibitors and metformin, and a near-zero HbA1c effect for rapamycin. Sensitivity analysis revealed largely orthogonal metabolic and aging parameter spaces. Combination simulations identified two mechanistically distinct optima: GLP-1 receptor agonist plus SGLT2 inhibitor plus metformin for metabolic improvement, and GLP-1 receptor agonist plus SGLT2 inhibitor plus rapamycin for aging-related benefit. Metabolic optimisation and aging optimisation are therefore mechanistically distinct objectives that do not converge on the same drug combination. These predictions are hypothesis-generating and require external validation against independent longitudinal datasets and clinical safety evaluation before translation to treatment recommendations.", "ai_intervention": "Rapamycin, metformin, SGLT2 inhibitors, GLP-1 receptor agonists (combination therapy, in silico)", "ai_target": "mTOR/aging pathway (rapamycin arm) within a multi-drug QSP model", "ai_species": "Human (in silico model calibrated to human trial data)", "ai_effect": "Predicts GLP-1RA+SGLT2i+rapamycin as the optimal combination for aging-related outcomes (frailty, biological age gap), distinct from the best metabolic-outcome combination", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GOR2026/" }, { "sid": "MAJ2004", "title": "mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways", "authors": "Majumder PK; Sellers WR et al.", "year": 2004, "journal": "Nature medicine", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (prostate)", "peer_reviewed": "Yes", "doi": "10.1038/nm1052", "pmid": "15156201", "pmcid": "", "finding": "mTOR inhibition (rapamycin/RAD001) reverses Akt-driven prostate intraepithelial neoplasia in mice.\n", "abstract": "Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.", "ai_intervention": "mTOR inhibition (rapamycin)", "ai_target": "mTOR / Akt / HIF-1", "ai_species": "Mouse (prostate, AKT1 transgenic)", "ai_effect": "mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia via apoptotic and HIF-1-dependent pathways", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MAJ2004/" }, { "sid": "DEL2011", "title": "The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2", "authors": "Delgoffe GM; Powell JD et al.", "year": 2011, "journal": "Nature immunology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1038/ni.2005", "pmid": "21358638", "pmcid": "PMC3077821", "finding": "mTORC1 and mTORC2 selectively program distinct CD4 helper T-cell lineages.\n", "abstract": "The kinase mTOR has emerged as an important regulator of the differentiation of helper T cells. Here we demonstrate that differentiation into the T(H)1 and T(H)17 subsets of helper T cells was selectively regulated by signaling from mTOR complex 1 (mTORC1) that was dependent on the small GTPase Rheb. Rheb-deficient T cells failed to generate T(H)1 and T(H)17 responses in vitro and in vivo and did not induce classical experimental autoimmune encephalomyelitis (EAE). However, they retained their ability to become T(H)2 cells. Alternatively, when mTORC2 signaling was deleted from T cells, they failed to generate T(H)2 cells in vitro and in vivo but preserved their ability to become T(H)1 and T(H)17 cells. Our data identify mechanisms by which two distinct signaling pathways downstream of mTOR regulate helper cell fate in different ways. These findings define a previously unknown paradigm that links T cell differentiation with selective metabolic signaling pathways.", "ai_intervention": "Genetic (Rheb/mTORC1; mTORC2)", "ai_target": "mTORC1 (Rheb) & mTORC2", "ai_species": "Mouse", "ai_effect": "mTORC1 (Rheb-dependent) selectively drives Th1/Th17 differentiation while mTORC2 controls Th2", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "Nearly 60% (on average) of MOG-immunized T- Rheb −/− mice developed 'non-classical EAE'.", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DEL2011/" }, { "sid": "JIN2026", "title": "Redox-sensitive mTOR-eIF4A signaling promotes selective P-glycoprotein translation.", "authors": "Jin P; Jin M; Feng L; He J; Ying Y; Bai R et al.", "year": 2026, "journal": "Free radical biology & medicine", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cell line", "peer_reviewed": "Yes", "doi": "10.1016/j.freeradbiomed.2026.07.033", "pmid": "", "pmcid": "", "finding": "Oxidative stress activates a redox-sensitive PI3K-AKT-mTORC1-eIF4A cascade that selectively promotes P-glycoprotein translation via cap-dependent mRNA engagement, revealing a transcription-independent mechanism of rapid multidrug resistance induction.\n", "abstract": "Cells face a temporal gap in oxidative stress adaptation, in which acute insults require rapid protein synthesis before transcriptional responses are fully established. Low-dose glucosamine (GlcN) induces a transient intracellular oxidation-sensitive response and activates redox-sensitive PI3K-AKT-mTORC1 signaling, leading to increased P-glycoprotein (P-gp) abundance without a detectable increase in total ABCB1 mRNA.", "ai_intervention": "Glucosamine; redox stress", "ai_target": "mTORC1 / eIF4A / 4E-BP1", "ai_species": "Cell line", "ai_effect": "mTOR-eIF4A selectively upregulates P-gp translation under oxidative stress; multidrug resistance", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JIN2026/" }, { "sid": "BAR2016", "title": "Tor forms a dimer through an N-terminal helical solenoid with a complex topology", "authors": "Baretic D; Williams RL et al.", "year": 2016, "journal": "Nature communications", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.1038/ncomms11016", "pmid": "27072897", "pmcid": "PMC4833857", "finding": "Cryo-EM shows TOR dimerizes through an N-terminal helical solenoid, informing mTORC1 architecture.\n", "abstract": "The target of rapamycin (Tor) is a Ser/Thr protein kinase that regulates a range of anabolic and catabolic processes. Tor is present in two complexes, TORC1 and TORC2, in which the Tor-Lst8 heterodimer forms a common sub-complex. We have determined the cryo-electron microscopy (EM) structure of Tor bound to Lst8. Two Tor-Lst8 heterodimers assemble further into a dyad-symmetry dimer mediated by Tor-Tor interactions. The first 1,300 residues of Tor form a HEAT repeat-containing alpha-solenoid with four distinct segments: a highly curved 800-residue N-terminal 'spiral', followed by a 400-residue low-curvature 'bridge' and an extended 'railing' running along the bridge leading to the 'cap' that links to FAT region. This complex topology was verified by domain insertions and offers a new interpretation of the mTORC1 structure. The spiral of one TOR interacts with the bridge of another, which together form a joint platform for the Regulatory Associated Protein of TOR (RAPTOR) regulatory subunit.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "TOR / Lst8", "ai_species": "Cryo-EM structure", "ai_effect": "Tor-Lst8 heterodimers assemble into a dyad-symmetric dimer via Tor-Tor interactions (N-terminal solenoid)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BAR2016/" }, { "sid": "PIR2026", "title": "Biological limits of lifespan extension: evidence for a shift from pathway leverage to system-level buffering across species", "authors": "Denisa Fv Pirscoveanu, Mihai-Cristian Papa, Britta Kaltwasser, Dirk M Hermann, Ulf Brockmeier, Andrea Cercel, Anthony Oliver, Johannes Gruillari, Marius Viorel Ionica, Aurel Popa-Wagner", "year": 2026, "journal": "Mechanisms of Ageing and Development", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Multi-species (C. elegans, Drosophila, rodents)", "peer_reviewed": "Yes", "doi": "10.1016/j.mad.2026.112231", "pmid": "42437600", "pmcid": "", "finding": "mTOR/TOR pathway interventions achieve large lifespan extensions in simple organisms but face declining efficacy in mammals due to distributed multi-tissue buffering, redundancy, and pharmacokinetic complexity - proposing a unifying framework for the translational challenge of aging pathway targeting.\n", "abstract": "Interventions targeting conserved aging pathways (including TOR/mTOR signaling) markedly extend lifespan in model organisms, yet efficacy declines with organismal complexity. Synthesizing data from C. elegans, Drosophila, and rodent models, the authors propose that simple organisms are governed by high-leverage pathways, while in mammals aging emerges from distributed, multi-tissue regulatory systems with redundancy, feedback, and competing physiological constraints. Key determinants include metabolic organization, genetic redundancy, endocrine regulation, microbiome interactions, and pharmacokinetic complexity.", "ai_intervention": "TOR/mTOR pathway interventions (rapamycin and analogues)", "ai_target": "TOR/mTOR signaling; conserved aging pathways", "ai_species": "Multi-species", "ai_effect": "Lifespan extension via mTOR inhibition declines with organismal complexity; mammals show system-level buffering that limits single-pathway leverage", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PIR2026/" }, { "sid": "WANG2026B", "title": "Pdcd4-Rictor interaction suppresses mTORC2-PFKFB3 axis and tumorigenesis in NSCLC.", "authors": "Wang Q; Xin Y; Zokaei E et al.", "year": 2026, "journal": "Neoplasia", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "NSCLC cell lines; mouse xenograft; human tumour tissue", "peer_reviewed": "Yes", "doi": "10.1016/j.neo.2026.101354", "pmid": "", "pmcid": "", "finding": "Pdcd4 binds Rictor via residues R105/K108/R110 to disrupt mTORC2 assembly and kinase activity, lowering PFKFB3 levels and suppressing glycolysis and NSCLC tumour growth.\n", "abstract": "Programmed cell death 4 (Pdcd4) is a tumour suppressor and inhibitor of protein translation with emerging translation-independent functions. Pdcd4 suppresses tumorigenesis by disrupting mTORC2 complex formation through binding Rictor. Deletion mapping and site-directed mutagenesis defined the Rictor-binding domain of Pdcd4 and identified residues R105, K108 and R110 as critical. Co-immunoprecipitation and in vitro kinase assays showed that Pdcd4 binding to Rictor disrupted mTORC2 assembly and inhibited its kinase activity. Reverse phase protein array revealed PFKFB3, a key glycolysis regulator, was markedly upregulated in Pdcd4-knockdown cells; restoration of wild-type Pdcd4 but not a Rictor-binding-deficient mutant reduced PFKFB3 via ubiquitin-proteasome degradation. The interaction suppressed glycolysis and tumour cell proliferation in culture and xenografts. NSCLC tissues showed elevated Rictor and PFKFB3 versus adjacent normal tissue, with positive correlation.", "ai_intervention": "Pdcd4 overexpression / knockdown; Rictor-binding-deficient mutants", "ai_target": "Rictor; mTORC2; PFKFB3", "ai_species": "Human cell lines; mouse xenograft", "ai_effect": "Disrupted mTORC2 assembly and kinase activity, degraded PFKFB3, suppressed glycolysis and tumour growth", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WANG2026B/" }, { "sid": "LOE2002", "title": "Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control", "authors": "Loewith R; Hall MN et al.", "year": 2002, "journal": "Molecular cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Yeast S. cerevisiae", "peer_reviewed": "Yes", "doi": "10.1016/s1097-2765(02)00636-6", "pmid": "12408816", "pmcid": "", "finding": "Defined two distinct TOR complexes, only one rapamycin-sensitive, founding the TORC1/TORC2 paradigm.\n", "abstract": "The target of rapamycin (TOR) proteins in Saccharomyces cerevisiae, TOR1 and TOR2, redundantly regulate growth in a rapamycin-sensitive manner. TOR2 additionally regulates polarization of the actin cytoskeleton in a rapamycin-insensitive manner. We describe two functionally distinct TOR complexes. TOR Complex 1 (TORC1) contains TOR1 or TOR2, KOG1 (YHR186c), and LST8. TORC2 contains TOR2, AVO1 (YOL078w), AVO2 (YMR068w), AVO3 (YER093c), and LST8. FKBP-rapamycin binds TORC1, and TORC1 disruption mimics rapamycin treatment, suggesting that TORC1 mediates the rapamycin-sensitive, TOR-shared pathway. FKBP-rapamycin fails to bind TORC2, and TORC2 disruption causes an actin defect, suggesting that TORC2 mediates the rapamycin-insensitive, TOR2-unique pathway. Thus, the distinct TOR complexes account for the diversity, specificity, and selective rapamycin inhibition of TOR signaling. TORC1 and possibly TORC2 are conserved from yeast to man.", "ai_intervention": "Genetic/biochemical (TOR1/TOR2 complexes)", "ai_target": "TORC1 / TORC2", "ai_species": "Yeast (S. cerevisiae)", "ai_effect": "Defines two TOR complexes: TORC1 (rapamycin-sensitive, growth) and TORC2 (rapamycin-insensitive, actin)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LOE2002/" }, { "sid": "BIS2008", "title": "Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis", "authors": "Bissler JJ; Franz DN et al.", "year": 2008, "journal": "The New England journal of medicine", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Human (clinical trial)", "peer_reviewed": "Yes", "doi": "10.1056/NEJMoa063564", "pmid": "18184959", "pmcid": "PMC3398441", "finding": "Sirolimus shrinks renal angiomyolipomas in tuberous sclerosis / lymphangioleiomyomatosis.\n", "abstract": "Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling. We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed. Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean angiomyolipoma volume at 12 months was 53.2% of the baseline value (P<0.001) and at 24 months was 85.9% of the baseline value (P=0.005). During sirolimus therapy, among patients with lymphangioleiomyomatosis, FEV1, FVC and residual volume improved relative to baseline. One year after sirolimus was discontinued, some spirometric improvements persisted; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections. Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after therapy was stopped. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)", "ai_intervention": "Sirolimus (rapamycin)", "ai_target": "mTOR", "ai_species": "Human – open-label trial (TSC/LAM)", "ai_effect": "Sirolimus reduced angiomyolipoma volume during treatment; tumors regrew after stopping", "ai_dose": "Oral sirolimus, 24-month non-randomized open-label trial (dose titrated to therapeutic trough); full text not retrievable via PMC.", "ai_samplesize": "~25 patients with TSC or sporadic LAM (full text unavailable; abstract-level).", "ai_effectsize": "Sirolimus reduced angiomyolipoma volume (~50%) during treatment; tumors regrew after the drug was stopped.", "ai_limitations": "Non-randomized open-label; benefit not durable off-drug; full text not retrievable, so figures from abstract only.", "atlas_url": "https://mtor-atlas.org/study/BIS2008/" }, { "sid": "RAO2026", "title": "An SLC7A5-dependent nutrient-sensing circuit overcomes cisplatin tolerance via mTOR-autophagy signaling.", "authors": "Rao P; Zhang T; Li Ju et al.", "year": 2026, "journal": "Biochemical and Biophysical Research Communications", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cancer cell lines (genome-wide CRISPR-Cas9 screen)", "peer_reviewed": "Yes", "doi": "10.1016/j.bbrc.2026.154478", "pmid": "", "pmcid": "", "finding": "A genome-wide CRISPR screen found that mTOR inhibition promotes cisplatin tolerance by activating cytoprotective autophagy — the opposite of the canonical view. SLC7A5 integrates this mTOR-autophagy axis, and leucine supplementation resensitises SLC7A5-expressing tumour cells to cisplatin.\n", "abstract": "Cisplatin-based chemotherapy responses are heterogeneous across cancers. Using genome-wide CRISPR-Cas9 knockout screening, the authors characterized regulators of cisplatin response and uncovered a counterintuitive finding: mTOR inhibition promotes cisplatin tolerance, contradicting the canonical view that PI3K-AKT-mTOR activation confers chemoresistance. Mechanistically, both mTOR suppression and cisplatin treatment converge to activate cytoprotective autophagy, enhancing cancer cell survival under therapeutic stress. The amino acid transporter SLC7A5 was identified and validated as a key integrator of the mTOR-autophagy axis modulating cisplatin sensitivity. SLC7A5 expression positively correlates with cisplatin sensitivity across cancer cell lines, and its downregulation is associated with cisplatin resistance. Leucine supplementation sensitizes cancer cells to cisplatin in an SLC7A5-mTOR-autophagy-dependent manner.", "ai_intervention": "mTOR inhibition; SLC7A5 knockout; leucine supplementation", "ai_target": "SLC7A5; mTOR; autophagy", "ai_species": "Human cell lines", "ai_effect": "mTOR inhibition increased cisplatin tolerance via cytoprotective autophagy; leucine supplementation restored cisplatin sensitivity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/RAO2026/" }, { "sid": "ROC2012", "title": "The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis", "authors": "Roczniak-Ferguson A; Ferguson SM et al.", "year": 2012, "journal": "Science signaling", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/scisignal.2002790", "pmid": "22692423", "pmcid": "PMC3437338", "finding": "mTORC1 phosphorylates TFEB to control lysosomal and autophagy gene transcription.\n", "abstract": "Lysosomes are the major cellular site for clearance of defective organelles and digestion of internalized material. Demand on lysosomal capacity can vary greatly, and lysosomal function must be adjusted to maintain cellular homeostasis. Here, we identified an interaction between the lysosome-localized mechanistic target of rapamycin complex 1 (mTORC1) and the transcription factor TFEB, which promotes lysosome biogenesis. When lysosomal activity was adequate, mTOR-dependent phosphorylation of TFEB on Ser(211) triggered the binding of 14-3-3 proteins to TFEB, resulting in retention of the transcription factor in the cytoplasm. Inhibition of lysosomal function reduced the mTOR-dependent phosphorylation of TFEB, resulting in diminished interactions between TFEB and 14-3-3 proteins and the translocation of TFEB into the nucleus, where it could stimulate genes involved in lysosomal biogenesis. These results identify TFEB as a target of mTOR and suggest a mechanism for matching the transcriptional regulation of genes encoding proteins of autophagosomes and lysosomes to cellular need. The closely related transcription factors MITF and TFE3 also localized to lysosomes and accumulated in the nucleus when lysosome function was inhibited, thus broadening the range of physiological contexts under which this regulatory mechanism may prove important.", "ai_intervention": "Genetic/pharmacologic (mTORC1/TFEB)", "ai_target": "mTORC1 / TFEB", "ai_species": "Mammalian cells", "ai_effect": "mTORC1 controls TFEB to transcriptionally regulate lysosome biogenesis and homeostasis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ROC2012/" }, { "sid": "VAL2022", "title": "Structure of the nutrient-sensing hub GATOR2", "authors": "Valenstein ML; Rogala KB; Saxton RA; Chantranupong L; Sabatini DM et al.", "year": 2022, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human GATOR2 complex (cryo-EM)", "peer_reviewed": "Yes", "doi": "10.1038/s41586-022-04939-z", "pmid": "35831510", "pmcid": "PMC9464592", "finding": "Cryo-EM structure of human GATOR2: a 1.1 MDa, two-fold symmetric cage built on an octagonal scaffold decorated with eight pairs of WD40 beta-propellers, and a map of where Sestrin2 and CASTOR1 dock. It substantially advances the GATOR2 side of the sensor module, though how GATOR2 inhibits GATOR1 is still not fully settled.\n", "abstract": "Mechanistic target of rapamycin complex 1 (mTORC1) controls growth by regulating anabolic and catabolic processes in response to environmental cues, including nutrients. Amino acids signal to mTORC1 through the Rag GTPases, which are regulated by several protein complexes, including GATOR1 and GATOR2. GATOR2, which has five components (WDR24, MIOS, WDR59, SEH1L and SEC13), is required for amino acids to activate mTORC1 and interacts with the leucine and arginine sensors SESN2 and CASTOR1, respectively. Despite this central role in nutrient sensing, GATOR2 remains mysterious as its subunit stoichiometry, biochemical function and structure are unknown. Here we used cryo-electron microscopy to determine the three-dimensional structure of the human GATOR2 complex. We found that GATOR2 adopts a large (1.1 MDa), two-fold symmetric, cage-like architecture, supported by an octagonal scaffold and decorated with eight pairs of WD40 beta-propellers. The scaffold contains two WDR24, four MIOS and two WDR59 subunits circularized via two distinct types of junction involving non-catalytic RING domains and alpha-solenoids. Integration of SEH1L and SEC13 into the scaffold through beta-propeller blade donation stabilizes the GATOR2 complex and reveals an evolutionary relationship to the nuclear pore and membrane-coating complexes. The scaffold orients the WD40 beta-propeller dimers, which mediate interactions with SESN2, CASTOR1 and GATOR1. Our work reveals the structure of an essential component of the nutrient-sensing machinery and provides a foundation for understanding the function of GATOR2 within the mTORC1 pathway.", "ai_intervention": "", "ai_target": "GATOR2 complex architecture; Sestrin2/CASTOR1 binding sites", "ai_species": "Human protein complex", "ai_effect": "Defines GATOR2 as a 1.1 MDa cage-like complex and maps the sensor-binding interfaces", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/VAL2022/" }, { "sid": "ZHOU2026", "title": "TET1-mediated DNA demethylation and transcription activation of MRPS17 induces lung adenocarcinoma through PI3K-AKT-mTOR pathway.", "authors": "Zhou N; Song L; Wu Y et al.", "year": 2026, "journal": "Journal of Molecular Histology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human LUAD cell lines; mouse xenograft", "peer_reviewed": "Yes", "doi": "10.1007/s10735-026-10862-8", "pmid": "", "pmcid": "", "finding": "TET1 demethylates the MRPS17 promoter to drive MRPS17 overexpression in lung adenocarcinoma, activating PI3K-AKT-mTOR signalling and increasing proliferation, migration and invasion. MRPS17 knockdown induces apoptosis and suppresses tumour growth in vitro and in vivo.\n", "abstract": "Lung adenocarcinoma (LUAD) poses significant therapeutic challenges. This study investigates the role of mitochondrial ribosomal protein S17 (MRPS17) in LUAD progression, focusing on its interaction with the PI3K-AKT-mTOR signaling pathway. MRPS17 is upregulated in LUAD tissues and associated with poor prognosis. MRPS17 overexpression promoted proliferation, migration and invasion, whereas knockdown induced apoptosis and diminished tumorigenic capability in vitro and in vivo. TET1 was identified as a crucial regulator of MRPS17, acting through demethylation of its promoter to enhance MRPS17 expression and subsequently activate the PI3K-AKT-mTOR pathway. MRPS17 is proposed as a prognostic marker and therapeutic target.", "ai_intervention": "MRPS17 overexpression / knockdown; TET1 modulation", "ai_target": "MRPS17; TET1; PI3K-AKT-mTOR", "ai_species": "Human cell lines; mouse xenograft", "ai_effect": "MRPS17 upregulation activates PI3K-AKT-mTOR and increases tumour aggressiveness; knockdown induces apoptosis and reduces tumour growth", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZHOU2026/" }, { "sid": "SCH2003", "title": "TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function", "authors": "Schalm SS; Blenis J et al.", "year": 2003, "journal": "Current biology : CB", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "In vitro", "peer_reviewed": "Yes", "doi": "10.1016/s0960-9822(03)00329-4", "pmid": "12747827", "pmcid": "", "finding": "The TOS motif mediates raptor binding and controls multisite 4E-BP1 phosphorylation by mTORC1.\n", "abstract": "The mammalian target of rapamycin, mTOR, is a serine/threonine kinase that controls cell growth and proliferation via the translation regulators eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). We recently identified a TOR signaling (TOS) motif in the N terminus of S6K1 and the C terminus of 4E-BP1 and demonstrated that in S6K1, the TOS motif is necessary to facilitate mTOR signaling to phosphorylate and activate S6K1. However, it is unclear how the TOS motif in S6K1 and 4E-BP1 mediates mTOR signaling. Here, we show that a functional TOS motif is required for 4E-BP1 to bind to raptor, for 4E-BP1 to be efficiently phosphorylated in vitro by the mTOR/raptor complex, and for 4E-BP1 to be phosphorylated in vivo at all identified mTOR-regulated sites. mTOR/raptor-regulated phosphorylation is necessary for 4E-BP's efficient release from the translational initiation factor eIF4E. Consistently, overexpression of a mutant of 4E-BP1 containing a single amino acid change in the TOS motif (F114A) reduces cell size, demonstrating that mTOR-dependent regulation of cell growth by 4E-BP1 is dependent on a functional TOS motif. Our data demonstrate that the TOS motif functions as a docking site for the mTOR/raptor complex, which is required for multisite phosphorylation of 4E-BP1, eIF4E release from 4E-BP1, and cell growth.", "ai_intervention": "Biochemical (TOS motif)", "ai_target": "mTOR / raptor / 4E-BP1", "ai_species": "In vitro", "ai_effect": "TOS-motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SCH2003/" }, { "sid": "GAR2009", "title": "Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)", "authors": "Garcia-Martinez JM; Alessi DR et al.", "year": 2009, "journal": "The Biochemical journal", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "In vitro; cells", "peer_reviewed": "Yes", "doi": "10.1042/BJ20090489", "pmid": "19402821", "pmcid": "PMC2708931", "finding": "Ku-0063794 is a specific ATP-competitive mTOR inhibitor blocking mTORC1 and mTORC2.\n", "abstract": "mTOR (mammalian target of rapamycin) stimulates cell growth by phosphorylating and promoting activation of AGC family kinases such as Akt (protein kinase B), S6K (p70 ribosomal S6 kinase) and SGK (serum and glucocorticoid protein kinase). mTORC1 phosphorylates the hydrophobic motif of S6K, whereas mTORC2 phosphorylates the hydrophobic motif of Akt and SGK. In the present paper we describe the small molecule Ku-0063794, which inhibits both mTORC1 and mTORC2 with an IC50 of approximately 10 nM, but does not suppress the activity of 76 other protein kinases or seven lipid kinases, including Class 1 PI3Ks at 1000-fold higher concentrations. Ku-0063794 is cell permeant, suppresses activation and hydrophobic motif phosphorylation of Akt, S6K and SGK, but not RSK, an AGC kinase not regulated by mTOR. Ku-0063794 also inhibited phosphorylation of the T-loop Thr308 residue of Akt phosphorylated by PDK1. In contrast, Ku-0063794 does not affect Thr308 phosphorylation in fibroblasts lacking essential mTORC2 subunits, suggesting that signalling processes have adapted to enable Thr308 phosphorylation to occur in the absence of Ser473 phosphorylation. We found that Ku-0063794 induced a much greater dephosphorylation of the mTORC1 substrate 4E-BP1 than rapamycin, even in mTORC2-deficient cells. Ku-0063794 also suppressed cell growth and induced a G1-cell-cycle arrest. Our results indicate that Ku-0063794 will be useful in delineating the physiological roles of mTOR and may have utility in treatment of cancers in which this pathway is inappropriately activated.", "ai_intervention": "Ku-0063794 (ATP-competitive mTOR inhibitor)", "ai_target": "mTORC1 & mTORC2", "ai_species": "In vitro; cells", "ai_effect": "Ku-0063794 is a specific mTOR inhibitor blocking both complexes (Akt/S6K/SGK signaling)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GAR2009/" }, { "sid": "CAO2026", "title": "Substrate-selective mTORC1 regulation and gene dosage-dependent tissue divergence in Birt-Hogg-Dubé syndrome", "authors": "Cao ZL; Zhao SC; Lin F; Liu YH; Hong XT; Hong LY; Xu LQ; Li FP; Yu HY; Yao WG; Chen WY", "year": 2026, "journal": "Frontiers in Oncology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Narrative synthesis (human genetics + mouse mechanistic data)", "peer_reviewed": "Yes", "doi": "10.3389/fonc.2026.1848740", "pmid": "42558438", "pmcid": "PMC13437482", "finding": "Reframes Birt-Hogg-Dube (BHD) syndrome beyond the classic 'global mTORC1 hyperactivation' model: FLCN acts as a GAP for RagC/D, giving substrate-selective (not global) mTORC1 control. Biallelic FLCN loss drives kidney tumors via MiT/TFE nuclear accumulation, while haploinsufficiency alone is sufficient for lung and skin lesions -- resolving the 'mTORC1 paradox' via gene dosage and signaling timing. Narrative synthesis of human genetics and mouse mechanistic data.\n", "abstract": "Birt-Hogg-Dube (BHD) syndrome, caused by mutations in the tumor suppressor gene, has traditionally been classified as a classic 'mTORopathy' characterized by global mTORC1 activation. Recent structural and multi-omic studies have fundamentally challenged this view, revealing that FLCN functions as a GAP for RagC/D to govern substrate-selective mTORC1 regulation. Synthesizing emerging evidence, we describe an integrated pathogenic framework: biallelic inactivation drives renal tumorigenesis via constitutive MiT/TFE nuclear accumulation and metabolic reprogramming, whereas haploinsufficiency suffices to disrupt structural integrity in the lung and skin. By reconciling the 'mTORC1 paradox' through the lens of gene dosage and temporal signaling dynamics, we highlight novel therapeutic vulnerabilities targeting MiT/TFE factors and kinase rewiring, providing a rationale for organ-specific precision medicine in BHD.", "ai_intervention": "", "ai_target": "FLCN / RagC-RagD / mTORC1 / MiT-TFE", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CAO2026/" }, { "sid": "VEZ1975", "title": "Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle", "authors": "Vezina C; Kudelski A; Sehgal SN", "year": 1975, "journal": "Journal of Antibiotics", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Streptomyces hygroscopicus (soil bacterium)", "peer_reviewed": "Yes", "doi": "10.7164/antibiotics.28.721", "pmid": "1102508", "pmcid": "", "finding": "The original isolation of rapamycin from a soil bacterium found on Easter Island, discovered first as an antifungal compound decades before its mTOR-inhibiting mechanism was known.\n", "abstract": "A streptomycete was isolated from an Easter Island soil sample and found to inhibit Candida albicans, Microsporum gypseum and Trichophyton granulosum. The antibiotic-producing microorganism was characterized and identified as Streptomyces hygroscopicus. The antifungal principle was extracted with organic solvent from the mycelium, isolated in crystalline form and named rapamycin. Rapamycin is mainly active against Candida albicans; minimum inhibitory concentration against ten strains ranged from 0.02 to 0.2 mug/ml. Its apparent activity against Microsporum gypseum and Trichophyton granulosum is lower because of its instability in culture media on prolonged incubation required by these fungi. No activity was observed against gram-positive and gram-negative bacteria. Acute toxicity in mice is low.", "ai_intervention": "Rapamycin (natural product isolation)", "ai_target": "Antifungal principle (later FKBP/TOR)", "ai_species": "Streptomyces hygroscopicus (soil bacterium)", "ai_effect": "Original isolation and characterization of rapamycin as an antifungal antibiotic from Easter Island soil", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/VEZ1975/" }, { "sid": "YAN2013", "title": "mTOR kinase structure, mechanism and regulation", "authors": "Yang H; Rudge DG; Koos JD; Vaidialingam B; Yang HJ; Pavletich NP", "year": 2013, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "X-ray crystallography (structural biology)", "peer_reviewed": "Yes", "doi": "10.1038/nature12122", "pmid": "23636326", "pmcid": "PMC4512754", "finding": "Solved the crystal structure of the mTOR kinase itself. Revealed why the active site is so hard to reach - it sits in a deep recess guarded by the FRB domain, which acts as a 'gatekeeper' letting substrates in. This structure explains at the atomic level exactly how FKBP12-rapamycin blocks access, and why activating cancer mutations cluster where they do.\n", "abstract": "The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and conformational changes that underlie inhibitor potency and specificity.", "ai_intervention": "Structural (X-ray crystallography)", "ai_target": "mTOR / mLST8", "ai_species": "X-ray crystallography", "ai_effect": "Co-crystal structures reveal mTOR's intrinsically active kinase and how ATP-site inhibitors bind", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/YAN2013/" }, { "sid": "MCNEILL2026", "title": "Sirolimus is effective for paediatric Evans syndrome and secondary autoimmune cytopenias: A retrospective cohort study.", "authors": "McNeill M; Cellarius C; Illamperuma N et al.", "year": 2026, "journal": "British Journal of Haematology", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Human (paediatric retrospective cohort)", "peer_reviewed": "Yes", "doi": "10.1111/bjh.70795", "pmid": "", "pmcid": "", "finding": "Retrospective single-centre paediatric cohort reporting that sirolimus is effective in paediatric Evans syndrome and secondary autoimmune cytopenias. Abstract not yet indexed — effect sizes to be confirmed.\n", "abstract": "[Abstract not available in the PubMed record at time of retrieval, 29 Aug 2026.]", "ai_intervention": "Sirolimus", "ai_target": "mTOR", "ai_species": "Human", "ai_effect": "Reported effective for paediatric Evans syndrome and secondary autoimmune cytopenias", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MCNEILL2026/" }, { "sid": "LI2026B", "title": "Brucella suis vaccine strain 2 promotes intracellular proliferation by inducing M2 macrophage polarization and autophagy through PI3K/Akt/mTOR signalling.", "authors": "Li H; Yang J; Xu T; Ji Z; Wang Zhenhai", "year": 2026, "journal": "Journal of Medical Microbiology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "BV2 murine microglial cells", "peer_reviewed": "Yes", "doi": "10.1099/jmm.0.002182", "pmid": "", "pmcid": "", "finding": "Brucella suis vaccine strain 2 drives mixed M1/M2 macrophage polarisation and autophagic activation in BV2 cells; the M2 state and autophagy synergistically promote intracellular bacterial replication through PI3K/Akt/mTOR signalling.\n", "abstract": "The persistent intracellular survival of Brucella is a key factor in immune evasion and chronic infection. This study investigated the interplay between macrophage polarization, autophagy and intracellular proliferation of Brucella suis vaccine strain 2 (S2) and the involvement of PI3K/AKT/mTOR signalling in BV2 cells. Following S2 infection, elevated expression of iNOS, Arg1, p-Akt, mTOR and autophagy-related proteins (LC3B-I, LC3B-II, ULK1) was observed with decreased p62. Laser confocal microscopy revealed efficient autophagosome-to-autolysosome conversion. Time-dependent increases in TNF and IL-10 secretion indicated a mixed M1/M2 phenotype. CFU assays demonstrated that PI3K/Akt/mTOR inhibition and autophagy induction promoted S2 intracellular proliferation, and pharmacological inhibition of the pathway reversed this effect by promoting M1 polarization while suppressing autophagic activity.", "ai_intervention": "Brucella suis S2 infection; PI3K/Akt/mTOR inhibitors; autophagy modulators", "ai_target": "PI3K/Akt/mTOR; autophagy (LC3B, ULK1, p62); macrophage polarization", "ai_species": "Mouse (BV2 cell line)", "ai_effect": "M2 polarization plus autophagy promoted intracellular bacterial replication; pathway inhibition shifted cells to M1 and suppressed autophagy", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LI2026B/" }, { "sid": "WOL2017", "title": "KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1", "authors": "Wolfson RL; Sabatini DM et al.", "year": 2017, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/nature21423", "pmid": "28199306", "pmcid": "PMC5360989", "finding": "KICSTOR tethers GATOR1 to the lysosome, required for nutrient control of mTORC1.\n", "abstract": "The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth that responds to diverse environmental signals and is deregulated in many human diseases, including cancer and epilepsy. Amino acids are a key input to this system, and act through the Rag GTPases to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. Multiple protein complexes regulate the Rag GTPases in response to amino acids, including GATOR1, a GTPase activating protein for RAGA, and GATOR2, a positive regulator of unknown molecular function. Here we identify a protein complex (KICSTOR) that is composed of four proteins, KPTN, ITFG2, C12orf66 and SZT2, and that is required for amino acid or glucose deprivation to inhibit mTORC1 in cultured human cells. In mice that lack SZT2, mTORC1 signalling is increased in several tissues, including in neurons in the brain. KICSTOR localizes to lysosomes; binds and recruits GATOR1, but not GATOR2, to the lysosomal surface; and is necessary for the interaction of GATOR1 with its substrates, the Rag GTPases, and with GATOR2. Notably, several KICSTOR components are mutated in neurological diseases associated with mutations that lead to hyperactive mTORC1 signalling. Thus, KICSTOR is a lysosome-associated negative regulator of mTORC1 signalling, which, like GATOR1, is mutated in human disease.", "ai_intervention": "Biochemical/genetic (KICSTOR)", "ai_target": "KICSTOR / GATOR1 / Rag / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "KICSTOR recruits GATOR1 to the lysosome and is required for nutrients to regulate mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WOL2017/" }, { "sid": "BET2013", "title": "mTOR complex 2-Akt signaling at mitochondria-associated endoplasmic reticulum membranes (MAM) regulates mitochondrial physiology", "authors": "Betz C; Hall MN et al.", "year": 2013, "journal": "Proceedings of the National Academy of Sciences of the United States of America", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1073/pnas.1302455110", "pmid": "23852728", "pmcid": "PMC3732980", "finding": "mTORC2-Akt signalling localizes to mitochondria-associated ER membranes to regulate mitochondrial function.\n", "abstract": "The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here we report that mTORC2 is localized to the endoplasmic reticulum (ER) subcompartment termed mitochondria-associated ER membrane (MAM). mTORC2 localization to MAM was growth factor-stimulated, and mTORC2 at MAM interacted with the IP3 receptor (IP3R)-Grp75-voltage-dependent anion-selective channel 1 ER-mitochondrial tethering complex. mTORC2 deficiency disrupted MAM, causing mitochondrial defects including increases in mitochondrial membrane potential, ATP production, and calcium uptake. mTORC2 controlled MAM integrity and mitochondrial function via Akt mediated phosphorylation of the MAM associated proteins IP3R, Hexokinase 2, and phosphofurin acidic cluster sorting protein 2. Thus, mTORC2 is at the core of a MAM signaling hub that controls growth and metabolism.", "ai_intervention": "Biochemical/genetic (mTORC2)", "ai_target": "mTORC2 / Akt / MAM", "ai_species": "Mammalian cells", "ai_effect": "mTORC2-Akt localizes to mitochondria-associated ER membranes (MAM) to regulate mitochondrial physiology", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BET2013/" }, { "sid": "OSH2007", "title": "The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1", "authors": "Oshiro N; Yonezawa K et al.", "year": 2007, "journal": "The Journal of biological chemistry", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1074/jbc.M702636200", "pmid": "17517883", "pmcid": "PMC3199301", "finding": "PRAS40 is a physiological raptor-bound substrate and inhibitor of mTORC1.\n", "abstract": "The proline-rich Akt substrate of 40 kilodaltons (PRAS40) was identified as a raptor-binding protein that is phosphorylated directly by mammalian target of rapamycin (mTOR) complex 1 (mTORC1) but not mTORC2 in vitro, predominantly at PRAS40 (Ser(183)). The binding of S6K1 and 4E-BP1 to raptor requires a TOR signaling (TOS) motif, which contains an essential Phe followed by four alternating acidic and small hydrophobic amino acids. PRAS40 binding to raptor was severely inhibited by mutation of PRAS40 (Phe(129) to Ala). Immediately carboxyl-terminal to Phe(129) are two small hydrophobic amino acid followed by two acidic residues. PRAS40 binding to raptor was also abolished by mutation of the major mTORC1 phosphorylation site, Ser(183), to Asp. PRAS40 (Ser(183)) was phosphorylated in intact cells; this phosphorylation was inhibited by rapamycin, by 2-deoxyglucose, and by overexpression of the tuberous sclerosis complex heterodimer. PRAS40 (Ser(183)) phosphorylation was also inhibited reversibly by withdrawal of all or of only the branched chain amino acids; this inhibition was reversed by overexpression of the Rheb GTPase. Overexpressed PRAS40 suppressed the phosphorylation of S6K1 and 4E-BP1 at their rapamycin-sensitive phosphorylation sites, and reciprocally, overexpression of S6K1 or 4E-BP1 suppressed phosphorylation of PRAS40 (Ser(183)) and its binding to raptor. RNA interference-induced depletion of PRAS40 enhanced the amino acid-stimulated phosphorylation of both S6K1 and 4E-BP1. These results establish PRAS40 as a physiological mTORC1 substrate that contains a variant TOS motif. Moreover, they indicate that the ability of raptor to bind endogenous substrates is limiting for the activity of mTORC1 in vivo and is therefore a potential locus of regulation.", "ai_intervention": "Biochemical (PRAS40)", "ai_target": "mTORC1 / PRAS40", "ai_species": "Mammalian cells", "ai_effect": "PRAS40 is a raptor-binding physiological mTORC1 substrate (phosphorylated at Ser183)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/OSH2007/" }, { "sid": "RAV2004", "title": "Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease", "authors": "Ravikumar B; Rubinsztein DC et al.", "year": 2004, "journal": "Nature Genetics", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Drosophila and mouse models of Huntington's disease", "peer_reviewed": "Yes", "doi": "10.1038/ng1362", "pmid": "15146184", "pmcid": "", "finding": "Rapamycin-induced autophagy cleared toxic clumped proteins and improved symptoms in fly and mouse models of Huntington's disease.\n", "abstract": "Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.", "ai_intervention": "Rapamycin (mTOR inhibition)", "ai_target": "mTOR / autophagy", "ai_species": "Drosophila and mouse Huntington's disease models", "ai_effect": "mTOR inhibition induces autophagy and reduces polyglutamine toxicity in Huntington's disease models", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/RAV2004/" }, { "sid": "HEN2026", "title": "Survival and Homeostasis of Alveolar Macrophages in Vivo Depend on mTOR Signaling", "authors": "Hennessy-Strahs S; Su X; Sun S; Deng G; Muo W; Li Jiarui; Miller T; Xiao X; Li XC", "year": 2026, "journal": "American Journal of Respiratory Cell and Molecular Biology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (myeloid-specific Mtor deletion); GM-CSF-driven alveolar-macrophage-like cell culture (in vitro)", "peer_reviewed": "Yes", "doi": "10.1093/ajrcmb/aanag139", "pmid": "42578718", "pmcid": "", "finding": "Myeloid-specific deletion of mTOR (and pharmacologic mTOR inhibition with temsirolimus) causes progressive depletion of alveolar macrophages, impaired phagocytosis, lipid accumulation and PAP-like lung pathology in mice, identifying mTOR as a nonredundant regulator of alveolar macrophage survival — mechanistic support for mTOR-inhibitor-associated pulmonary toxicity.\n", "abstract": "Alveolar homeostasis depends on tissue-resident professional phagocytes known as alveolar macrophages (AMs) that catabolize pulmonary surfactant. Pulmonary alveolar proteinosis (PAP) arises from impaired surfactant clearance due to loss or dysfunction of AMs, most commonly from disrupted GM-CSF-dependent AM homeostasis and less frequently from congenital defects in surfactant synthesis or processing. PAP has also been reported as a pulmonary toxicity associated with mTOR inhibitor-based immunosuppressive therapy. Although mTOR activity regulates macrophage metabolism and proliferation, its requirement for AM survival and lipid homeostasis remains unclear. Here, we examined the role of mTOR in AM survival and surfactant homeostasis, using complementary genetic and pharmacologic approaches in vivo, and GM-CSF-driven AM-like cell culture models in vitro. Myeloid-specific deletion of mTOR caused progressive, preferential depletion of AMs among tissue-resident macrophage populations, accompanied by impaired phagocytosis, intracellular lipid accumulation, and development of PAP-like lung pathology. In vivo, pharmacologic mTOR inhibition with temsirolimus reproduced key features of genetic mTOR deletion, including AM depletion, apoptosis, lipid accumulation, and PAP-like pathology. In vitro, mTOR activity was required to sustain GM-CSF-dependent expansion, maturation, and survival of AM-like cells. Mechanistically, mTOR loss reduced expression of PPARgamma and pro-survival Bcl-2 family members, linking mTOR activity to AM viability and lipid handling capacity. In summary, these findings identify mTOR as a nonredundant, cell-intrinsic regulator of alveolar macrophage survival and function required to maintain alveolar homeostasis. This work provides experimental support for AM-intrinsic mechanisms contributing to mTOR inhibitor-associated pulmonary toxicity, including PAP.", "ai_intervention": "Myeloid-specific Mtor genetic deletion; temsirolimus (pharmacologic mTOR inhibitor)", "ai_target": "mTOR / PPARgamma / Bcl-2 family", "ai_species": "Mouse (in vivo); GM-CSF-driven AM-like cells (in vitro)", "ai_effect": "mTOR loss (genetic or pharmacologic) depletes alveolar macrophages and causes PAP-like lung pathology; mTOR required for AM survival, phagocytosis and lipid handling", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HEN2026/" }, { "sid": "ZHOU2026B", "title": "Corilagin attenuates osteoarthritis progression by coordinating NF-κB inhibition with PI3K/AKT/mTOR-associated autophagy restoration.", "authors": "Zhou R; Li Jie; Chen S et al.", "year": 2026, "journal": "International Immunopharmacology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (DMM OA model); primary mouse chondrocytes", "peer_reviewed": "Yes", "doi": "10.1016/j.intimp.2026.117342", "pmid": "", "pmcid": "", "finding": "Corilagin restores chondrocyte autophagic flux and ECM synthesis by inhibiting PI3K/AKT/mTOR and NF-κB signalling, reducing cartilage erosion and OARSI scores in the mouse DMM osteoarthritis model.\n", "abstract": "Osteoarthritis (OA) is characterized by persistent inflammation, extracellular matrix degradation and impaired autophagy. IL-1β-stimulated primary mouse chondrocytes were used to evaluate Corilagin. Corilagin restored chondrocyte proliferation and increased Aggrecan, collagen II and SOX9 expression while reducing MMP3, MMP13, iNOS and COX2. Mechanistically, Corilagin inhibited PI3K/AKT/mTOR and NF-κB signaling, reduced p65 nuclear translocation and restored autophagic flux (increased Beclin-1 and LC3 II/I, decreased p62). 3-MA partially abolished these protective effects. In vivo, intra-articular Corilagin reduced osteophyte formation, cartilage erosion, proteoglycan loss and OARSI scores in a destabilization of the medial meniscus mouse OA model.", "ai_intervention": "Corilagin (intra-articular)", "ai_target": "PI3K/AKT/mTOR; NF-κB; autophagy (Beclin-1, LC3, p62)", "ai_species": "Mouse", "ai_effect": "Restored autophagic flux, suppressed catabolic and inflammatory markers, protected cartilage in vivo", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZHOU2026B/" }, { "sid": "TAO2026", "title": "Impaired mTOR/SREBP1-Mediated Lipogenesis as a Mechanism of Hepatic Glycogen Accumulation in a Carnivorous Fish Model, Largemouth Bass (Micropterus salmoides)", "authors": "Tao J; Chen S; Liu N; Gong Y; Zhang S; He J; Huang X; Chen N; Li S", "year": 2026, "journal": "FASEB Journal", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Carnivorous fish (hepatic glycogen accumulation model)", "peer_reviewed": "Yes", "doi": "10.1096/fj.202602519R", "pmid": "42606523", "pmcid": "", "finding": "mTOR/SREBP1 signaling governs hepatic glucose partitioning; the insulin-responsive mTOR/SREBP1 axis promotes lipogenesis versus glycogen accumulation. In this model -- a carnivorous fish -- an impaired axis causes hepatic glycogen overload mimicking glucose intolerance.\n", "abstract": "", "ai_intervention": "", "ai_target": "", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/TAO2026/" }, { "sid": "MCC2011", "title": "Efficacy and safety of sirolimus in lymphangioleiomyomatosis (MILES)", "authors": "McCormack FX; Inoue Y; Moss J; Singer LG; Strange C; et al.; Trapnell BC", "year": 2011, "journal": "New England Journal of Medicine", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, RCT (n=89, women with LAM)", "peer_reviewed": "Yes", "doi": "10.1056/NEJMoa1100391", "pmid": "21410393", "pmcid": "PMC3118601", "finding": "A landmark placebo-controlled RCT (n=89) - the first to show that rapamycin (sirolimus) benefits a human lung disease. In LAM, lung function normally declines relentlessly; sirolimus STOPPED that decline while patients took it (and it resumed after stopping). Randomised human evidence that mTOR inhibition can suspend progression of this disease; the benefit did not persist after withdrawal.\n", "abstract": "Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM.\n\nWe conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)).\n\nDuring the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups.\n\nIn patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).", "ai_intervention": "Sirolimus (rapamycin)", "ai_target": "mTOR", "ai_species": "Human – RCT (MILES, n=89, women with LAM)", "ai_effect": "Sirolimus stabilized lung function (FEV1) in lymphangioleiomyomatosis during treatment", "ai_dose": "Oral sirolimus, initial 2 mg/day titrated to trough 5-15 ng/ml; 12-month double-blind treatment + 12-month observation off-drug; 1:1 vs placebo (MILES).", "ai_samplesize": "111 consented, 89 randomized (43 placebo / 46 sirolimus); women with LAM, FEV1 <=70% predicted.", "ai_effectsize": "Primary outcome FEV1 slope (mL/month): sirolimus stabilized lung function during treatment while placebo declined; benefit waned after stopping the drug.", "ai_limitations": "Interim analysis delayed by site/contracting issues; other health-symptom measures not significantly different; benefit tied to continued dosing.", "atlas_url": "https://mtor-atlas.org/study/MCC2011/" }, { "sid": "BOD2001", "title": "Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo", "authors": "Bodine SC; Yancopoulos GD et al.", "year": 2001, "journal": "Nature cell biology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse; muscle", "peer_reviewed": "Yes", "doi": "10.1038/ncb1101-1014", "pmid": "11715023", "pmcid": "", "finding": "Akt/mTOR signalling is necessary and sufficient to drive skeletal-muscle hypertrophy and counteract atrophy in vivo.\n", "abstract": "Skeletal muscles adapt to changes in their workload by regulating fibre size by unknown mechanisms. The roles of two signalling pathways implicated in muscle hypertrophy on the basis of findings in vitro, Akt/mTOR (mammalian target of rapamycin) and calcineurin/NFAT (nuclear factor of activated T cells), were investigated in several models of skeletal muscle hypertrophy and atrophy in vivo. The Akt/mTOR pathway was upregulated during hypertrophy and downregulated during muscle atrophy. Furthermore, rapamycin, a selective blocker of mTOR, blocked hypertrophy in all models tested, without causing atrophy in control muscles. In contrast, the calcineurin pathway was not activated during hypertrophy in vivo, and inhibitors of calcineurin, cyclosporin A and FK506 did not blunt hypertrophy. Finally, genetic activation of the Akt/mTOR pathway was sufficient to cause hypertrophy and prevent atrophy in vivo, whereas genetic blockade of this pathway blocked hypertrophy in vivo. We conclude that the activation of the Akt/mTOR pathway and its downstream targets, p70S6K and PHAS-1/4E-BP1, is requisitely involved in regulating skeletal muscle fibre size, and that activation of the Akt/mTOR pathway can oppose muscle atrophy induced by disuse.", "ai_intervention": "Genetic/pharmacologic (Akt/mTOR; rapamycin)", "ai_target": "Akt / mTOR", "ai_species": "Mouse; muscle", "ai_effect": "Akt/mTOR is necessary and sufficient for skeletal muscle hypertrophy and prevents atrophy in vivo", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BOD2001/" }, { "sid": "DIB2012", "title": "TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1", "authors": "Dibble CC; Manning BD et al.", "year": 2012, "journal": "Molecular cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.molcel.2012.06.009", "pmid": "22795129", "pmcid": "PMC3693578", "finding": "TBC1D7 is the third core subunit of the TSC1-TSC2 complex regulating Rheb/mTORC1.\n", "abstract": "The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.", "ai_intervention": "Biochemical/genetic (TBC1D7)", "ai_target": "TSC1-TSC2-TBC1D7 / Rheb / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "TBC1D7 is a third subunit of the TSC1-TSC2 complex that regulates Rheb and mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DIB2012/" }, { "sid": "BIT2016", "title": "Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice", "authors": "Bitto A; Kaeberlein M et al.", "year": 2016, "journal": "eLife", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Negative_result", "model": "Mouse (middle-aged)", "peer_reviewed": "Yes", "doi": "10.7554/eLife.16351", "pmid": "27549339", "pmcid": "PMC4996648", "finding": "Just 3 months of rapamycin late in life increased subsequent life expectancy by up to 60% - evidence that transient, not lifelong, dosing can capture the benefit.\n", "abstract": "The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.", "ai_intervention": "Rapamycin (transient, 3 months)", "ai_target": "mTOR", "ai_species": "Mouse (middle-aged)", "ai_effect": "A 3-month transient rapamycin course increased life expectancy up to 60% and improved healthspan", "ai_dose": "8 mg/kg rapamycin via intraperitoneal (i.p.) injections daily for 90 days, starting at 20–21 months of age.", "ai_samplesize": "Males: N=18 vehicle, N=17 rapamycin; Females: N=20 vehicle, N=20 rapamycin for survival analysis.", "ai_effectsize": "Male mice: 60% increase in median life expectancy from end of treatment (p=0.02) and 16% increase in overall median lifespan from birth (p=0.03). Female mice: no significant increase in survival (p=0.261), but increased incidence of aggressive hematopoietic cancers (16/16 vs 6/12 controls, p=0.002) and decreased non-hematopoietic neoplasms (1/16 vs 7/12 controls, p=0.004).", "ai_limitations": "No data on animals that may have died prior to receipt from NIA for lifespan curves.", "atlas_url": "https://mtor-atlas.org/study/BIT2016/" }, { "sid": "THO2009", "title": "An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1", "authors": "Thoreen CC; Kang SA; Chang JW; Liu Q; Zhang Jianming; Gao Y; Reichling LJ; Sim T; Sabatini DM; Gray NS", "year": 2009, "journal": "Journal of Biological Chemistry", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse/human cells", "peer_reviewed": "Yes", "doi": "10.1074/jbc.M900301200", "pmid": "19150980", "pmcid": "PMC2658096", "finding": "Dropped a bombshell: rapamycin does NOT fully block mTORC1. Using Torin1 (which jams the active site directly), the authors showed rapamycin leaves important mTORC1 jobs running - notably 4E-BP1 phosphorylation and autophagy suppression. This reframed a decade of rapamycin experiments and launched the search for complete inhibitors.\n", "abstract": "The mammalian target of rapamycin (mTOR) kinase is the catalytic subunit of two functionally distinct complexes, mTORC1 and mTORC2, that coordinately promote cell growth, proliferation, and survival. Rapamycin is a potent allosteric mTORC1 inhibitor with clinical applications as an immunosuppressant and anti-cancer agent. Here we find that Torin1, a highly potent and selective ATP-competitive mTOR inhibitor that directly inhibits both complexes, impairs cell growth and proliferation to a far greater degree than rapamycin. Surprisingly, these effects are independent of mTORC2 inhibition and are instead because of suppression of rapamycin-resistant functions of mTORC1 that are necessary for cap-dependent translation and suppression of autophagy. These effects are at least partly mediated by mTORC1-dependent and rapamycin-resistant phosphorylation of 4E-BP1. Our findings challenge the assumption that rapamycin completely inhibits mTORC1 and indicate that direct inhibitors of mTORC1 kinase activity may be more successful than rapamycin at inhibiting tumors that depend on mTORC1.", "ai_intervention": "Torin1 (ATP-competitive mTOR inhibitor)", "ai_target": "mTORC1 (rapamycin-resistant outputs, 4E-BP)", "ai_species": "Mouse/human cells", "ai_effect": "Torin1 reveals rapamycin-resistant functions of mTORC1 (e.g. 4E-BP1 phosphorylation, autophagy)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/THO2009/" }, { "sid": "LI2026", "title": "GPR143, a novel immunohistochemical marker for renal tumors with FLCN/TSC/MTOR-TFE alterations.", "authors": "Li Q, Singh A, Hu R, Huang J, Shapiro JB", "year": 2026, "journal": "Virchows Archiv", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human tissue (renal tumor specimens)", "peer_reviewed": "Yes", "doi": "10.1007/s00428-026-04646-4", "pmid": "42463886", "pmcid": "", "finding": "GPR143 is a sensitive and specific immunohistochemical biomarker for renal tumors driven by FLCN/TSC/MTOR-TFE pathway alterations, offering a practical diagnostic tool beyond existing ancillary tests.\n", "abstract": "Diagnosis of MiT/TFE family translocation renal cell carcinoma is challenging. This study identifies GPR143 as a novel immunohistochemical marker that reliably identifies renal tumors harboring FLCN/TSC/mTOR-TFE pathway alterations, offering a practical diagnostic aid.", "ai_intervention": "GPR143 immunohistochemistry", "ai_target": "MTOR / FLCN / TSC pathway in renal cell carcinoma", "ai_species": "Human", "ai_effect": "GPR143 overexpression identifies mTOR-pathway-driven renal tumors; positive diagnostic marker", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LI2026/" }, { "sid": "LAM2012", "title": "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity", "authors": "Lamming DW et al.; Sabatini DM", "year": 2012, "journal": "Science", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Side effect", "model": "Mouse (in vivo glucose and insulin tolerance)", "peer_reviewed": "Yes", "doi": "10.1126/science.1215135", "pmid": "22461615", "pmcid": "PMC3324089", "finding": "In mice, chronic rapamycin also disrupts mTORC2, causing insulin resistance; lifespan extension can be uncoupled from this side effect.\n", "abstract": "Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.", "ai_intervention": "Rapamycin (chronic)", "ai_target": "mTORC1 vs mTORC2", "ai_species": "Mouse", "ai_effect": "In mice, chronic rapamycin causes insulin resistance via disruption of mTORC2, uncoupled from its longevity effect", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LAM2012/" }, { "sid": "BAR2013", "title": "A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1", "authors": "Bar-Peled L; Chantranupong L; Cherniack AD; Chen WW; Ottina KA; Grabiner BC; Spear ED; Carter SL; Meyerson M; Sabatini DM", "year": 2013, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells + cancer genomics", "peer_reviewed": "Yes", "doi": "10.1126/science.1232044", "pmid": "23723238", "pmcid": "PMC3728654", "finding": "Found the OFF switch for amino acid signaling: the GATOR1 complex is a GAP that shuts the Rag GTPases (and thus mTORC1) down when amino acids run low, while GATOR2 opposes it. GATOR1 genes are mutated in cancers, making those tumors 'blind' to starvation and hypersensitive to rapamycin.\n", "abstract": "The mTOR complex 1 (mTORC1) pathway promotes cell growth in response to many cues, including amino acids, which act through the Rag guanosine triphosphatases (GTPases) to promote mTORC1 translocation to the lysosomal surface, its site of activation. Although progress has been made in identifying positive regulators of the Rags, it is unknown if negative factors also exist. Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and -2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, and Sec13) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, we identify a key negative regulator of the Rag GTPases and reveal that, like other mTORC1 regulators, Rag function can be deregulated in cancer.", "ai_intervention": "Biochemical/genetic (GATOR1/GATOR2)", "ai_target": "GATOR / Rag GTPases / mTORC1", "ai_species": "Human cells + cancer genomics", "ai_effect": "GATOR1 is a GAP for RagA/B (negative regulator); GATOR2 acts positively; GATOR1 lost in some cancers", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BAR2013/" }, { "sid": "MARCHANT2026", "title": "Constitutive mTORC1 Activation in Skeletal Muscle Increases Inflammation but is not Sufficient to Impair Glucose Tolerance.", "authors": "Marchant ED; Kalenta H; Kilroe SP; May J; Martini WZ; Weldon KS et al.", "year": 2026, "journal": "Function (Oxford, England)", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1152/function.039.2026", "pmid": "", "pmcid": "", "finding": "Constitutive mTORC1 activation in mouse skeletal muscle (via GATOR1 complex KO) increases inflammatory markers but is not sufficient to impair glucose tolerance, indicating that additional metabolic inputs beyond muscle mTORC1 hyperactivation are required to drive insulin resistance.\n", "abstract": "Aberrant mTORC1 signaling in skeletal muscle has been implicated in aging and insulin resistance, however, it is not known whether chronic mTORC1 activation directly causes glucose intolerance. We tested the hypothesis that constitutive mTORC1 activation in mouse skeletal muscle impairs glucose homeostasis using tamoxifen-inducible, muscle-specific GATOR1 complex knockout.", "ai_intervention": "Constitutive mTORC1 activation (GATOR1 muscle-specific KO)", "ai_target": "mTORC1 / GATOR1 complex", "ai_species": "Mouse", "ai_effect": "Increased skeletal muscle inflammation without impairment of glucose tolerance", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MARCHANT2026/" }, { "sid": "CHE2018", "title": "Cryo-EM structure of human mTOR complex 2", "authors": "Chen Xizi; Xu Y et al.", "year": 2018, "journal": "Cell research", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.1038/s41422-018-0029-3", "pmid": "29567957", "pmcid": "PMC5951902", "finding": "Cryo-EM structure of human mTORC2 defines its subunit organization and substrate access.\n", "abstract": "Mechanistic target of rapamycin (mTOR) complex 2 (mTORC2) plays an essential role in regulating cell proliferation through phosphorylating AGC protein kinase family members, including AKT, PKC and SGK1. The functional core complex consists of mTOR, mLST8, and two mTORC2-specific components, Rictor and mSin1. Here we investigated the intermolecular interactions within mTORC2 complex and determined its cryo-electron microscopy structure at 4.9 A resolution. The structure reveals a hollow rhombohedral fold with a 2-fold symmetry. The dimerized mTOR serves as a scaffold for the complex assembly. The N-terminal half of Rictor is composed of helical repeat clusters and binds to mTOR through multiple contacts. mSin1 is located close to the FRB domain and catalytic cavity of mTOR. Rictor and mSin1 together generate steric hindrance to inhibit binding of FKBP12-rapamycin to mTOR, revealing the mechanism for rapamycin insensitivity of mTORC2. The mTOR dimer in mTORC2 shows more compact conformation than that of mTORC1 (rapamycin sensitive), which might result from the interaction between mTOR and Rictor-mSin1. Structural comparison shows that binding of Rictor and Raptor (mTORC1-specific component) to mTOR is mutually exclusive. Our study provides a basis for understanding the assembly of mTORC2 and a framework to further characterize the regulatory mechanism of mTORC2 pathway.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "mTORC2 (mTOR/mLST8/Rictor/mSin1)", "ai_species": "Cryo-EM structure", "ai_effect": "Cryo-EM structure of human mTORC2 reveals intermolecular interactions of Rictor and mSin1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHE2018/" }, { "sid": "SET2012", "title": "A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB", "authors": "Settembre C; Ballabio A et al.", "year": 2012, "journal": "The EMBO journal", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/emboj.2012.32", "pmid": "22343943", "pmcid": "PMC3298007", "finding": "A lysosome-to-nucleus mechanism uses mTOR-dependent TFEB phosphorylation to sense lysosomal state.\n", "abstract": "The lysosome plays a key role in cellular homeostasis by controlling both cellular clearance and energy production to respond to environmental cues. However, the mechanisms mediating lysosomal adaptation are largely unknown. Here, we show that the Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, colocalizes with master growth regulator mTOR complex 1 (mTORC1) on the lysosomal membrane. When nutrients are present, phosphorylation of TFEB by mTORC1 inhibits TFEB activity. Conversely, pharmacological inhibition of mTORC1, as well as starvation and lysosomal disruption, activates TFEB by promoting its nuclear translocation. In addition, the transcriptional response of lysosomal and autophagic genes to either lysosomal dysfunction or pharmacological inhibition of mTORC1 is suppressed in TFEB-/- cells. Interestingly, the Rag GTPase complex, which senses lysosomal amino acids and activates mTORC1, is both necessary and sufficient to regulate starvation- and stress-induced nuclear translocation of TFEB. These data indicate that the lysosome senses its content and regulates its own biogenesis by a lysosome-to-nucleus signalling mechanism that involves TFEB and mTOR.", "ai_intervention": "Genetic/pharmacologic (mTORC1/TFEB)", "ai_target": "mTORC1 / TFEB", "ai_species": "Mammalian cells", "ai_effect": "A lysosome-to-nucleus signalling mechanism via mTORC1-TFEB senses and regulates the lysosome", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SET2012/" }, { "sid": "ANA2019", "title": "Architecture of human Rag GTPase heterodimers and their complex with mTORC1", "authors": "Anandapadamanaban M; Williams RL et al.", "year": 2019, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.1126/science.aax3939", "pmid": "31601764", "pmcid": "PMC6795536", "finding": "Structures of Rag GTPase heterodimers with mTORC1 explain nucleotide-state-dependent recruitment.\n", "abstract": "The Rag guanosine triphosphatases (GTPases) recruit the master kinase mTORC1 to lysosomes to regulate cell growth and proliferation in response to amino acid availability. The nucleotide state of Rag heterodimers is critical for their association with mTORC1. Our cryo-electron microscopy structure of RagA/RagC in complex with mTORC1 shows the details of RagA/RagC binding to the RAPTOR subunit of mTORC1 and explains why only the RagA/RagCnucleotide state binds mTORC1. Previous kinetic studies suggested that GTP binding to one Rag locks the heterodimer to prevent GTP binding to the other. Our crystal structures and dynamics of RagA/RagC show the mechanism for this locking and explain how oncogenic hotspot mutations disrupt this process. In contrast to allosteric activation by RHEB, Rag heterodimer binding does not change mTORC1 conformation and activates mTORC1 by targeting it to lysosomes.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "RagA/RagC / RAPTOR / mTORC1", "ai_species": "Cryo-EM structure", "ai_effect": "Structure of RagA/RagC bound to mTORC1 (RAPTOR) explains nucleotide-state-dependent recruitment", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ANA2019/" }, { "sid": "LON2005", "title": "Rheb binds and regulates the mTOR kinase", "authors": "Long X; Avruch J et al.", "year": 2005, "journal": "Current biology : CB", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "In vitro", "peer_reviewed": "Yes", "doi": "10.1016/j.cub.2005.02.053", "pmid": "15854902", "pmcid": "", "finding": "Rheb binds the mTOR kinase domain and directly stimulates its activity.\n", "abstract": "The target of rapamycin (TOR), in complex with the proteins raptor and LST8 (TOR complex 1), phosphorylates the p70S6K and 4E-BP1 to promote mRNA translation. Genetic evidence establishes that TOR complex activity in vivo requires the small GTPase Rheb, and overexpression of Rheb can rescue TOR from inactivation in vivo by amino-acid withdrawal. The Tuberous Sclerosis heterodimer (TSC1/TSC2) functions as a Rheb GTPase activator and inhibits TOR signaling in vivo. Here, we show that Rheb binds to the TOR complex specifically, independently of its ability to bind TSC2, through separate interactions with the mTOR catalytic domain and with LST8. Rheb binding to the TOR complex in vivo and in vitro does not require Rheb guanyl nucleotide charging but is modulated by GTP and impaired by certain mutations (Ile39Lys) in the switch 1 loop. Nucleotide-deficient Rheb mutants, although capable of binding mTOR in vivo and in vitro, are inhibitory in vivo, and the mTOR polypeptides that associate with nucleotide-deficient Rheb in vivo lack kinase activity in vitro. Reciprocally, mTOR polypeptides bound to Rheb(Gln64Leu), a mutant that is nearly 90% GTP charged, exhibit substantially higher protein kinase specific activity than mTOR bound to wild-type Rheb. The TOR complex 1 is a direct target of Rheb-GTP, whose binding enables activation of the TOR kinase.", "ai_intervention": "Biochemical (Rheb)", "ai_target": "Rheb / mTORC1", "ai_species": "In vitro", "ai_effect": "Rheb binds and directly regulates the mTOR kinase (with TSC1/2 acting as its GAP)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LON2005/" }, { "sid": "SHI2014", "title": "Making new contacts: the mTOR network in metabolism and signalling crosstalk", "authors": "Shimobayashi M; Hall MN et al.", "year": 2014, "journal": "Nature reviews. Molecular cell biology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1038/nrm3757", "pmid": "24556838", "pmcid": "", "finding": "Review of the mTOR network in metabolism and signalling crosstalk.\n", "abstract": "More than 20 years after its discovery, our understanding of target of rapamycin (TOR) signalling continues to grow. Recent global omics studies have revealed physiological roles of mammalian TOR (mTOR) in protein, nucleotide and lipid synthesis. Furthermore, emerging evidence provides new insight into the control of mTOR by other pathways such as Hippo, WNT and Notch signalling. Together, this progress has expanded the list of downstream effectors and upstream regulators of mTOR signalling.", "ai_intervention": "Not applicable (review)", "ai_target": "mTOR network", "ai_species": "Review", "ai_effect": "Reviews mTOR crosstalk with Hippo/WNT/Notch and its roles in protein, nucleotide and lipid synthesis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SHI2014/" }, { "sid": "JOH2013", "title": "mTOR is a key modulator of ageing and age-related disease", "authors": "Johnson SC; Rabinovitch PS; Kaeberlein M", "year": 2013, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review (multi-species synthesis)", "peer_reviewed": "Yes", "doi": "10.1038/nature11861", "pmid": "23325216", "pmcid": "PMC3687363", "finding": "The landmark Nature review that put mTOR at the center of aging biology. Lays out the case that inhibiting mTOR extends lifespan across species and guards against a growing list of age-related diseases - while being candid that side effects currently block its use in healthy people. Excellent orientation map for the whole field.\n", "abstract": "Many experts in the biology of ageing believe that pharmacological interventions to slow ageing are a matter of 'when' rather than 'if'. A leading target for such interventions is the nutrient response pathway defined by the mechanistic target of rapamycin (mTOR). Inhibition of this pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies. Characterized inhibitors of this pathway are already clinically approved, and others are under development. Although adverse side effects currently preclude use in otherwise healthy individuals, drugs that target the mTOR pathway could one day become widely used to slow ageing and reduce age-related pathologies in humans.", "ai_intervention": "Not applicable (review)", "ai_target": "mTOR", "ai_species": "Review", "ai_effect": "Reviews mTOR as a key modulator of ageing and age-related disease across species", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JOH2013/" }, { "sid": "DRU2009", "title": "Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis", "authors": "Drummond MJ; Rasmussen BB et al.", "year": 2009, "journal": "Journal of Physiology", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, controlled trial", "peer_reviewed": "Yes", "doi": "10.1113/jphysiol.2008.163816", "pmid": "19188252", "pmcid": "PMC2678224", "finding": "Rapamycin given before resistance exercise completely blocked the normal post-exercise increase in human muscle protein synthesis.\n", "abstract": "Muscle protein synthesis and mTORC1 signalling are concurrently stimulated following muscle contraction in humans. In an effort to determine whether mTORC1 signalling is essential for regulating muscle protein synthesis in humans, we treated subjects with a potent mTORC1 inhibitor (rapamycin) prior to performing a series of high-intensity muscle contractions. Here we show that rapamycin treatment blocks the early (1-2 h) acute contraction-induced increase ( approximately 40%) in human muscle protein synthesis. In addition, several downstream components of the mTORC1 signalling pathway were also blunted or blocked by rapamycin. For instance, S6K1 phosphorylation (Thr421/Ser424) was increased post-exercise 6-fold in the control group while being unchanged with rapamycin treatment. Furthermore, eEF2 phosphorylation (Thr56) was reduced by approximately 25% post-exercise in the control group but phosphorylation following rapamycin treatment was unaltered, indicating that translation elongation was inhibited. Rapamycin administration prior to exercise also reduced the ability of raptor to associate with mTORC1 during post-exercise recovery. Surprisingly, rapamycin treatment prior to resistance exercise completely blocked the contraction-induced increase in the phosphorylation of ERK1/2 (Thr202/Tyr204) and blunted the increase in MNK1 (Thr197/202) phosphorylation. However, the phosphorylation of a known target of MNK1, eIF4E (Ser208), was similar in both groups (P > 0.05) which is consistent with the notion that rapamycin does not directly inhibit MAPK signalling. We conclude that mTORC1 signalling is, in part, playing a key role in regulating the contraction-induced stimulation of muscle protein synthesis in humans, while dual activation of mTORC1 and ERK1/2 stimulation may be required for full stimulation of human skeletal muscle protein synthesis.", "ai_intervention": "Rapamycin (pre-exercise)", "ai_target": "mTORC1", "ai_species": "Human – controlled trial", "ai_effect": "Rapamycin blocks the contraction-induced increase in human skeletal muscle protein synthesis", "ai_dose": "Rapamycin, single oral dose before a bout of high-intensity resistance exercise (exact mg not captured; full text not retrievable via PMC).", "ai_samplesize": "Small human controlled trial (full text unavailable; abstract-level).", "ai_effectsize": "Rapamycin blocked the early (1-2 h) ~40% contraction-induced increase in human muscle protein synthesis; downstream mTORC1 signaling (S6K1) blunted.", "ai_limitations": "Small sample; full text not retrievable via PMC, so dose/n taken from abstract only.", "atlas_url": "https://mtor-atlas.org/study/DRU2009/" }, { "sid": "NEF2013", "title": "Rapamycin extends murine lifespan but has limited effects on aging", "authors": "Neff F; Ehninger D et al.", "year": 2013, "journal": "The Journal of clinical investigation", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1172/JCI67674", "pmid": "23863708", "pmcid": "PMC3726163", "finding": "Rapamycin extends murine lifespan but has only limited effects on classic aging phenotypes.\n", "abstract": "Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.", "ai_intervention": "Rapamycin", "ai_target": "mTOR", "ai_species": "Mouse", "ai_effect": "Rapamycin extends lifespan but improves relatively few aging phenotypes – lifespan effect partly separable from aging", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/NEF2013/" }, { "sid": "YANG2026", "title": "Early-life exposure to polypropylene microplastics and DEHP induces ASD-relevant neurodevelopmental alterations involving mTOR-regulated autophagy impairment", "authors": "Yang G; Gong C; Zheng X; Chen H; Wang Y; Zhang H; Hu F; Wan J; Zhu Z; Sun X; Zhang L; Li R", "year": 2026, "journal": "Ecotoxicology and Environmental Safety", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (ICR, early-life exposure model)", "peer_reviewed": "Yes", "doi": "10.1016/j.ecoenv.2026.120659", "pmid": "", "pmcid": "", "finding": "PP-MPs and DEHP activate mTOR and impair autophagy, inducing ASD-like neurodevelopmental deficits in mice; rapamycin rescues autophagic flux and social/behavioral phenotypes.\n", "abstract": "Early-life exposure of ICR mice to polypropylene microplastics (PP-MPs) and/or DEHP caused ASD-relevant neurodevelopmental alterations including social interaction deficits, anxiety, and neuronal/synaptic damage in the prefrontal cortex. Proteomic analysis identified the mTOR signaling pathway as a key mechanism. PP-MPs/DEHP exposure activated mTOR signaling with autophagic impairment and dysregulated synaptic plasticity. Rapamycin restored autophagic activity and ameliorated ASD-relevant neurodevelopmental alterations, confirming mTOR-regulated autophagic impairment as the mechanistic basis.", "ai_intervention": "Polypropylene microplastics (PP-MPs); DEHP; Rapamycin (rescue)", "ai_target": "mTOR signaling; autophagy; Shank3; Nlgn1 (synaptic plasticity)", "ai_species": "Mouse", "ai_effect": "mTOR hyperactivation + autophagy impairment mediates ASD-like neurotoxicity from early-life plastic/plasticizer exposure; mTOR inhibition is protective", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/YANG2026/" }, { "sid": "FOK2014", "title": "Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome", "authors": "Fok WC; Richardson A et al.", "year": 2014, "journal": "PloS one", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1371/journal.pone.0083988", "pmid": "24409289", "pmcid": "PMC3883653", "finding": "Rapamycin-fed mice show extended lifespan with major changes in the liver transcriptome.\n", "abstract": "Rapamycin was found to increase (11% to 16%) the lifespan of male and female C57BL/6J mice most likely by reducing the increase in the hazard for mortality (i.e., the rate of aging) term in the Gompertz mortality analysis. To identify the pathways that could be responsible for rapamycin's longevity effect, we analyzed the transcriptome of liver from 25-month-old male and female mice fed rapamycin starting at 4 months of age. Few changes (<300 transcripts) were observed in transcriptome of rapamycin-fed males; however, a large number of transcripts (>4,500) changed significantly in females. Using multidimensional scaling and heatmap analyses, the male mice fed rapamycin were found to segregate into two groups: one group that is almost identical to control males (Rapa-1) and a second group (Rapa-2) that shows a change in gene expression (>4,000 transcripts) with more than 60% of the genes shared with female mice fed Rapa. Using ingenuity pathway analysis, 13 pathways were significantly altered in both Rapa-2 males and rapamycin-fed females with mitochondrial function as the most significantly changed pathway. Our findings show that rapamycin has a major effect on the transcriptome and point to several pathways that would likely impact the longevity.", "ai_intervention": "Rapamycin (from 4 months of age)", "ai_target": "mTOR", "ai_species": "Mouse (C57BL/6J)", "ai_effect": "Rapamycin increased lifespan 11-16% with major changes in the liver transcriptome", "ai_dose": "14 ppm encapsulated rapamycin in food, ad libitum, starting at 4 months of age until end of life", "ai_samplesize": "175 mice total (40 control males, 45 Rapa males, 45 control females, 45 Rapa females)", "ai_effectsize": "Rapamycin increased lifespan 16% in females and 11% in males (entire survival curve analysis), and significantly increased mean (14% females, 7% males) and maximum (19% females, 8% males) survival.", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/FOK2014/" }, { "sid": "WAG2014", "title": "Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib", "authors": "Wagle N; Rosenberg JE et al.", "year": 2014, "journal": "Cancer discovery", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Human (patient)", "peer_reviewed": "Yes", "doi": "10.1158/2159-8290.CD-13-0353", "pmid": "24625776", "pmcid": "PMC4122326", "finding": "An activating MTOR mutation is implicated in an extraordinary clinical response to rapalog therapy. Single-patient observation: hypothesis-generating, not evidence of a general response predictor.\n", "abstract": "Understanding the genetic mechanisms of sensitivity to targeted anticancer therapies may improve patient selection, response to therapy, and rational treatment designs. One approach to increase this understanding involves detailed studies of exceptional responders: rare patients with unexpected exquisite sensitivity or durable responses to therapy. We identified an exceptional responder in a phase I study of pazopanib and everolimus in advanced solid tumors. Whole-exome sequencing of a patient with a 14-month complete response on this trial revealed two concurrent mutations in mTOR, the target of everolimus. In vitro experiments demonstrate that both mutations are activating, suggesting a biologic mechanism for exquisite sensitivity to everolimus in this patient. The use of precision (or personalized) medicine approaches to screen patients with cancer for alterations in the mTOR pathway may help to identify subsets of patients who may benefit from targeted therapies directed against mTOR.", "ai_intervention": "Everolimus + pazopanib (mTOR inhibition)", "ai_target": "mTOR (activating mutations)", "ai_species": "Human (patient, phase I)", "ai_effect": "Activating mTOR mutations underlie an extraordinary response to everolimus in a phase I patient", "ai_dose": "Pazopanib 400 mg daily + everolimus 5 mg daily (MTD; 600 mg + 5 mg gave dose-limiting toxicities); phase I.", "ai_samplesize": "9 patients enrolled (5 urothelial, others lung/carcinoid); an exceptional responder analyzed by sequencing.", "ai_effectsize": "Activating mTOR mutations underlie the extraordinary response to everolimus+pazopanib. 5/9 patients had grade >=3 toxicity (56%, 95% CI 21.2-86.3%); everolimus AUC 41% higher when combined with pazopanib.", "ai_limitations": "Inference from a single exceptional responder; basis of mTOR-inhibitor sensitivity incompletely understood; short drug exposure in some.", "atlas_url": "https://mtor-atlas.org/study/WAG2014/" }, { "sid": "KAL2010", "title": "Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner", "authors": "Kalender A; Selvaraj A; Thomas G; Kozma SC et al.", "year": 2010, "journal": "Cell Metabolism", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells (AMPK-null and TSC1/2-null)", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2010.03.014", "pmid": "20444419", "pmcid": "", "finding": "Metformin inhibits mTORC1 even in cells lacking AMPK or TSC1/TSC2, and the effect requires the Rag GTPases instead. Together with Foretz 2010 this places a large part of metformin's action outside the AMPK axis it is usually credited to.\n", "abstract": "Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. Consistent with these observations, in two distinct preclinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.", "ai_intervention": "", "ai_target": "Metformin -> Rag GTPases -> mTORC1 (AMPK-independent)", "ai_species": "Mammalian cells", "ai_effect": "Metformin inhibits mTORC1 without AMPK or TSC1/2, in a Rag GTPase-dependent manner", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KAL2010/" }, { "sid": "REB2015", "title": "SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1", "authors": "Rebsamen M; Superti-Furga G et al.", "year": 2015, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/nature14107", "pmid": "25561175", "pmcid": "PMC4376665", "finding": "SLC38A9 is a component of the lysosomal amino-acid sensing machinery controlling mTORC1.\n", "abstract": "Cell growth and proliferation are tightly linked to nutrient availability. The mechanistic target of rapamycin complex 1 (mTORC1) integrates the presence of growth factors, energy levels, glucose and amino acids to modulate metabolic status and cellular responses. mTORC1 is activated at the surface of lysosomes by the RAG GTPases and the Ragulator complex through a not fully understood mechanism monitoring amino acid availability in the lysosomal lumen and involving the vacuolar H(+)-ATPase. Here we describe the uncharacterized human member 9 of the solute carrier family 38 (SLC38A9) as a lysosomal membrane-resident protein competent in amino acid transport. Extensive functional proteomic analysis established SLC38A9 as an integral part of the Ragulator-RAG GTPases machinery. Gain of SLC38A9 function rendered cells resistant to amino acid withdrawal, whereas loss of SLC38A9 expression impaired amino-acid-induced mTORC1 activation. Thus SLC38A9 is a physical and functional component of the amino acid sensing machinery that controls the activation of mTOR.", "ai_intervention": "Biochemical/genetic (SLC38A9)", "ai_target": "SLC38A9 / Rag-Ragulator / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "SLC38A9 is a lysosomal amino-acid (arginine) transporter/sensor component that controls mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/REB2015/" }, { "sid": "WEI2008", "title": "The TSC-mTOR signaling pathway regulates the innate inflammatory response", "authors": "Weichhart T; Saemann MD et al.", "year": 2008, "journal": "Immunity", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse/human monocytes", "peer_reviewed": "Yes", "doi": "10.1016/j.immuni.2008.08.012", "pmid": "18848473", "pmcid": "", "finding": "The TSC-mTOR pathway controls the innate inflammatory response of monocytes/macrophages.\n", "abstract": "The innate inflammatory immune response must be tightly controlled to avoid damage to the host. Here, we showed that the tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) pathway regulated inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Inhibition of mTOR by rapamycin promoted production of proinflammatory cytokines via the transcription factor NF-kappaB but blocked the release of interleukin-10 via the transcription factor STAT3. Conversely, deletion of TSC2, the key negative regulator of mTOR, diminished NF-kappaB but enhanced STAT3 activity and reversed this proinflammatory cytokine shift. Rapamycin-hyperactivated monocytes displayed a strong T helper 1 (Th1) cell- and Th17 cell-polarizing potency. Inhibition of mTOR in vivo regulated the inflammatory response and protected genetically susceptible mice against lethal Listeria monocytogenes infection. These data identify the TSC2-mTOR pathway as a key regulator of innate immune homeostasis with broad clinical implications for infectious and autoimmune diseases, vaccination, cancer, and transplantation.", "ai_intervention": "Rapamycin (mTOR inhibition)", "ai_target": "TSC-mTOR / NF-κB", "ai_species": "Mouse/human monocytes", "ai_effect": "mTOR inhibition promotes pro-inflammatory cytokines via NF-κB – TSC-mTOR regulates the innate inflammatory response", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WEI2008/" }, { "sid": "NOR2026", "title": "Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations", "authors": "Nordbeck AJ; Martá-Ariza M; Ek Olofsson H; Kanshin E; Ueberheide B et al.", "year": 2026, "journal": "Alzheimer's & Dementia", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human post-mortem hippocampus (Down syndrome with AD neuropathology vs neurotypical controls)", "peer_reviewed": "Yes", "doi": "10.1002/alz.71776", "pmid": "42635110", "pmcid": "PMC13501503", "finding": "Spatial transcriptomics plus localized proteomics on human post-mortem hippocampus show that mTOR pathway signalling is significantly altered in specific hippocampal subfields in Down syndrome with Alzheimer's disease neuropathology, while insulin pathway signalling is altered specifically in dentate granule neurons — pointing to subregion- and cell-type-specific mTOR/insulin dysregulation rather than a uniform whole-tissue shift. Explicitly framed by the authors as preliminary.\n", "abstract": "Down syndrome (DS) is caused by a complete or partial trisomy of chromosome 21, resulting in variable intellectual disabilities and a high risk for early-onset Alzheimer's disease (DS-AD). Dysregulation of the mammalian target of rapamycin (mTOR) and insulin (INS) signaling pathways has been reported in DS. We hypothesized that upstream alterations in these two pathways contribute to hippocampal dysfunction in DS-AD. We used spatial transcriptomics and localized proteomic techniques to examine mTOR/INS signaling pathways in subregions of the hippocampus in post mortem tissue from individuals with DS-AD and age-matched neurotypical controls. mTOR pathways were significantly altered in specific hippocampal subfields in DS-AD, and INS pathways were significantly altered in dentate granule neurons. These preliminary spatial transcriptomics and localized proteomics findings demonstrate an interplay between select hippocampal mTOR/INS pathways and cellular populations, suggesting potential novel drug targets and early biomarkers for DS.", "ai_intervention": "", "ai_target": "", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/NOR2026/" }, { "sid": "SCA2020", "title": "The 3.2-A resolution structure of human mTORC2", "authors": "Scaiola A; Maier T et al.", "year": 2020, "journal": "Science advances", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.1126/sciadv.abc1251", "pmid": "33158864", "pmcid": "PMC7673708", "finding": "The 3.2 A cryo-EM structure of human mTORC2 pinpoints Rictor's C-terminus as the source of rapamycin insensitivity.\n", "abstract": "The protein kinase mammalian target of rapamycin (mTOR) is the central regulator of cell growth. Aberrant mTOR signaling is linked to cancer, diabetes, and neurological disorders. mTOR exerts its functions in two distinct multiprotein complexes, mTORC1 and mTORC2. Here, we report a 3.2-A resolution cryo-EM reconstruction of mTORC2. It reveals entangled folds of the defining Rictor and the substrate-binding SIN1 subunits, identifies the carboxyl-terminal domain of Rictor as the source of the rapamycin insensitivity of mTORC2, and resolves mechanisms for mTORC2 regulation by complex destabilization. Two previously uncharacterized small-molecule binding sites are visualized, an inositol hexakisphosphate (InsP6) pocket in mTOR and an mTORC2-specific nucleotide binding site in Rictor, which also forms a zinc finger. Structural and biochemical analyses suggest that InsP6 and nucleotide binding do not control mTORC2 activity directly but rather have roles in folding or ternary interactions. These insights provide a firm basis for studying mTORC2 signaling and for developing mTORC2-specific inhibitors.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "mTORC2 (Rictor/SIN1)", "ai_species": "Cryo-EM structure", "ai_effect": "3.2-Å cryo-EM structure of human mTORC2 reveals the entangled Rictor and SIN1 folds", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SCA2020/" }, { "sid": "WUX2013", "title": "Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression", "authors": "Wu JJ; Finkel T et al.", "year": 2013, "journal": "Cell reports", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (mTOR hypomorph)", "peer_reviewed": "Yes", "doi": "10.1016/j.celrep.2013.07.030", "pmid": "23994476", "pmcid": "PMC3784301", "finding": "Genetically reduced mTOR increases mouse lifespan with tissue-specific slowing of aging.\n", "abstract": "We analyzed aging parameters using a mechanistic target of rapamycin (mTOR) hypomorphic mouse model. Mice with two hypomorphic alleles are viable but express mTOR at approximately 25% of wild-type levels. These animals demonstrate reduced mTORC1 and mTORC2 activity and exhibit an approximately 20% increase in median survival. While these mice are smaller than wild-type mice, they do not demonstrate any alterations in normalized food intake, glucose homeostasis, or metabolic rate. Consistent with their increased lifespan, the mice exhibited a reduction in a number of aging tissue biomarkers. Functional assessment suggested that, as these mice age, they exhibit a marked functional preservation in many, but not all, organ systems. Thus, in a mammalian model, while reducing mTOR expression markedly increases overall lifespan, it affects the age-dependent decline in tissue and organ function in a segmental fashion.", "ai_intervention": "Genetic (mTOR hypomorph, ~25% expression)", "ai_target": "mTORC1 & mTORC2", "ai_species": "Mouse (mTOR hypomorph)", "ai_effect": "Genetic reduction of mTOR extends median lifespan ~20% with segmental, tissue-specific slowing of aging", "ai_dose": "mTOR protein reduced to approximately 25% of wild type levels", "ai_samplesize": "males: n=17 (mTOR Δ/Δ), n=10 (WT); females: n=26 (mTOR Δ/Δ), n=24 (WT); combined: n=43 (mTOR Δ/Δ), n=34 (WT)", "ai_effectsize": "Median survival increased by 22% for males (p=0.02) and 19% for females (p=0.047); overall median survival 30.3 months for mTOR Δ/Δ vs 26.2 months for WT (p=0.0057)", "ai_limitations": "Higher euthanasia rate for mTOR Δ/Δ mice due to severe infections (37% vs 17% WT, p<0.01); exacerbated age-dependent decrease in trabecular bone volume and increased age-dependent infections (mouth, eye, skin) in mTOR Δ/Δ mice", "atlas_url": "https://mtor-atlas.org/study/WUX2013/" }, { "sid": "POW2006", "title": "Extension of chronological life span in yeast by decreased TOR pathway signaling", "authors": "Powers RW; Fields S et al.", "year": 2006, "journal": "Genes & development", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Yeast (S. cerevisiae)", "peer_reviewed": "Yes", "doi": "10.1101/gad.1381406", "pmid": "16418483", "pmcid": "PMC1356109", "finding": "Decreased TOR pathway signalling extends chronological lifespan in yeast.\n", "abstract": "Chronological life span (CLS) in Saccharomyces cerevisiae, defined as the time cells in a stationary phase culture remain viable, has been proposed as a model for the aging of post-mitotic tissues in mammals. We developed a high-throughput assay to determine CLS for approximately 4800 single-gene deletion strains of yeast, and identified long-lived strains carrying mutations in the conserved TOR pathway. TOR signaling regulates multiple cellular processes in response to nutrients, especially amino acids, raising the possibility that decreased TOR signaling mediates life span extension by calorie restriction. In support of this possibility, removal of either asparagine or glutamate from the media significantly increased stationary phase survival. Pharmacological inhibition of TOR signaling by methionine sulfoximine or rapamycin also increased CLS. Decreased TOR activity also promoted increased accumulation of storage carbohydrates and enhanced stress resistance and nuclear relocalization of the stress-related transcription factor Msn2. We propose that up-regulation of a highly conserved response to starvation-induced stress is important for life span extension by decreased TOR signaling in yeast and higher eukaryotes.", "ai_intervention": "Genetic (TOR pathway deletions)", "ai_target": "TOR / Sch9", "ai_species": "Yeast (S. cerevisiae)", "ai_effect": "Decreased TOR pathway signaling extends yeast chronological lifespan", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/POW2006/" }, { "sid": "SAB1995", "title": "Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells", "authors": "Sabers CJ; Abraham RT et al.", "year": 1995, "journal": "The Journal of biological chemistry", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Rat/mouse cells; in vitro", "peer_reviewed": "Yes", "doi": "10.1074/jbc.270.2.815", "pmid": "7822316", "pmcid": "", "finding": "Isolated mTOR as the FKBP12-rapamycin-associated protein controlling G1-S progression.\n", "abstract": "The immunosuppressive drug, rapamycin, interferes with an undefined signaling pathway required for the progression of G1-phase T-cells into S phase. Genetic analyses in yeast indicate that binding of rapamycin to its intracellular receptor, FKBP12, generates a toxic complex that inhibits cell growth in G1 phase. These analyses implicated two related proteins, TOR1 and TOR2, as targets of the FKBP12-rapamycin complex in yeast. In this study, we have used a glutathione S-transferase (GST)-FKBP12-rapamycin affinity matrix to isolate putative mammalian targets of rapamycin (mTOR) from tissue extracts. In the presence of rapamycin, immobilized GST-FKBP12 specifically precipitates similar high molecular mass proteins from both rat brain and murine T-lymphoma cell extracts. Binding experiments performed with rapamycin-sensitive and -resistant mutant clones derived from the YAC-1 T-lymphoma cell line demonstrate that the GST-FKBP12-rapamycin complex recovers significantly lower amounts of the candidate mTOR from rapamycin-resistant cell lines. The latter results suggest that mTOR is a relevant target of rapamycin in these cells. Finally, we report the isolation of a full-length mTOR cDNA that encodes a direct ligand for the FKBP12-rapamycin complex. The deduced amino acid sequence of mTOR displays 42 and 45% identity to those of yeast TOR1 and TOR2, respectively. These results strongly suggest that the FKBP12-rapamycin complex interacts with homologous ligands in yeast and mammalian cells and that the loss of mTOR function is directly related to the inhibitory effect of rapamycin on G1- to S-phase progression in T-lymphocytes and other sensitive cell types.", "ai_intervention": "Biochemical (FKBP12-rapamycin affinity)", "ai_target": "mTOR (FRAP/RAFT1) / FKBP12", "ai_species": "Rat/mouse cells; in vitro", "ai_effect": "Isolation of the mammalian FKBP12-rapamycin target protein (mTOR)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAB1995/" }, { "sid": "SAN2007", "title": "PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase", "authors": "Sancak Y; Thoreen CC; Peterson TR; Lindquist RA; Kang SA; Spooner E; Carr SA; Sabatini DM", "year": 2007, "journal": "Molecular Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells (biochemistry)", "peer_reviewed": "Yes", "doi": "10.1016/j.molcel.2007.03.003", "pmid": "17386266", "pmcid": "", "finding": "Identified PRAS40 as the missing insulin-controlled brake INSIDE mTORC1. When insulin is absent PRAS40 clamps the complex shut; insulin makes Akt phosphorylate PRAS40, releasing the brake so Rheb can fully switch mTORC1 on. Explained how hormone signals set the exact strength of mTORC1 activity.\n", "abstract": "The heterotrimeric mTORC1 protein kinase nucleates a signaling network that promotes cell growth in response to insulin and becomes constitutively active in cells missing the TSC1 or TSC2 tumor suppressors. Insulin stimulates the phosphorylation of S6K1, an mTORC1 substrate, but it is not known how mTORC1 kinase activity is regulated. We identify PRAS40 as a raptor-interacting protein that binds to mTORC1 in insulin-deprived cells and whose in vitro interaction with mTORC1 is disrupted by high salt concentrations. PRAS40 inhibits cell growth, S6K1 phosphorylation, and rheb-induced activation of the mTORC1 pathway, and in vitro it prevents the great increase in mTORC1 kinase activity induced by rheb1-GTP. Insulin stimulates Akt/PKB-mediated phosphorylation of PRAS40, which prevents its inhibition of mTORC1 in cells and in vitro. We propose that the relative strengths of the rheb- and PRAS40-mediated inputs to mTORC1 set overall pathway activity and that insulin activates mTORC1 through the coordinated regulation of both.", "ai_intervention": "Biochemical/genetic (PRAS40)", "ai_target": "mTORC1 / PRAS40", "ai_species": "Human cells (biochemistry)", "ai_effect": "PRAS40 is an insulin-regulated inhibitor of the mTORC1 kinase (raptor-binding)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAN2007/" }, { "sid": "HSU2011", "title": "The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling", "authors": "Hsu PP; Sabatini DM et al.", "year": 2011, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/science.1199498", "pmid": "21659604", "pmcid": "PMC3177140", "finding": "mTOR-dependent phosphoproteomics reveal Grb10 as a substrate mediating feedback inhibition of PI3K.\n", "abstract": "The mammalian target of rapamycin (mTOR) protein kinase is a master growth promoter that nucleates two complexes, mTORC1 and mTORC2. Despite the diverse processes controlled by mTOR, few substrates are known. We defined the mTOR-regulated phosphoproteome by quantitative mass spectrometry and characterized the primary sequence motif specificity of mTOR using positional scanning peptide libraries. We found that the phosphorylation response to insulin is largely mTOR dependent and that mTOR exhibits a unique preference for proline, hydrophobic, and aromatic residues at the +1 position. The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1. Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.", "ai_intervention": "Phosphoproteomics (mTOR)", "ai_target": "mTORC1 / Grb10 / growth-factor signaling", "ai_species": "Mammalian cells", "ai_effect": "Defines the mTOR phosphoproteome; reveals mTORC1-mediated (Grb10) feedback inhibition of growth-factor signaling", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HSU2011/" }, { "sid": "INO2003", "title": "TSC2 mediates cellular energy response to control cell growth and survival", "authors": "Inoki K; Zhu T; Guan KL", "year": 2003, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells (biochemistry)", "peer_reviewed": "Yes", "doi": "10.1016/s0092-8674(03)00929-2", "pmid": "14651849", "pmcid": "", "finding": "Established the energy-sensing arm of the pathway. When energy runs low, AMPK phosphorylates TSC2, boosting its ability to shut mTOR down - protecting the cell from burning through resources and from starvation-induced death. The founding paper for how mTOR reads the cell's fuel gauge (complements the Akt-TSC2 growth-factor arm).\n", "abstract": "Mutations in either the TSC1 or TSC2 tumor suppressor gene are responsible for Tuberous Sclerosis Complex. The gene products of TSC1 and TSC2 form a functional complex and inhibit the phosphorylation of S6K and 4EBP1, two key regulators of translation. Here, we describe that TSC2 is regulated by cellular energy levels and plays an essential role in the cellular energy response pathway. Under energy starvation conditions, the AMP-activated protein kinase (AMPK) phosphorylates TSC2 and enhances its activity. Phosphorylation of TSC2 by AMPK is required for translation regulation and cell size control in response to energy deprivation. Furthermore, TSC2 and its phosphorylation by AMPK protect cells from energy deprivation-induced apoptosis. These observations demonstrate a model where TSC2 functions as a key player in regulation of the common mTOR pathway of protein synthesis, cell growth, and viability in response to cellular energy levels.", "ai_intervention": "Biochemical/genetic (AMPK/TSC2)", "ai_target": "TSC2 / AMPK / mTOR", "ai_species": "Mammalian cells (biochemistry)", "ai_effect": "TSC2 mediates the cellular energy response (via AMPK) to control cell growth and survival", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/INO2003/" }, { "sid": "WIL2012", "title": "Rapamycin slows aging in mice", "authors": "Wilkinson JE; Burmeister L; Brooks SV; Chan CC; Friedline S; Harrison DE; Hejtmancik JF; Nadon N; Strong R; Wood LK; Woodward MA; Miller RA", "year": 2012, "journal": "Aging Cell", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Genetically heterogeneous mice", "peer_reviewed": "Yes", "doi": "10.1111/j.1474-9726.2012.00832.x", "pmid": "22587563", "pmcid": "PMC3434687", "finding": "Answered a crucial objection: does rapamycin really slow AGING, or just prevent the cancers that kill mice? By showing slower age-related change across many tissues (heart, liver, tendon, activity), it argued for genuine slowing of aging. Honestly reported harms too - more cataracts and testicular degeneration - making it a balanced landmark, not hype.\n", "abstract": "Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in spontaneous activity, occur more slowly in rapamycin-treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action.", "ai_intervention": "Rapamycin", "ai_target": "mTOR", "ai_species": "Genetically heterogeneous mice", "ai_effect": "Rapamycin slows multiple aspects of aging (heart, liver, tendon, activity), beyond just suppressing cancer", "ai_dose": "4.7, 14, or 42 ppm rapamycin in food, administered from age 9 months.", "ai_samplesize": "Genetically heterogeneous mice; young (4 month) and old (20-22 month) control groups, and old mice treated with rapamycin at 4.7, 14, or 42 ppm; N varies by outcome (e.g., 15-80 per group).", "ai_effectsize": "Rapamycin significantly reduced incidences of liver degeneration (P=0.02), myocardial nuclear abnormalities (P=0.047), endometrial hyperplasia (P=0.05), and adrenal tumors (P=0.04); however, it increased cataract severity (P=0.014 males, P=0.001 females) and testicular degeneration (P<0.001).", "ai_limitations": "Histological evaluation of cataracts was limited to a small number of specimens; site-to-site variation was considerable for spontaneous activity; some observed trends did not reach statistical significance.", "atlas_url": "https://mtor-atlas.org/study/WIL2012/" }, { "sid": "HOX2019", "title": "The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism", "authors": "Hoxhaj G; Manning BD et al.", "year": 2019, "journal": "Nature reviews. Cancer", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1038/s41568-019-0216-7", "pmid": "31686003", "pmcid": "PMC7314312", "finding": "Review of the PI3K-AKT-mTOR network at the interface of oncogenic signalling and metabolism.\n", "abstract": "The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. The ubiquitous, growth factor-regulated phosphoinositide 3-kinase (PI3K)-AKT signalling network has diverse downstream effects on cellular metabolism, through either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the expression of key components of metabolic pathways. Aberrant activation of this signalling network is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli. Here we discuss our current understanding of the molecular events controlling cellular metabolism downstream of PI3K and AKT and of how these events couple two major hallmarks of cancer: growth factor independence through oncogenic signalling and metabolic reprogramming to support cell survival and proliferation.", "ai_intervention": "Not applicable (review)", "ai_target": "PI3K-AKT (upstream of mTOR)", "ai_species": "Review", "ai_effect": "Reviews the PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HOX2019/" }, { "sid": "WYA2017", "title": "mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient", "authors": "Wyant GA; Sabatini DM et al.", "year": 2017, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2017.09.046", "pmid": "29053970", "pmcid": "PMC5704964", "finding": "SLC38A9 effluxes essential amino acids (e.g. leucine) from lysosomes to activate mTORC1.\n", "abstract": "The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Pancreatic cancer cells, which use macropinocytosed protein as a nutrient source, require SLC38A9 to form tumors. Thus, through SLC38A9, arginine serves as a lysosomal messenger that couples mTORC1 activation to the release from lysosomes of the essential amino acids needed to drive cell growth.", "ai_intervention": "Biochemical/genetic (SLC38A9)", "ai_target": "SLC38A9 / mTORC1 (arginine)", "ai_species": "Mammalian cells", "ai_effect": "SLC38A9 is an arginine sensor that also effluxes essential amino acids from lysosomes, letting cells use protein as a nutrient", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WYA2017/" }, { "sid": "SPI2010", "title": "Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease", "authors": "Spilman P; Podlutskaya N; Hart MJ; Debnath J; Gorostiza O; Bredesen D; Richardson A; Strong R; Galvan V", "year": 2010, "journal": "PLoS ONE", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "PDAPP transgenic mice (Alzheimer's model)", "peer_reviewed": "Yes", "doi": "10.1371/journal.pone.0009979", "pmid": "20376313", "pmcid": "PMC2848616", "finding": "Connected the longevity drug to a specific age-related disease. Long-term rapamycin prevented memory deficits and lowered toxic amyloid-beta in an Alzheimer's mouse model - and the benefit tracked with INCREASED autophagy in neurons. Suggested that the same autophagy boost that may slow aging could also help clear disease-causing proteins.\n", "abstract": "Reduced TOR signaling has been shown to significantly increase lifespan in a variety of organisms [1], [2], [3], [4]. It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target p70S6K[6] extends lifespan in mice, possibly by delaying aging. Whether inhibition of the mTOR pathway would delay or prevent age-associated disease such as AD remained to be determined.\n\nWe used rapamycin administration and behavioral tools in a mouse model of AD as well as standard biochemical and immunohistochemical measures in brain tissue to provide answers for this question. Here we show that long-term inhibition of mTOR by rapamycin prevented AD-like cognitive deficits and lowered levels of Abeta(42), a major toxic species in AD[7], in the PDAPP transgenic mouse model. These data indicate that inhibition of the mTOR pathway can reduce Abeta(42) levels in vivo and block or delay AD in mice. As expected from the inhibition of mTOR, autophagy was increased in neurons of rapamycin-treated transgenic, but not in non-transgenic, PDAPP mice, suggesting that the reduction in Abeta and the improvement in cognitive function are due in part to increased autophagy, possibly as a response to high levels of Abeta.\n\nOur data suggest that inhibition of mTOR by rapamycin, an intervention that extends lifespan in mice, can slow or block AD progression in a transgenic mouse model of the disease. Rapamycin, already used in clinical settings, may be a potentially effective therapeutic agent for the treatment of AD.", "ai_intervention": "Rapamycin", "ai_target": "mTOR / amyloid-β", "ai_species": "PDAPP transgenic mice (Alzheimer's model)", "ai_effect": "Rapamycin reduces amyloid-β levels and abolishes cognitive deficits in an Alzheimer's mouse model", "ai_dose": "rapamycin-supplemented diet for 13 weeks starting at 4 months of age, identical to the diet that extended lifespan in mice [5]", "ai_samplesize": "groups of PDAPP mice and littermate non-transgenic controls (total N=124 for cognitive tests, based on F(3,120))", "ai_effectsize": "improved learning in rapamycin-fed PDAPP mice at day 4 (P=0.036); memory in rapamycin-fed PDAPP mice was indistinguishable from non-Tg groups; significantly decreased soluble Aβ42 levels in transgenic PDAPP mice (P=0.02)", "ai_limitations": "Aβ deposition was not determined", "atlas_url": "https://mtor-atlas.org/study/SPI2010/" }, { "sid": "HUANG2026", "title": "Recurrent PIK3CA-E545K mutation promotes cervical cancer growth and invasion via AKT/mTOR signaling.", "authors": "Huang C; Zhang W; Ma X; Li X; Sun X", "year": 2026, "journal": "Molecular genetics and genomics", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human (cancer cell lines + xenograft)", "peer_reviewed": "Yes", "doi": "10.1007/s00438-026-02495-z", "pmid": "", "pmcid": "", "finding": "PIK3CA-E545K hotspot mutation enhances cervical cancer cell proliferation and invasion by activating AKT/mTOR signaling, validated in xenograft models.\n", "abstract": "Cervical cancer remains a leading cause of cancer-related morbidity and mortality among women worldwide. Whole-exome sequencing was performed on paired tumor and matched non-tumor tissues from 61 patients to identify recurrent somatic alterations. Functional significance was subsequently evaluated using cervical cancer cell models. Genomic profiling identified PIK3CA as one of the most frequently mutated genes in cervical cancer. Functional analyses demonstrated that PIK3CA E545K mutation significantly enhanced tumor cell proliferation and invasive capacity while suppressing apoptosis. These effects were associated with activation of AKT/mTOR signaling.", "ai_intervention": "PIK3CA-E545K mutation", "ai_target": "AKT/mTOR", "ai_species": "Human", "ai_effect": "Promotes tumor cell proliferation and invasion", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HUANG2026/" }, { "sid": "ROB2013", "title": "Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis", "authors": "Robitaille AM; Hall MN et al.", "year": 2013, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/science.1228771", "pmid": "23429704", "pmcid": "", "finding": "Quantitative phosphoproteomics show mTORC1 activates de novo pyrimidine synthesis.\n", "abstract": "The Ser-Thr kinase mammalian target of rapamycin (mTOR) controls cell growth and metabolism by stimulating glycolysis and synthesis of proteins and lipids. To further understand the central role of mTOR in cell physiology, we used quantitative phosphoproteomics to identify substrates or downstream effectors of the two mTOR complexes. mTOR controlled the phosphorylation of 335 proteins, including CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase). CAD catalyzes the first three steps in de novo pyrimidine synthesis. mTORC1 indirectly phosphorylated CAD-S1859 through S6 kinase (S6K). CAD-S1859 phosphorylation promoted CAD oligomerization and thereby stimulated de novo synthesis of pyrimidines and progression through S phase of the cell cycle in mammalian cells. Thus, mTORC1 also stimulates the synthesis of nucleotides to control cell proliferation.", "ai_intervention": "Quantitative phosphoproteomics", "ai_target": "mTORC1 / S6K1 / CAD", "ai_species": "Mammalian cells", "ai_effect": "mTORC1 activates de novo pyrimidine synthesis (CAD phosphorylation), among 335 mTOR-controlled phosphosites", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ROB2013/" }, { "sid": "MUT2026", "title": "ER-Lysosome Cholesterol Exchange Regulates Lysosomal Motility Through mTOR-Dependent LAMTOR1 Phosphorylation", "authors": "Muthukottiappan P; Winter D et al.", "year": 2026, "journal": "bioRxiv (preprint)", "tier": "Preprint", "pyramid": "Preprint", "category": "Preprint", "model": "Human cell lines", "peer_reviewed": "No", "doi": "10.64898/2026.03.31.715514", "pmid": "", "pmcid": "", "finding": "Identifies a new layer of control over mTORC1's lysosomal machinery: cholesterol exchange between the ER and lysosome regulates lysosome movement via mTOR-dependent phosphorylation of LAMTOR1, a core component of the Ragulator complex that anchors the Rag GTPases already in this Atlas.\n", "abstract": "The subcellular distribution of lysosomes, the main degradative organelles of mammalian cells, responds to metabolic cues in a highly dynamic way. While lysosomal positioning due to amino acid levels is well-characterized, cholesterol-dependent regulation of lysosomal motility is incompletely understood. We explored impaired lysosomal cholesterol export using a mass spectrometry-based multi-OMICs approach, identifying widespread reallocation of resources and signaling pathway modulation. We identified increased phosphorylation at LAMTOR1 serine 56 in response to cholesterol level perturbations. We demonstrate that this phosphorylation site is sufficient to disrupt Rag GTPases/SLC38A9 binding to the Ragulator complex, inhibiting canonical mTORC1 and facilitating binding of BORC, therefore promoting lysosomal retrograde movement. LAMTOR1 S56 phosphorylation responds exclusively to depletion of lysosomal limiting membrane cholesterol, is facilitated by mTOR, and presents a negative feedback loop for amino acid independent displacement of Ragulator bound Rag GTPases, limiting canonical mTORC1 activity. Mass spectrometry data are available via ProteomeXchange with identifier PXD073489. (Preprint abstract; source: bioRxiv.)", "ai_intervention": "Perturbation of lysosomal cholesterol export (multi-omics)", "ai_target": "mTOR / LAMTOR1 (Ragulator)", "ai_species": "Human cell lines", "ai_effect": "Cholesterol perturbation → mTOR-dependent LAMTOR1 (Ser56) phosphorylation controlling lysosomal motility", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MUT2026/" }, { "sid": "ROM2001", "title": "Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways", "authors": "Rommel C; Bodine SC et al.", "year": 2001, "journal": "Nature Cell Biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cultured muscle cells (mouse)", "peer_reviewed": "Yes", "doi": "10.1038/ncb1101-1009", "pmid": "11715022", "pmcid": "", "finding": "Shows IGF-1 drives muscle fiber hypertrophy specifically through the Akt-mTOR pathway, establishing mTORC1 as a central node for muscle growth signaling.\n", "abstract": "Skeletal muscle is composed of multinucleated fibres, formed after the differentiation and fusion of myoblast precursors. Skeletal muscle atrophy and hypertrophy refer to changes in the diameter of these pre-existing muscle fibres. The prevention of atrophy would provide an obvious clinical benefit; insulin-like growth factor 1 (IGF-1) is a promising anti-atrophy agent because of its ability to promote hypertrophy. However, the signalling pathways by which IGF-1 promotes hypertrophy remain unclear, with roles suggested for both the calcineurin/NFAT (nuclear factor of activated T cells) pathway and the PtdIns-3-OH kinase (PI(3)K)/Akt pathway. Here we employ a battery of approaches to examine these pathways during the hypertrophic response of cultured myotubes to IGF-1. We report that Akt promotes hypertrophy by activating downstream signalling pathways previously implicated in activating protein synthesis: the pathways downstream of mammalian target of rapamycin (mTOR) and the pathway activated by phosphorylating and thereby inhibiting glycogen synthase kinase 3 (GSK3). In contrast, in addition to demonstrating that calcineurin does not mediate IGF-1-induced hypertrophy, we show that IGF-1 unexpectedly acts via Akt to antagonize calcineurin signalling during myotube hypertrophy.", "ai_intervention": "IGF-1", "ai_target": "PI3K/Akt/mTOR & Akt/GSK3", "ai_species": "Cultured muscle cells (mouse)", "ai_effect": "IGF-1 drives skeletal myotube hypertrophy via PI3K/Akt/mTOR and PI3K/Akt/GSK3 pathways", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ROM2001/" }, { "sid": "SUX2017", "title": "Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex", "authors": "Su MY; Hurley JH et al.", "year": 2017, "journal": "Molecular cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Hybrid structure", "peer_reviewed": "Yes", "doi": "10.1016/j.molcel.2017.10.016", "pmid": "29107538", "pmcid": "PMC5722659", "finding": "Hybrid structural model of the RagA/C-Ragulator mTORC1 activation complex.\n", "abstract": "The lysosomal membrane is the locus for sensing cellular nutrient levels, which are transduced to mTORC1 via the Rag GTPases and the Ragulator complex. The crystal structure of the five-subunit human Ragulator at 1.4 A resolution was determined. Lamtor1 wraps around the other four subunits to stabilize the assembly. The Lamtor2:Lamtor3 dimer stacks upon Lamtor4:Lamtor5 to create a platform for Rag binding. Hydrogen-deuterium exchange was used to map the Rag binding site to the outer face of the Lamtor2:Lamtor3 dimer and to the N-terminal intrinsically disordered region of Lamtor1. EM was used to reconstruct the assembly of the full-length RagA:RagCdimer bound to Ragulator at 16 A resolution, revealing that the G-domains of the Rags project away from the Ragulator core. The combined structural model shows how Ragulator functions as a platform for the presentation of active Rags for mTORC1 recruitment, and might suggest an unconventional mechanism for Rag GEF activity.", "ai_intervention": "Structural (crystal/hybrid)", "ai_target": "Rag GTPases / Ragulator (Lamtor1-5) / mTORC1", "ai_species": "Hybrid structure", "ai_effect": "Structure of the RagA/C-Ragulator activation complex; Lamtor1 wraps the subunits to form the Rag-binding platform", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SUX2017/" }, { "sid": "LEE2024", "title": "Targeting ageing with rapamycin and its derivatives in humans: a systematic review", "authors": "Lee DJW; Hodzic Kuerec A; Maier AB", "year": 2024, "journal": "Lancet Healthy Longevity", "tier": "A - Systematic review", "pyramid": "1 - Systematic Review", "category": "Review", "model": "Systematic review (19 human studies, 5 databases)", "peer_reviewed": "Yes", "doi": "10.1016/S2666-7568(23)00258-1", "pmid": "38310895", "pmcid": "", "finding": "The first systematic review of rapamycin/rapalogs in humans for aging. Screened 18,400 articles, included 19 studies. Found improvements in immune, cardiovascular, and skin (integumentary) parameters; NO significant effect on endocrine, muscular, or neurological systems. No serious adverse events in healthy people, but more infections and raised cholesterol/triglycerides in people with age-related disease. This is the highest-tier human-evidence summary in the whole Atlas - it aggregates many individual human studies rather than reporting one.\n", "abstract": "Rapamycin and its derivatives (rapalogs) are inhibitors of mTOR, a major regulator of the ageing process. We aimed to summarise the effects of rapamycin and its derivatives on the severity of ageing-related physiological changes and disease in adults. A search across five databases yielded 18 400 unique articles, resulting in 19 included studies. Rapamycin and its derivatives improved physiological parameters associated with ageing in the immune, cardiovascular, and integumentary systems of healthy individuals or individuals with ageing-related diseases. Overall, no significant effects on the endocrine, muscular, or neurological systems were found. The effects of rapamycin or its derivatives on the respiratory, digestive, renal, and reproductive systems were not assessed. No serious adverse events attributed to rapamycin and its derivatives were reported in healthy individuals; however, there were increased numbers of infections and increases in total cholesterol, LDL cholesterol, and triglycerides in individuals with ageing-related diseases. Future studies should assess the remaining unexamined systems and test the effects of long-term exposure to rapamycin and its derivatives.", "ai_intervention": "Rapamycin and rapalogs (aggregate of 19 studies)", "ai_target": "mTOR", "ai_species": "Human – systematic review (19 studies, 5 databases)", "ai_effect": "Improved immune, cardiovascular and skin parameters; no effect on endocrine/muscular/neurological systems", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LEE2024/" }, { "sid": "ZHAI2026", "title": "Pungenin Promotes Hair Growth in Mouse Models of Androgenic Alopecia Through Transcriptional Regulation of the PI3K/AKT/mTOR Axis.", "authors": "Zhai W; Yang J; Zhang L et al.", "year": 2026, "journal": "Molecules", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (DHT-induced AGA); primary mouse hair follicle cells", "peer_reviewed": "Yes", "doi": "10.3390/molecules31162864", "pmid": "", "pmcid": "", "finding": "Topical pungenin accelerated hair regrowth in DHT-induced androgenetic alopecia mice, reducing type II 5α-reductase expression and modulating PI3K/AKT/FoxO/mTOR transcriptional signalling in hair follicle cells.\n", "abstract": "Androgenetic alopecia (AGA) is characterized by progressive miniaturization of hair follicles driven by dihydrotestosterone (DHT)-mediated androgen receptor signalling. Pungenin, a phenolic glucoside, was investigated in DHT-induced AGA model mice. In primary mouse hair follicle cells exposed to DHT, pungenin mitigated cellular injury, restored morphology and viability, and significantly reduced type II 5alpha-reductase expression. Topical pungenin markedly accelerated hair regeneration by histological analysis and serum biochemistry. Transcriptomic profiling with network pharmacology suggested the protective effects are associated with transcriptional regulation of the PI3K/AKT/FoxO/mTOR axis, identifying 25 putative therapeutic targets, with qPCR confirming altered expression of key genes.", "ai_intervention": "Pungenin (topical)", "ai_target": "PI3K/AKT/FoxO/mTOR; SRD5A2", "ai_species": "Mouse", "ai_effect": "Accelerated hair regeneration, restored follicle cell viability, reduced 5α-reductase expression", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZHAI2026/" }, { "sid": "HAFEZ2026", "title": "Melittin attenuates imiquimod-induced psoriatic dermatitis in mice: a role for autophagy activation via PI3K/Akt/mTOR pathway suppression.", "authors": "Hafez SA; Ahmed AA; Elkhoely A; Ahmed AAE", "year": 2026, "journal": "Saudi pharmaceutical journal", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (psoriasis model)", "peer_reviewed": "Yes", "doi": "10.1007/s44446-026-00105-y", "pmid": "", "pmcid": "", "finding": "Melittin (bee venom, 80 mg/kg i.p.) reduces psoriatic dermatitis severity by 60% in an imiquimod mouse model by suppressing PI3K/Akt/mTOR signaling and activating autophagy.\n", "abstract": "Melittin, the main component in bee venom, exhibits valuable anti-inflammatory and immunomodulatory properties in various diseases; meanwhile, its effect on psoriasis has not been explored yet. Mice were divided into 5 groups: Control, Imiquimod (IMQ), methotrexate (MTX, 1 mg/kg), melittin (40 mg/kg), or melittin (80 mg/kg). All groups except the control received topical IMQ for seven days. Melittin 80 demonstrated superior efficacy, significantly reducing the clinical Psoriasis Area and Severity Index score by 60% and attenuating psoriatic lesions through suppression of the PI3K/Akt/mTOR pathway and activation of autophagy.", "ai_intervention": "Melittin", "ai_target": "PI3K/Akt/mTOR", "ai_species": "Mouse", "ai_effect": "Reduces psoriatic inflammation via mTOR suppression and autophagy activation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HAFEZ2026/" }, { "sid": "MOE2025", "title": "Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results", "authors": "Moel M; Harinath G; Lee V; Nyquist A; Morgan SL; Isman A; Zalzala S", "year": 2025, "journal": "Aging (Albany NY)", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, RCT, ages 50-85 (n=114 completed)", "peer_reviewed": "Yes", "doi": "10.18632/aging.206235", "pmid": "40188830", "pmcid": "PMC12074816", "finding": "First completed long-term RCT of rapamycin for healthy human aging (NCT04488601, 48 weeks, n=114). Primary endpoint (visceral fat by DXA) showed NO significant change (p=0.942) - a null result exactly as pre-registered. Secondary endpoints were more promising: women on the 10mg/week dose had significant improvements in lean muscle mass and self-reported pain. A textbook example of why the pre-registered primary endpoint, not the most exciting secondary finding, is what should drive the headline conclusion.\n", "abstract": "This 48-week decentralized, double-blinded, randomized, placebo-controlled trial (NCT04488601) evaluated the long-term safety of intermittent low-dose rapamycin in a healthy, normative-aging human cohort. Participants received placebo, 5 mg or 10 mg compounded rapamycin weekly. The primary outcome measure was visceral adiposity (by DXA scan), secondary outcomes were blood biomarkers, and lean tissue and bone mineral content (by DXA scan). Established surveys were utilized to evaluate health and well-being. Safety was assessed through adverse events and blood biomarker monitoring.\n\nAdverse and serious adverse events were similar across all groups. Visceral adiposity did not change significantly (η= 0.001,= 0.942), and changes in blood biomarkers remained within normal ranges. Lean tissue mass (η= 0.202,= 0.013) and self-reported pain (η= 0.168,= 0.015) improved significantly for women using 10 mg rapamycin. Self-reported emotional well-being (η= 0.108,= 0.023) and general health (η= 0.166,= 0.004) also improved for those using 5 mg rapamycin. No other significant effects were observed.\n\nLow-dose, intermittent rapamycin administration over 48 weeks is relatively safe in healthy, normative-aging adults, and was associated with significant improvements in lean tissue mass and pain in women. Future work will evaluate benefits of a broader range of rapamycin doses on healthspan metrics for longevity, and will aim to more comprehensively establish efficacy.", "ai_intervention": "Intermittent low-dose rapamycin (5/10 mg weekly, 48 wk)", "ai_target": "mTOR", "ai_species": "Human – RCT (PEARL, ages 50-85, n=114 completed)", "ai_effect": "Intermittent low-dose rapamycin was safe over 1 year; some healthspan gains (e.g. lean tissue in women at 10 mg)", "ai_dose": "Rapamycin (compounded), 5 mg/week or 10 mg/week orally, 48 weeks; randomized double-blind placebo-controlled. Note: compounded effective dose ~66% lower than the advertised dose.", "ai_samplesize": "114 completed: 40 at 5 mg/wk, 35 at 10 mg/wk, 39 placebo. Low female enrollment (35.1%).", "ai_effectsize": "Primary endpoint (visceral adipose tissue) NOT met. Secondary: decreased bone mineral density (OR 0.24, 95% CI 0.06-0.93, p=0.04); increased lean tissue (esp. women at 10 mg); small HbA1c rise in 5 mg males (p=0.010). Overall safe/well tolerated over 1 year.", "ai_limitations": "Small n -> wide 95% CIs / underpowered; low female enrollment; compounded-dose uncertainty; minor changes in RBC / BUN / HbA1c; human gerotherapeutic data still limited.", "atlas_url": "https://mtor-atlas.org/study/MOE2025/" }, { "sid": "FLY2013", "title": "Late-life rapamycin treatment reverses age-related heart dysfunction", "authors": "Flynn JM; O'Leary MN; Zambataro CA; Academia EC; Presley MP; et al.; Melov S", "year": 2013, "journal": "Aging Cell", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Aged (24-month) female mice", "peer_reviewed": "Yes", "doi": "10.1111/acel.12109", "pmid": "23734717", "pmcid": "PMC4098908", "finding": "Striking evidence that in mice mTOR inhibition doesn't just SLOW aging - it can partly reverse an established age-related phenotype. Giving rapamycin to already-old (24-month) mice for 3 months improved aged heart function, reversing age-related cardiac changes via anti-hypertrophic and anti-inflammatory effects. Started late, still worked.\n", "abstract": "Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity-enhancing paradigm in mammalian tissues. We treated 24-month-old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late-life cardiovascular function with a reversal or attenuation of age-related changes in the heart. RNA-seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late-life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age-related inflammation.", "ai_intervention": "Rapamycin (3 months, late life)", "ai_target": "mTOR", "ai_species": "Aged (24-month) female mice", "ai_effect": "Late-life rapamycin reverses age-related cardiac dysfunction in aged mice", "ai_dose": "oral delivery of microencapsulated rapamycin diet at 14 parts per million (ppm) for 3 months", "ai_samplesize": "N = 18 for each group (treated vs. nontreated)", "ai_effectsize": "Significant systemic reduction in 4 cytokines (G-CSF, LIX, IL-17, IL-7) linked to inflammation (n=10 per group, P<0.05)", "ai_limitations": "Under- or overestimation of body composition in energy expenditure (EE) calculation is a known pitfall of indirect calorimetry", "atlas_url": "https://mtor-atlas.org/study/FLY2013/" }, { "sid": "ZHO2009", "title": "Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice", "authors": "Zhou J; Parada LF et al.", "year": 2009, "journal": "The Journal of neuroscience", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (Pten KO)", "peer_reviewed": "Yes", "doi": "10.1523/JNEUROSCI.5685-08.2009", "pmid": "19211884", "pmcid": "PMC3904448", "finding": "mTORC1 inhibition reverses neurological abnormalities in neural Pten-knockout mice.\n", "abstract": "PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a lipid phosphatase that counteracts the function of phosphatidylinositol-3 kinase (PI3K). Loss of function of PTEN results in constitutive activation of AKT and downstream effectors and correlates with many human cancers, as well as various brain disorders, including macrocephaly, seizures, Lhermitte-Duclos disease, and autism. We previously generated a conditional Pten knock-out mouse line with Pten loss in limited postmitotic neurons in the cortex and hippocampus. Pten-null neurons developed neuronal hypertrophy and loss of neuronal polarity. The mutant mice exhibited macrocephaly and behavioral abnormalities reminiscent of certain features of human autism. Here, we report that rapamycin, a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1), can prevent and reverse neuronal hypertrophy, resulting in the amelioration of a subset of PTEN-associated abnormal behaviors, providing evidence that the mTORC1 pathway downstream of PTEN is critical for this complex phenotype.", "ai_intervention": "mTORC1 inhibition (rapamycin)", "ai_target": "mTORC1 / PTEN-Akt", "ai_species": "Mouse (neural Pten KO)", "ai_effect": "mTORC1 inhibition suppresses anatomical, cellular and behavioral abnormalities in Pten-null brain (macrocephaly, seizures, autism-like)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZHO2009/" }, { "sid": "FOR2010", "title": "Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state", "authors": "Foretz M; Hebrard S; Andreelli F; Viollet B et al.", "year": 2010, "journal": "The Journal of Clinical Investigation", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (liver-specific AMPK-null and LKB1-null); primary hepatocytes", "peer_reviewed": "Yes", "doi": "10.1172/JCI40671", "pmid": "20577053", "pmcid": "", "finding": "The paper that broke the simple 'metformin works through AMPK' story. Metformin still suppressed hepatic glucose production in mice and hepatocytes lacking AMPK or LKB1, acting instead through a fall in hepatic energy charge. Any claim that metformin's benefit is AMPK-mediated has to answer this result.\n", "abstract": "Metformin is widely used to treat hyperglycemia in individuals with type 2 diabetes. Recently the LKB1/AMP-activated protein kinase (LKB1/AMPK) pathway was proposed to mediate the action of metformin on hepatic gluconeogenesis. However, the molecular mechanism by which this pathway operates had remained elusive. Surprisingly, here we have found that in mice lacking AMPK in the liver, blood glucose levels were comparable to those in wild-type mice, and the hypoglycemic effect of metformin was maintained. Hepatocytes lacking AMPK displayed normal glucose production and gluconeogenic gene expression compared with wild-type hepatocytes. In contrast, gluconeogenesis was upregulated in LKB1-deficient hepatocytes. Metformin decreased expression of the gene encoding the catalytic subunit of glucose-6-phosphatase (G6Pase), while cytosolic phosphoenolpyruvate carboxykinase (Pepck) gene expression was unaffected in wild-type, AMPK-deficient, and LKB1-deficient hepatocytes. Surprisingly, metformin-induced inhibition of glucose production was amplified in both AMPK- and LKB1-deficient compared with wild-type hepatocytes. This inhibition correlated in a dose-dependent manner with a reduction in intracellular ATP content, which is crucial for glucose production. Moreover, metformin-induced inhibition of glucose production was preserved under forced expression of gluconeogenic genes through PPARgamma coactivator 1alpha (PGC-1alpha) overexpression, indicating that metformin suppresses gluconeogenesis via a transcription-independent process. In conclusion, we demonstrate that metformin inhibits hepatic gluconeogenesis in an LKB1- and AMPK-independent manner via a decrease in hepatic energy state.", "ai_intervention": "Metformin in AMPK-null / LKB1-null mouse liver", "ai_target": "Hepatic energy state (AMPK-independent)", "ai_species": "Mouse", "ai_effect": "Metformin suppresses hepatic gluconeogenesis without AMPK or LKB1, via reduced hepatic energy charge", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/FOR2010/" }, { "sid": "VEL2003", "title": "Genetics: influence of TOR kinase on lifespan in C. elegans", "authors": "Vellai T et al.", "year": 2003, "journal": "Nature", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Caenorhabditis elegans (RNAi)", "peer_reviewed": "Yes", "doi": "10.1038/426620a", "pmid": "14668850", "pmcid": "", "finding": "Silencing the single worm TOR gene roughly doubled C. elegans lifespan, showing the longevity role of TOR inhibition is conserved across an enormous evolutionary distance.\n", "abstract": "(Brief communication; no formal abstract in PubMed — editorial summary.) This report provides the first genetic evidence that the TOR kinase controls animal lifespan: RNAi inactivation of the Caenorhabditis elegans TOR ortholog (let-363/CeTOR) roughly doubles adult lifespan. The longevity effect operates largely in parallel to the insulin/IGF-1–DAF-16 pathway and is associated with a dauer-like shift in energy metabolism, establishing nutrient-sensing TOR signalling as an evolutionarily conserved regulator of ageing and laying the groundwork for later work on rapamycin and lifespan extension.", "ai_intervention": "Genetic (RNAi of let-363/CeTOR)", "ai_target": "TOR (CeTOR)", "ai_species": "C. elegans", "ai_effect": "RNAi of C. elegans TOR roughly doubles adult lifespan, acting largely parallel to insulin/IGF-1-DAF-16", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/VEL2003/" }, { "sid": "JAC2026", "title": "Diet-dependent, beneficial and adverse effects of rapamycin on life span of Drosophila melanogaster", "authors": "Jackson LN; Boles AM; Frye CT; Patel IA; Mockett RJ", "year": 2026, "journal": "GeroScience", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Drosophila melanogaster (5 fly strains)", "peer_reviewed": "Yes", "doi": "10.1007/s11357-026-02372-y", "pmid": "42570192", "pmcid": "", "finding": "Rapamycin's effect on Drosophila lifespan is highly diet-dependent: on a cornmeal/torula-yeast medium it was harmful in 19 of 26 experiments across 5 strains, but on a nutrient-rich brewer's-yeast medium it was beneficial in 8 and neutral in 14, with no significant harm. Effects on median lifespan ranged from -51.3% to +5.4%, varying by sex and strain; rapamycin was also toxic to development at 10-200 µM.\n", "abstract": "Rapamycin supplementation has been reported to extend life spans in numerous species, including Drosophila melanogaster, but a recent study in this laboratory revealed a marked life-shortening effect in y w male flies. The experiments reported here were performed to characterize conditions under which rapamycin could extend or shorten life spans in five fly strains. On a cornmeal/torula yeast-based medium, rapamycin extended life in one experiment, had no effect in six and was harmful in 19. On a nutrient-rich brewer's yeast medium favored by 4/5 strains for egg-laying, rapamycin was beneficial in eight, neutral in 14 and not significantly harmful in any experiment. Effects on median life span ranged from -51.3 to +5.4% and were sex- and strain-specific. Rapamycin prevented development to adulthood at 10-200 µM and delayed it at 0.1-1 µM concentrations. The results confirm the adverse effects of rapamycin during development and demonstrate its potential to switch between beneficial and harmful effects on adult life span depending on other components of the diet.", "ai_intervention": "Rapamycin (dietary supplementation, varying concentration and food medium)", "ai_target": "TOR/mTOR pathway (rapamycin-FKBP12-TOR)", "ai_species": "Drosophila melanogaster (5 strains, incl. y w and Dahomey)", "ai_effect": "Diet-dependent bidirectional effect on adult lifespan (beneficial on nutrient-rich medium, harmful on cornmeal/torula medium); developmental toxicity at high doses", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JAC2026/" }, { "sid": "NAZ2013", "title": "mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6", "authors": "Nazio F; Cecconi F et al.", "year": 2013, "journal": "Nature cell biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/ncb2708", "pmid": "23524951", "pmcid": "", "finding": "mTOR restrains autophagy by controlling ULK1 ubiquitylation and stability via AMBRA1/TRAF6.\n", "abstract": "Autophagy is important in the basal or stress-induced clearance of bulk cytosol, damaged organelles, pathogens and selected proteins by specific vesicles, the autophagosomes. Following mTOR (mammalian target of rapamycin) inhibition, autophagosome formation is primed by the ULK1 and the beclin-1-Vps34-AMBRA1 complexes, which are linked together by a scaffold platform, the exocyst. Although several regulative steps have been described along this pathway, few targets of mTOR are known, and the cross-talk between ULK1 and beclin 1 complexes is still not fully understood. We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.", "ai_intervention": "Genetic/biochemical (mTOR/ULK1/AMBRA1/TRAF6)", "ai_target": "mTOR / ULK1 / AMBRA1 / TRAF6", "ai_species": "Mammalian cells", "ai_effect": "mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function via AMBRA1-TRAF6", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/NAZ2013/" }, { "sid": "SAX2026", "title": "Everolimus for the treatment of neuropsychological deficits in tuberous sclerosis complex: findings from the TRON multicentre randomised controlled trial", "authors": "Saxena A; Drew CJ; Cannings-John R; Pickles T; Mills LJ; Sampson JR et al.", "year": 2026, "journal": "Journal of medical genetics", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Human (TSC patients, aged 16-60, RCT)", "peer_reviewed": "Yes", "doi": "10.1136/jmg-2026-111529", "pmid": "42562625", "pmcid": "", "finding": "In a multicentre RCT of TSC patients (n=38 randomised, 2:1 everolimus:placebo), 24 weeks of everolimus produced similarly large 'responder' rates for neuropsychological improvement as placebo (87% vs 75%), suggesting large practice/placebo effects rather than a clear drug benefit on cognition -- despite everolimus's established efficacy for TSC tumours and epilepsy. Adverse events were more frequent with everolimus (88% vs 61.5%).\n", "abstract": "Mammalian target of rapamycin (mTOR) inhibitors are effective treatments for tumours and epilepsy in tuberous sclerosis complex (TSC). This study aimed to determine the effects of the mTOR inhibitor everolimus and a placebo on neuropsychological functioning in TSC. Individuals with TSC aged 16-60 years and IQ>60 who scored <=5th percentile in one or more of 10 memory or executive function variables were randomised 2:1 to 24 weeks everolimus or placebo and retested at baseline and 4, 12, 24 and 36 weeks. The primary outcome was the proportion of responders, defined as improvement by >=1 SD in at least one variable. 38 participants were randomised; 23 in the everolimus arm and 12 in the placebo arm completed all primary endpoint assessments. Effect sizes were small to medium (Cohen's d=0-0.465), but 20/23 (87%) in the everolimus arm and 9/12 (75%) in the placebo arm were responders. Adverse events were reported in 22/25 (88%) randomised to everolimus versus 8/13 (61.5%) for placebo. The large proportions of responders in both arms may reflect unexpectedly large familiarity, practice or placebo effects in TSC, psychometric issues with parallel test forms, and how a response was defined.", "ai_intervention": "Everolimus (mTOR inhibitor) vs placebo, 24 weeks, randomised 2:1", "ai_target": "mTOR (mTORC1)", "ai_species": "Human (TSC patients, aged 16-60 years)", "ai_effect": "No clear benefit of everolimus over placebo on neuropsychological function; both arms showed large responder rates (87% vs 75%), likely reflecting practice/placebo effects rather than a true drug effect", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAX2026/" }, { "sid": "RAUCH2026", "title": "Tankyrase-2 regulates adipocyte differentiation through AMPK/mTOR signaling.", "authors": "Rauch B; Ujlaki G; Poliska S; Murahwa N; Kovacs P; et al.", "year": 2026, "journal": "The FEBS journal", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cell line (adipocytes)", "peer_reviewed": "Yes", "doi": "10.1111/febs.70676", "pmid": "", "pmcid": "", "finding": "Deletion of tankyrase-2 (TNKS2) impairs adipocyte differentiation through AMPK activation and mTORC1 suppression; pharmacological autophagy activation rescues the differentiation defect.\n", "abstract": "Although tankyrases (TNKSs) were originally described as enzymes safeguarding genome integrity, TNKSs are also associated with metabolism and are involved in the differentiation of multiple cell lineages including adipocytes. Here we aimed to understand the role of TNKSs specifically in adipocyte differentiation. We found that the deletion of TNKS1 or TNKS2 decreased the rate of adipocyte differentiation. Furthermore, the loss of TNKs induced a multi-pronged cellular adaptation characterized by changes in cellular proteostasis centered around the inhibition of autophagy, AMPK activation and the suppression of mTORC1 activity. The lower differentiation rate of TNKS2 knockout cells was salvaged by pharmacological activation of autophagy (by NV-5138) and the pharmacological inhibition of AMPK (by compound C).", "ai_intervention": "TNKS2 knockout / NV-5138 (autophagy activator)", "ai_target": "AMPK/mTORC1", "ai_species": "Cell line", "ai_effect": "Reduces adipocyte differentiation rate; AMPK activation suppresses mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/RAUCH2026/" }, { "sid": "KAP2004", "title": "Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway", "authors": "Kapahi P et al.", "year": 2004, "journal": "Current Biology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Drosophila melanogaster", "peer_reviewed": "Yes", "doi": "10.1016/j.cub.2004.03.059", "pmid": "15186745", "pmcid": "PMC2754830", "finding": "Genetically reducing TOR pathway activity extends fruit fly lifespan, overlapping with dietary restriction effects.\n", "abstract": "In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.", "ai_intervention": "Genetic (TOR pathway modulation)", "ai_target": "TOR", "ai_species": "Drosophila melanogaster", "ai_effect": "Reducing TOR pathway activity extends fly lifespan, overlapping with dietary restriction", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KAP2004/" }, { "sid": "WAN2015", "title": "Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1", "authors": "Wang S; Sabatini DM et al.", "year": 2015, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/science.1257132", "pmid": "25567906", "pmcid": "PMC4295826", "finding": "The lysosomal transporter SLC38A9 signals arginine sufficiency to mTORC1.\n", "abstract": "The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine with a high Michaelis constant, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway.", "ai_intervention": "Biochemical/genetic (SLC38A9)", "ai_target": "SLC38A9 / Rag-Ragulator / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "SLC38A9 signals arginine sufficiency to mTORC1 at the lysosomal surface", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WAN2015/" }, { "sid": "CAR2008", "title": "Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer", "authors": "Carracedo A; Pandolfi PP et al.", "year": 2008, "journal": "The Journal of clinical investigation", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cancer cells", "peer_reviewed": "Yes", "doi": "10.1172/JCI34739", "pmid": "18725988", "pmcid": "PMC2518073", "finding": "mTORC1 inhibition activates the MAPK pathway via a PI3K-dependent feedback loop in cancer.\n", "abstract": "Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers.", "ai_intervention": "mTOR inhibition (rapamycin/rapalogs)", "ai_target": "mTORC1 / MAPK / PI3K", "ai_species": "Cancer cells", "ai_effect": "mTORC1 inhibition activates the MAPK pathway through a PI3K-dependent feedback loop (a resistance mechanism)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CAR2008/" }, { "sid": "CHA2016", "title": "The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway", "authors": "Chantranupong L; Scaria SM; Saxton RA; Gygi MP; Shen K; Wyant GA; Wang T; Harper JW; Gygi SP; Sabatini DM", "year": 2016, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells (biochemistry)", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2016.02.035", "pmid": "26972053", "pmcid": "PMC4808398", "finding": "Identified CASTOR1 as the direct arginine sensor: when arginine binds CASTOR1, it lets go of GATOR2, switching mTORC1 on. Together with Sestrin2 (leucine) this built the picture of mTORC1 as a cell that literally tastes individual amino acids.\n", "abstract": "Amino acids signal to the mTOR complex I (mTORC1) growth pathway through the Rag GTPases. Multiple distinct complexes regulate the Rags, including GATOR1, a GTPase activating protein (GAP), and GATOR2, a positive regulator of unknown molecular function. Arginine stimulation of cells activates mTORC1, but how it is sensed is not well understood. Recently, SLC38A9 was identified as a putative lysosomal arginine sensor required for arginine to activate mTORC1 but how arginine deprivation represses mTORC1 is unknown. Here, we show that CASTOR1, a previously uncharacterized protein, interacts with GATOR2 and is required for arginine deprivation to inhibit mTORC1. CASTOR1 homodimerizes and can also heterodimerize with the related protein, CASTOR2. Arginine disrupts the CASTOR1-GATOR2 complex by binding to CASTOR1 with a dissociation constant of ~30 μM, and its arginine-binding capacity is required for arginine to activate mTORC1 in cells. Collectively, these results establish CASTOR1 as an arginine sensor for the mTORC1 pathway.", "ai_intervention": "Biochemical/genetic (CASTOR1/2)", "ai_target": "CASTOR / GATOR2 / mTORC1 (arginine)", "ai_species": "Human cells (biochemistry)", "ai_effect": "The CASTOR proteins are direct arginine sensors for the mTORC1 pathway", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHA2016/" }, { "sid": "DIB2015", "title": "Regulation of mTORC1 by PI3K signaling", "authors": "Dibble CC; Cantley LC et al.", "year": 2015, "journal": "Trends in cell biology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1016/j.tcb.2015.06.002", "pmid": "26159692", "pmcid": "PMC4734635", "finding": "Review of mTORC1 regulation by PI3K signalling.\n", "abstract": "The class I phosphoinositide 3-kinase (PI3K)-mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) signaling network directs cellular metabolism and growth. Activation of mTORC1 [composed of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (mLST8), 40-kDa proline-rich Akt substrate (PRAS40), and DEP domain-containing mTOR-interacting protein (DEPTOR)] depends on the Ras-related GTPases (Rags) and Ras homolog enriched in brain (Rheb) GTPase and requires signals from amino acids, glucose, oxygen, energy (ATP), and growth factors (including cytokines and hormones such as insulin). Here we discuss the signal transduction mechanisms through which growth factor-responsive PI3K signaling activates mTORC1. We focus on how PI3K-dependent activation of Akt and spatial regulation of the tuberous sclerosis complex (TSC) complex [composed of TSC1, TSC2, and Tre2-Bub2-Cdc16-1 domain family member 7 (TBC1D7)] switches on Rheb at the lysosome, where mTORC1 is activated. Integration of PI3K- and amino acid-dependent signals upstream of mTORC1 at the lysosome is detailed in a working model. A coherent understanding of the PI3K-mTORC1 network is imperative as its dysregulation has been implicated in diverse pathologies including cancer, diabetes, autism, and aging.", "ai_intervention": "Not applicable (review)", "ai_target": "PI3K / mTORC1", "ai_species": "Review", "ai_effect": "Reviews how PI3K signaling activates mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DIB2015/" }, { "sid": "DAB2026", "title": "mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia", "authors": "Dąbkowska A, Janowska M, Pastorczak A, Domka K, Nowicka Z, Urbanska Z, Zając W, Bugajewski M, Grzybowska J, Pruchniak P, Fidyt K, Fendler W, Taslim J, Crump NT, Ushmorov A, Patkowska E, Firczuk M", "year": 2026, "journal": "Leukemia", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "BCP-ALL cell lines; patient-derived and in vivo models", "peer_reviewed": "Yes", "doi": "10.1038/s41375-026-03093-z", "pmid": "42618701", "pmcid": "", "finding": "mTORC1 inhibitors upregulate CD20 via the AKT-FOXO1 axis and promote B-lineage maturation in B-cell precursor ALL, enhancing the antitumor efficacy of anti-CD20 monoclonal antibodies -- including in high-risk IKZF1-deleted disease -- providing a rationale for combining mTORC1 inhibition with CD20-directed immunotherapy.\n", "abstract": "", "ai_intervention": "", "ai_target": "", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DAB2026/" }, { "sid": "DIB2013", "title": "Signal integration by mTORC1 coordinates nutrient input with biosynthetic output", "authors": "Dibble CC; Manning BD et al.", "year": 2013, "journal": "Nature cell biology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1038/ncb2763", "pmid": "23728461", "pmcid": "PMC3743096", "finding": "Review: mTORC1 integrates nutrient input with biosynthetic output.\n", "abstract": "Flux through metabolic pathways is inherently sensitive to the levels of specific substrates and products, but cellular metabolism is also managed by integrated control mechanisms that sense the nutrient and energy status of a cell or organism. The mechanistic target of rapamycin complex 1 (mTORC1), a protein kinase complex ubiquitous to eukaryotic cells, has emerged as a critical signalling node that links nutrient sensing to the coordinated regulation of cellular metabolism. Here, we discuss the role of mTORC1 as a conduit between cellular growth conditions and the anabolic processes that promote cell growth. The emerging network of signalling pathways through which mTORC1 integrates systemic signals (secreted growth factors) with local signals (cellular nutrients - amino acids, glucose and oxygen - and energy, ATP) is detailed. Our expanding understanding of the regulatory network upstream of mTORC1 provides molecular insights into the integrated sensing mechanisms by which diverse cellular signals converge to control cell physiology.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1", "ai_species": "Review", "ai_effect": "Reviews how mTORC1 integrates signals to coordinate nutrient input with biosynthetic output", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DIB2013/" }, { "sid": "ULL2026", "title": "FLCN loss is characterized by SQSTM1/p62 accumulation despite functional autophagy flux in Birt-Hogg-Dubé syndrome-associated kidney cancer", "authors": "Ullern H; Johannessen JA; Kasikci F; Formica M; Karimi Melve N; Andresen S; Brech A; Axcrona K; Jørgensen K; Farkas L; Enserink JM; Knævelsrud H", "year": 2026, "journal": "Autophagy Reports", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "BHD patient-derived kidney cancer cell line; Norwegian BHD patient tumor cohort", "peer_reviewed": "Yes", "doi": "10.1080/27694127.2026.2705631", "pmid": "42569319", "pmcid": "PMC13449739", "finding": "In BHD patient-derived kidney cancer cells, FLCN loss causes constitutive nuclear TFEB localization and mTORC1 hyperactivation, but leaves bulk autophagy flux and LC3 lipidation unaffected; however, the autophagy receptor SQSTM1/p62 accumulates in enlarged puncta, a finding replicated in a Norwegian cohort of BHD patient kidney tumors, showing p62 accumulation is dissociable from bulk autophagic flux.\n", "abstract": "Birt-Hogg-Dubé syndrome (BHD) is an autosomal, dominant condition caused by FLCN mutation and characterized by enhanced risk for kidney tumors. Previous studies have shown constitutive nuclear localization of the transcription factor TFEB and simultaneous hyperactivation of canonical MTORC1 signaling in the absence of FLCN. Here we assess the impact on autophagy under the situation of combined anabolic and catabolic activation. Using an established BHD patient-derived kidney cancer cell line, we confirmed that TFEB was permanently localized in the nucleus combined with an increase in canonical MTORC1 signaling, whereas bulk autophagy flux and LC3 lipidation were unaffected by FLCN status. However, we found that the autophagy receptor SQSTM1/p62 accumulated in enlarged puncta in the absence of FLCN. Finally, we recapitulate aberrant p62 accumulation in a Norwegian cohort of BHD kidney tumor samples. Our results demonstrate that FLCN loss is characterized by SQSTM1/p62 accumulation, although SQSTM1/p62 appears dispensable for anchorage-independent growth in cell models.", "ai_intervention": "FLCN gene loss (patient-derived model; no pharmacological intervention)", "ai_target": "FLCN / mTORC1 / TFEB / SQSTM1 (p62)", "ai_species": "Human (BHD patient-derived kidney cancer cell line; Norwegian patient tumor cohort)", "ai_effect": "FLCN loss decouples SQSTM1/p62 accumulation from bulk autophagy flux despite mTORC1 hyperactivation and nuclear TFEB", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ULL2026/" }, { "sid": "KAH2000", "title": "Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study", "authors": "Kahan BD (Rapamune US Study Group)", "year": 2000, "journal": "Lancet", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, phase III RCT (n=719)", "peer_reviewed": "Yes", "doi": "10.1016/S0140-6736(00)02480-6", "pmid": "10963197", "pmcid": "", "finding": "The trial that established rapamycin (sirolimus) as an immunosuppressant in kidney transplant patients - its original, still-standard clinical use.\n", "abstract": "Acute rejection episodes after renal transplantation are an important clinical challenge, despite use of multidrug immunosuppressive regimens. We did a prospective, multicentre, randomised, double-blind trial to investigate the impact of the addition of sirolimus, compared with azathioprine, to a cyclosporin and prednisone regimen.\n\n719 recipients of primary HLA-mismatched cadaveric or living-donor renal allografts who displayed initial graft function were randomly assigned, after transplantation, sirolimus 2 mg daily (n=284) or 5 mg daily (n=274), or azathioprine (n=161). We assessed the primary composite endpoint of efficacy failure, occurrence of biopsy-confirmed acute rejection episodes, graft loss, or death, and various secondary endpoints that characterise these episodes at 6 months and 12 months. Analyses were done by intention to treat.\n\nThe rate of efficacy failure at 6 months was lower in the two sirolimus groups (2 mg 18.7%, p=0.002; 5 mg 16.8%, p<0.001) than in the azathioprine group (32.3%). The frequency of biopsy-confirmed acute rejection episodes was also lower (2 mg 16.9%, p=0.002; 5 mg 12.0%, p<0.001; azathioprine 29.8%). At 12 months, survival was similar in all groups for grafts (97.2%, 96.0%, and 98.1%) and patients (94.7%, 92.7%, and 93.8%). Patients on sirolimus showed a delay in the time to first acute rejection episode and decreased frequency of moderate and severe histological grades of rejection episodes and related antibody treatment, compared with the azathioprine group. Rates of infection and malignant disorders were similar in all groups.\n\nUse of sirolimus reduced occurrence and severity of biopsy-confirmed acute rejection episodes with no increase in complications. Further studies are needed to establish the optimum doses for the combined regimen.", "ai_intervention": "Sirolimus (vs azathioprine; + cyclosporine/prednisone)", "ai_target": "mTOR", "ai_species": "Human – phase III RCT (n=719, renal transplant)", "ai_effect": "Adding sirolimus reduced acute renal allograft rejection compared with azathioprine", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KAH2000/" }, { "sid": "ROB2012", "title": "TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO", "authors": "Robida-Stubbs S; Blackwell TK et al.", "year": 2012, "journal": "Cell metabolism", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "C. elegans", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2012.04.007", "pmid": "22560223", "pmcid": "PMC3348514", "finding": "TOR/rapamycin extend lifespan by engaging SKN-1/Nrf and DAF-16/FoxO transcriptional programs.\n", "abstract": "The TOR kinase, which is present in the functionally distinct complexes TORC1 and TORC2, is essential for growth but associated with disease and aging. Elucidation of how TOR influences life span will identify mechanisms of fundamental importance in aging and TOR functions. Here we show that when TORC1 is inhibited genetically in C. elegans, SKN-1/Nrf, and DAF-16/FoxO activate protective genes, and increase stress resistance and longevity. SKN-1 also upregulates TORC1 pathway gene expression in a feedback loop. Rapamycin triggers a similar protective response in C. elegans and mice, but increases worm life span dependent upon SKN-1 and not DAF-16, apparently by interfering with TORC2 along with TORC1. TORC1, TORC2, and insulin/IGF-1-like signaling regulate SKN-1 activity through different mechanisms. We conclude that modulation of SKN-1/Nrf and DAF-16/FoxO may be generally important in the effects of TOR signaling in vivo and that these transcription factors mediate an opposing relationship between growth signals and longevity.", "ai_intervention": "Genetic + rapamycin (TORC1 inhibition)", "ai_target": "TORC1 / SKN-1(Nrf) / DAF-16(FoxO)", "ai_species": "C. elegans", "ai_effect": "TORC1 inhibition extends lifespan by activating SKN-1/Nrf and DAF-16/FoxO protective programs", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ROB2012/" }, { "sid": "MIL2011", "title": "Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice", "authors": "Miller RA; Harrison DE et al.", "year": 2011, "journal": "J Gerontol A Biol Sci Med Sci", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Negative_result", "model": "Mouse (genetically heterogeneous, ITP, 3 sites)", "peer_reviewed": "Yes", "doi": "10.1093/gerona/glq178", "pmid": "20974732", "pmcid": "PMC3021372", "finding": "In the same experimental design that showed rapamycin extended median lifespan by 10-18%, neither resveratrol nor simvastatin had any significant effect on survival - a direct head-to-head negative control run at the same time, in the same mice.\n", "abstract": "Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males but not in females. Causes of death were similar in control and rapamycin-treated mice. Resveratrol (at 300 and 1200 ppm food) and simvastatin (12 and 120 ppm) did not have significant effects on survival in male or female mice. Further evaluation of rapamycin's effects on mice is likely to help delineate the role of the mammalian target of rapamycin complexes in the regulation of aging rate and age-dependent diseases and may help to guide a search for drugs that retard some or all of the diseases of aging.", "ai_intervention": "Rapamycin (vs resveratrol, simvastatin)", "ai_target": "mTOR", "ai_species": "Mouse (genetically heterogeneous, ITP, 3 sites)", "ai_effect": "Rapamycin from 9 months extended lifespan (males +10%, females +18%); resveratrol and simvastatin did not", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MIL2011/" }, { "sid": "SEL2009", "title": "Ribosomal protein S6 kinase 1 signaling regulates mammalian life span", "authors": "Selman C; Withers DJ et al.", "year": 2009, "journal": "Science", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (S6K1 knockout)", "peer_reviewed": "Yes", "doi": "10.1126/science.1177221", "pmid": "19797661", "pmcid": "PMC4954603", "finding": "Deleting S6K1 (a direct mTORC1 effector) extended lifespan in FEMALE mice (+19% median); the effect was not significant in males. It also protected against age-related bone, immune and motor decline. One of the clearest cases of the sex dimorphism catalogued in gap H6 - and a reminder that a single downstream branch, not mTORC1 as a whole, can carry much of the ageing signal.\n", "abstract": "Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging.", "ai_intervention": "Genetic (S6K1 knockout)", "ai_target": "S6K1 / mTOR", "ai_species": "Mouse (S6K1 KO)", "ai_effect": "S6K1 deletion extends lifespan in female mice only (+19% median, not significant in males) and improves healthspan measures", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "Median lifespan in S6K1 -/- mice increased by 80 days (from 862 to 942 days) or 9% relative to WT mice (X 2 = 10.52, p < 0.001) for both sexes combined. Female S6K1 -/- mice median lifespan increased by 153 days (19%) (p < 0.001), while male S6K1 -/- mice showed no effect (p > 0.05).", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SEL2009/" }, { "sid": "YAO2011", "title": "Everolimus for advanced pancreatic neuroendocrine tumors (RADIANT-3)", "authors": "Yao JC; Shah MH; Ito T; Bohas CL; Wolin EM; et al.; Oberg K", "year": 2011, "journal": "New England Journal of Medicine", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, phase 3 RCT (n=410)", "peer_reviewed": "Yes", "doi": "10.1056/NEJMoa1009290", "pmid": "21306238", "pmcid": "PMC4208619", "finding": "A phase 3 RCT (n=410) that made everolimus a standard treatment for pancreatic neuroendocrine tumors. It more than doubled progression-free survival (11.0 vs 4.6 months, a 65% reduction in risk of progression/death) with mostly mild side effects. Another FDA-approved indication built on blocking mTOR.\n", "abstract": "Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.\n\nWe randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.\n\nThe median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).\n\nEverolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).", "ai_intervention": "Everolimus", "ai_target": "mTORC1", "ai_species": "Human – phase 3 RCT (RADIANT-3, n=410)", "ai_effect": "Everolimus prolonged progression-free survival in advanced pancreatic neuroendocrine tumors", "ai_dose": "Everolimus 10 mg once daily vs placebo; oral; international multicenter double-blind phase 3 (RADIANT-3).", "ai_samplesize": "410 patients, 82 centers, 18 countries (target 392) with advanced pancreatic neuroendocrine tumors.", "ai_effectsize": "Everolimus prolonged progression-free survival vs placebo (primary endpoint). Confirmed objective responses 5% (everolimus) vs 2% (placebo).", "ai_limitations": "Noninfectious pneumonitis / interstitial lung disease in 7 patients (5 drug-related, ~2%); other cancer therapies debated as comparators.", "atlas_url": "https://mtor-atlas.org/study/YAO2011/" }, { "sid": "LAW2018", "title": "A nutrient-induced affinity switch controls mTORC1 activation by its Rag GTPase-Ragulator lysosomal scaffold", "authors": "Lawrence RE; Zoncu R et al.", "year": 2018, "journal": "Nature cell biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/s41556-018-0148-6", "pmid": "30061680", "pmcid": "PMC6279252", "finding": "A nutrient-induced affinity switch in the Rag-Ragulator scaffold controls mTORC1 lysosomal recruitment.\n", "abstract": "A key step in nutrient sensing is activation of the master growth regulator, mTORC1 kinase, on the lysosomal membrane. Nutrients enable mTORC1 scaffolding by a complex composed of the Rag GTPases (Rags) and Ragulator, but the underlying mechanism of mTORC1 capture is poorly understood. Combining dynamic imaging in cells and reconstituted systems, we uncover an affinity switch that controls mTORC1 lifetime and activation at the lysosome. Nutrients destabilize the Rag-Ragulator interface, causing cycling of the Rags between lysosome-bound Ragulator and the cytoplasm, and rendering mTORC1 capture contingent on simultaneous engagement of two Rag-binding interfaces. Rag GTPase domains trigger cycling by coordinately weakening binding of the C-terminal domains to Ragulator in a nucleotide-controlled manner. Cancer-specific Rag mutants override release from Ragulator and enhance mTORC1 recruitment and signalling output. Cycling in the active state sets the Rags apart from most signalling GTPases, and provides a mechanism to attenuate mTORC1 signalling.", "ai_intervention": "Biochemical/imaging (Rag-Ragulator)", "ai_target": "Rag GTPases / Ragulator / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "A nutrient-induced affinity switch controls mTORC1 capture and lifetime on the Rag-Ragulator lysosomal scaffold", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LAW2018/" }, { "sid": "MAT2017", "title": "Caloric restriction improves health and survival of rhesus monkeys", "authors": "Mattison JA et al.", "year": 2017, "journal": "Nature Communications", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Rhesus macaque (2 independent cohorts)", "peer_reviewed": "Yes", "doi": "10.1038/ncomms14063", "pmid": "28094793", "pmcid": "PMC5247583", "finding": "Direct comparison of two long-term primate CR studies (NIA, Wisconsin) supports consistent health benefits; the survival effect depended on study design and control-diet composition.\n", "abstract": "Caloric restriction (CR) without malnutrition extends lifespan and delays the onset of age-related disorders in most species but its impact in nonhuman primates has been controversial. In the late 1980s two parallel studies were initiated to determine the effect of CR in rhesus monkeys. The University of Wisconsin study reported a significant positive impact of CR on survival, but the National Institute on Aging study detected no significant survival effect. Here we present a direct comparison of longitudinal data from both studies including survival, bodyweight, food intake, fasting glucose levels and age-related morbidity. We describe differences in study design that could contribute to differences in outcomes, and we report species specificity in the impact of CR in terms of optimal onset and diet. Taken together these data confirm that health benefits of CR are conserved in monkeys and suggest that CR mechanisms are likely translatable to human health.", "ai_intervention": "Caloric restriction", "ai_target": "Nutrient-sensing / mTOR (indirect)", "ai_species": "Rhesus macaque (2 independent cohorts)", "ai_effect": "Caloric restriction improved health and (in the Wisconsin cohort) survival in rhesus monkeys", "ai_dose": "CR monkeys received 30% less food than height-, age- and sex-matched control monkeys (NIA); CR was implemented on a per-individual basis after establishing baseline food intake (UW).", "ai_samplesize": "NIA study: 121 monkeys; UW study: 76 monkeys.", "ai_effectsize": "UW study: statistically significant effect of CR in increasing survival (Cox regression P =0.017); NIA study: no significant impact of CR on survival.", "ai_limitations": "Fundamental differences in study design and implementation between NIA and UW studies (e.g., age of onset, genetic origin, diet composition, feeding practices); NIA study's wide age of onset precluded grouping for analysis; UW study likely lacked statistical power for longevity.", "atlas_url": "https://mtor-atlas.org/study/MAT2017/" }, { "sid": "YAN2026", "title": "SLC15A3-mediated dipeptide metabolism confers antimetabolite resistance in lymphoma via mTORC1 activation.", "authors": "Yang X, Zingaro VA, Boardman AP", "year": 2026, "journal": "Journal of Clinical Investigation", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Mechanism", "model": "Lymphoma cell lines / mouse", "peer_reviewed": "Yes", "doi": "10.1172/JCI199709", "pmid": "42454485", "pmcid": "PMC13367966", "finding": "SLC15A3-mediated dipeptide import sustains mTORC1 activation in B cell lymphomas, enabling resistance to antimetabolite chemotherapy; inhibiting SLC15A3 or mTORC1 restores drug sensitivity.\n", "abstract": "Antimetabolite chemotherapy resistance is a major barrier in B cell lymphoma. This study demonstrates that SLC15A3, a dipeptide transporter, mediates import of dipeptides that sustain mTORC1 activation in lymphoma cells, providing a metabolic route to antimetabolite resistance independent of de novo nucleotide synthesis. SLC15A3 inhibition resensitized resistant lymphoma cells to antimetabolite treatment.", "ai_intervention": "SLC15A3 inhibition; mTORC1 inhibition", "ai_target": "mTORC1; SLC15A3 dipeptide transporter; nutrient sensing", "ai_species": "Mouse; human lymphoma cell lines", "ai_effect": "SLC15A3 imports dipeptides to activate mTORC1, conferring antimetabolite chemoresistance; SLC15A3 or mTORC1 inhibition reverses resistance", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/YAN2026/" }, { "sid": "GIN1999", "title": "Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism", "authors": "Gingras AC; Sonenberg N et al.", "year": 1999, "journal": "Genes & development", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells; in vitro", "peer_reviewed": "Yes", "doi": "10.1101/gad.13.11.1422", "pmid": "10364159", "pmcid": "PMC316780", "finding": "4E-BP1 is phosphorylated by an ordered, priming two-step mechanism that controls its release of eIF4E.\n", "abstract": "The multisubunit eukaryotic translation initiation factor (eIF) 4F recruits 40S ribosomal subunits to the 5' end of mRNA. The eIF4F subunit eIF4E interacts directly with the mRNA 5' cap structure. Assembly of the eIF4F complex is inhibited by a family of repressor polypeptides, the eIF4E-binding proteins (4E-BPs). Binding of the 4E-BPs to eIF4E is regulated by phosphorylation: Hypophosphorylated 4E-BP isoforms interact strongly with eIF4E, whereas hyperphosphorylated isoforms do not. 4E-BP1 is hypophosphorylated in quiescent cells, but is hyperphosphorylated on multiple sites following exposure to a variety of extracellular stimuli. The PI3-kinase/Akt pathway and the kinase FRAP/mTOR signal to 4E-BP1. FRAP/mTOR has been reported to phosphorylate 4E-BP1 directly in vitro. However, it is not known if FRAP/mTOR is responsible for the phosphorylation of all 4E-BP1 sites, nor which sites must be phosphorylated to release 4E-BP1 from eIF4E. To address these questions, a recombinant FRAP/mTOR protein and a FRAP/mTOR immunoprecipitate were utilized in in vitro kinase assays to phosphorylate 4E-BP1. Phosphopeptide mapping of the in vitro-labeled protein yielded two 4E-BP1 phosphopeptides that comigrated with phosphopeptides produced in vivo. Mass spectrometry analysis indicated that these peptides contain phosphorylated Thr-37 and Thr-46. Thr-37 and Thr-46 are efficiently phosphorylated in vitro by FRAP/mTOR when 4E-BP1 is bound to eIF4E. However, phosphorylation at these sites was not associated with a loss of eIF4E binding. Phosphorylated Thr-37 and Thr-46 are detected in all phosphorylated in vivo 4E-BP1 isoforms, including those that interact with eIF4E. Finally, mutational analysis demonstrated that phosphorylation of Thr-37/Thr-46 is required for subsequent phosphorylation of several carboxy-terminal serum-sensitive sites. Taken together, our results suggest that 4E-BP1 phosphorylation by FRAP/mTOR on Thr-37 and Thr-46 is a priming event for subsequent phosphorylation of the carboxy-terminal serum-sensitive sites.", "ai_intervention": "Biochemical (mTOR / 4E-BP1)", "ai_target": "mTOR / 4E-BP1 / eIF4E", "ai_species": "Mammalian cells; in vitro", "ai_effect": "4E-BP1 phosphorylation follows a two-step mechanism that regulates its binding to eIF4E", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GIN1999/" }, { "sid": "BEN2016", "title": "mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle", "authors": "Ben-Sahra I; Manning BD et al.", "year": 2016, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/science.aad0489", "pmid": "26912861", "pmcid": "PMC4786372", "finding": "mTORC1 promotes purine synthesis via ATF4-driven mitochondrial tetrahydrofolate metabolism.\n", "abstract": "In response to growth signals, mechanistic target of rapamycin complex 1 (mTORC1) stimulates anabolic processes underlying cell growth. We found that mTORC1 increases metabolic flux through the de novo purine synthesis pathway in various mouse and human cells, thereby influencing the nucleotide pool available for nucleic acid synthesis. mTORC1 had transcriptional effects on multiple enzymes contributing to purine synthesis, with expression of the mitochondrial tetrahydrofolate (mTHF) cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) being closely associated with mTORC1 signaling in both normal and cancer cells. MTHFD2 expression and purine synthesis were stimulated by activating transcription factor 4 (ATF4), which was activated by mTORC1 independent of its canonical induction downstream of eukaryotic initiation factor 2alpha phosphorylation. Thus, mTORC1 stimulates the mTHF cycle, which contributes one-carbon units to enhance production of purine nucleotides in response to growth signals.", "ai_intervention": "Genetic/pharmacologic (mTORC1)", "ai_target": "mTORC1 / ATF4 / mitochondrial folate (THF) cycle", "ai_species": "Mammalian cells", "ai_effect": "mTORC1 induces de novo purine synthesis through control of the mitochondrial tetrahydrofolate cycle", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BEN2016/" }, { "sid": "LV2026S", "title": "Deubiquitinase USP7 stabilizes the histone demethylase KDM5B and promotes the progression of renal fibrosis through the TSC1/mTOR axis", "authors": "Lv S; Zhang Xiaoyan et al.", "year": 2026, "journal": "Molecular biomedicine", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Mechanism", "model": "Mouse (UUO and unilateral renal ischemia-reperfusion injury models); human CKD kidney tissue (correlative)", "peer_reviewed": "Yes", "doi": "10.1186/s43556-026-00531-3", "pmid": "42554966", "pmcid": "PMC13442801", "finding": "USP7 deubiquitinates and stabilizes the histone demethylase KDM5B, which represses TSC1 transcription and thereby activates mTOR, promoting kidney fibrosis in two mouse injury models; USP7 is upregulated in human CKD kidneys and correlates with fibrosis severity. Genetic or pharmacological USP7 inhibition restores TSC1 expression, suppresses mTOR activation, and attenuates fibrosis in these mice, making the USP7-KDM5B-TSC1-mTOR axis a candidate intervention point; the human data are correlative only.\n", "abstract": "Ubiquitin-specific protease 7 (USP7) is a deubiquitinase implicated in tumor progression; its role in renal fibrosis was unclear. USP7 was significantly upregulated in kidneys of patients with chronic kidney disease (CKD), correlating with fibrotic lesions and renal dysfunction. Genetic depletion and pharmacological blockade of USP7 significantly attenuated fibroblast activation and extracellular matrix deposition in unilateral ureteral obstruction and unilateral renal ischemia-reperfusion injury mouse models. Mechanistically, integrated proteomic and phosphoproteomic sequencing revealed that USP7 modulated the tuberous sclerosis complex 1 (TSC1)-mTOR pathway: USP7 knockdown restored TSC1 expression and inhibited mTOR activation. USP7 did not directly interact with TSC1; instead it deubiquitinated and stabilized lysine-specific demethylase 5B (KDM5B), which reduced H3K4me3 at the Tsc1 promoter to repress its transcription. Inhibition of USP7 promoted KDM5B degradation, restoring TSC1 expression and suppressing mTOR-driven fibrogenesis.", "ai_intervention": "Genetic (USP7 knockdown) and pharmacological USP7 inhibition", "ai_target": "USP7 -> KDM5B -> TSC1 -> mTOR axis", "ai_species": "Mouse (UUO, unilateral renal I/R injury models); human CKD kidney tissue (correlative)", "ai_effect": "USP7 depletion/inhibition restores TSC1 expression, suppresses mTOR activation, and attenuates fibroblast activation and renal fibrosis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LV2026S/" }, { "sid": "MEI2008", "title": "Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function", "authors": "Meikle L; Kwiatkowski DJ et al.", "year": 2008, "journal": "The Journal of neuroscience", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (Tsc1 neuronal KO)", "peer_reviewed": "Yes", "doi": "10.1523/JNEUROSCI.0955-08.2008", "pmid": "18495876", "pmcid": "PMC2633923", "finding": "mTOR inhibition rescues a neuronal tuberous-sclerosis model, supporting rapamycin for TSC neurology.\n", "abstract": "Tuberous sclerosis (TSC) is a hamartoma syndrome attributable to mutations in either TSC1 or TSC2 in which brain involvement causes epilepsy, mental retardation, and autism. We have reported recently a mouse neuronal model of TSC in which Tsc1 is ablated in most neurons during cortical development. We have tested rapamycin and RAD001, both mammalian target of rapamycin mTORC1 inhibitors, as potential therapeutic agents in this model. Median survival is improved from 33 d to more than 100 d; behavior, phenotype, and weight gain are all also markedly improved. There is brain penetration of both drugs, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream target of mTORC1. In addition, there is restoration of phospho-Akt and phospho-glycogen synthase kinase 3 levels in the treated mice, consistent with restoration of Akt function. Neurofilament abnormalities, myelination, and cell enlargement are all improved by the treatment. However, dysplastic neuronal features persist, and there are only modest changes in dendritic spine density and length. Strikingly, mice treated with rapamycin or RAD001 for 23 d only (postnatal days 7-30) displayed a persistent improvement in phenotype, with median survival of 78 d. In summary, rapamycin/RAD001 are highly effective therapies for this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 and Akt signaling and, consequently, cell size and myelination. Although caution is appropriate, the results suggest the possibility that rapamycin/RAD001 may have benefit in the treatment of TSC brain disease, including infantile spasms.", "ai_intervention": "Rapamycin / RAD001 (mTORC1 inhibition)", "ai_target": "mTORC1 / Akt", "ai_species": "Mouse (Tsc1 neuronal KO)", "ai_effect": "mTOR inhibitors improve survival and function in a neuronal model of tuberous sclerosis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MEI2008/" }, { "sid": "GRA2014", "title": "A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity", "authors": "Grabiner BC; Sabatini DM et al.", "year": 2014, "journal": "Cancer discovery", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cancer cell panels", "peer_reviewed": "Yes", "doi": "10.1158/2159-8290.CD-13-0929", "pmid": "24631838", "pmcid": "PMC4012430", "finding": "A spectrum of cancer-associated MTOR mutations are hyperactivating and predict rapamycin sensitivity.\n", "abstract": "Genes encoding components of the PI3K-AKT-mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene encoding the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor DEPTOR. mTOR complex 1 (mTORC1) signaling in cells expressing various activating mutations remains sensitive to pharmacologic mTOR inhibition, but is partially resistant to nutrient deprivation. Finally, cancer cell lines with hyperactivating MTOR mutations display heightened sensitivity to rapamycin both in culture and in vivo xenografts, suggesting that such mutations confer mTOR pathway dependency.", "ai_intervention": "Genomics (MTOR mutations)", "ai_target": "mTOR (hyperactivating mutations)", "ai_species": "Cancer cell panels", "ai_effect": "Catalogs 33 hyperactivating cancer-associated MTOR mutations (6 clusters) that can predict rapamycin sensitivity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GRA2014/" }, { "sid": "SONH2026", "title": "Urolithin A activates mitophagy via the AMPK-mTOR axis and modulates the gut-ceramide axis to ameliorate cardiac remodeling in HFpEF", "authors": "Hangyul Song, Chahyeon Yun, Yunju Choi, Wooju Jeong, Yumin Kim, Jaeyoung Kim, Ju-Yeon Lee, Dongryeol Ryu, Sang-Wook Park, Chang-Myung Oh", "year": 2026, "journal": "Experimental and Molecular Medicine", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (HFpEF two-hit model)", "peer_reviewed": "Yes", "doi": "10.1038/s12276-026-01776-2", "pmid": "42432192", "pmcid": "", "finding": "Urolithin A ameliorates HFpEF cardiac remodeling in mice by activating AMPK and inhibiting mTOR to restore mitophagic flux, while simultaneously remodeling the gut microbiome-ceramide axis to reduce lipotoxic stress.\n", "abstract": "In a two-hit HFpEF mouse model (high-fat diet + L-NAME), urolithin A (UA) alleviated diastolic dysfunction, cardiac hypertrophy, and fibrosis. UA activated AMPK signaling while inhibiting mTOR, promoting ULK1-dependent autophagy initiation and restoring impaired mitophagic flux. Multi-omics revealed UA remodels the gut microbiome-ceramide axis, reducing circulating ceramide accumulation and lipotoxic stress. Single-nucleus transcriptomics in human iPSC-derived cardiomyocytes confirmed attenuation of fibrosis-related cellular programming.", "ai_intervention": "Urolithin A (gut microbiome-derived compound)", "ai_target": "AMPK / mTOR / ULK1 / mitophagy / ceramide axis", "ai_species": "Mouse", "ai_effect": "Improved diastolic function, reduced cardiac hypertrophy and fibrosis via mitophagy restoration; reduced ceramide accumulation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SONH2026/" }, { "sid": "LANDOAS2026", "title": "Does the duration of exposure to everolimus influence the occurrence of chronic lung allograft dysfunction?", "authors": "Landoas A; Perrier Q; Falque L et al.", "year": 2026, "journal": "Transplant Immunology", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Human (single-centre retrospective observational)", "peer_reviewed": "Yes", "doi": "10.1016/j.trim.2026.102436", "pmid": "", "pmcid": "", "finding": "In lung transplant recipients, later introduction of everolimus and a greater number of treatment interruptions were both risk factors for chronic lung allograft dysfunction — suggesting early, uninterrupted mTOR inhibition is protective.\n", "abstract": "Everolimus has been incorporated into the immunosuppressive management of lung transplant patients. Due to its anti-proliferative properties it is being studied in the context of chronic lung allograft dysfunction (CLAD). A retrospective single-centre observational study of lung transplant patients between January 2000 and August 2021 treated with everolimus during follow-up. The timing of everolimus introduction was identified as a risk factor for CLAD (OR 1.069, 95% CI 1.017-1.123), as was the number of everolimus discontinuations (OR 12.660, 95% CI 1.025-156.329). The study suggests a beneficial role of everolimus in preventing CLAD, particularly when introduced early and with minimal treatment interruptions. Lung function stability was maintained.", "ai_intervention": "Everolimus", "ai_target": "mTOR", "ai_species": "Human", "ai_effect": "Early introduction and fewer interruptions associated with lower CLAD risk; lung function stability maintained", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LANDOAS2026/" }, { "sid": "TIW2026", "title": "Firefox, a protein encoded by circular RNA circPVT1, is essential for MYC-driven oncogenesis", "authors": "Tiwari A, Paithane U, Tashiro K, Hall B, Friedlein J, Saraswat M, Saulnier O, Barbosa K, Trinh Q, Bagchi A, et al.", "year": 2026, "journal": "Genes & Development", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human MYC-amplified cancer cell lines; xenograft mouse models", "peer_reviewed": "Yes", "doi": "10.1101/gad.353355.125", "pmid": "42618323", "pmcid": "", "finding": "A micropeptide (Firefox/FFX) encoded by the circular RNA circPVT1 stimulates AKT-mTORC1 signaling and cap-dependent translation to sustain MYC protein abundance and transcriptional output. FFX depletion reduces MYC levels and impairs tumor growth in MYC-amplified xenograft models, identifying an mTORC1-linked vulnerability in MYC-driven cancers.\n", "abstract": "", "ai_intervention": "", "ai_target": "", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/TIW2026/" }, { "sid": "MAR2026", "title": "EVERolimus effectiveness after proGREssion on ENdocrine therapy plus CDK4/6 inhibitor for ER-positive/HER2-negative advanced breast cancer: EVERGREEN study", "authors": "Diogo Martins-Branco, Soraia Lobo-Martins, Philippe Aftimos, Bernardo Pereira, Leonor Vasconcelos de Matos, Leonor Fernandes, Guilherme Nader-Marta, Michel Moreau, Donatienne Taylor, Francois P Duhoux, Evandro de Azambuja", "year": 2026, "journal": "Breast Cancer Research and Treatment", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Human (multicenter retrospective cohort)", "peer_reviewed": "Yes", "doi": "10.1007/s10549-026-08012-5", "pmid": "42429895", "pmcid": "", "finding": "Everolimus added to endocrine therapy provided modest but statistically significant PFS benefit (5.0 vs 4.3 months; HR 0.68) in ER+/HER2- advanced breast cancer post-CDK4/6 inhibitor progression, without demonstrable OS benefit, supporting selective use. Retrospective and non-randomised, so treatment-selection bias cannot be excluded.\n", "abstract": "Multicentre, international, retrospective quasi-experimental study (n=207 women with ER+/HER2- advanced breast cancer after CDK4/6 inhibitor progression). Everolimus + endocrine therapy (n=150) vs endocrine therapy alone (n=57). Median real-world PFS: 5.0 vs 4.3 months (adjusted HR 0.68, 95% CI 0.47-0.99). Time to everolimus failure: 4.2 months. No significant differences in time to chemotherapy or overall survival. Safety profile consistent with prior reports. Median follow-up 31.8 months.", "ai_intervention": "Everolimus (mTOR inhibitor) + endocrine therapy", "ai_target": "mTORC1", "ai_species": "Human", "ai_effect": "Modest PFS improvement (HR 0.68) in post-CDK4/6i ER+ breast cancer; no OS benefit demonstrated", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MAR2026/" }, { "sid": "AYL2015", "title": "Architecture of human mTOR complex 1", "authors": "Aylett CH; Maier T et al.", "year": 2015, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.1126/science.aaa3870", "pmid": "26678875", "pmcid": "", "finding": "Cryo-EM architecture of human mTORC1 reveals its dimeric organization and active site access.\n", "abstract": "Target of rapamycin (TOR), a conserved protein kinase and central controller of cell growth, functions in two structurally and functionally distinct complexes: TORC1 and TORC2. Dysregulation of mammalian TOR (mTOR) signaling is implicated in pathologies that include diabetes, cancer, and neurodegeneration. We resolved the architecture of human mTORC1 (mTOR with subunits Raptor and mLST8) bound to FK506 binding protein (FKBP)-rapamycin, by combining cryo-electron microscopy at 5.9 angstrom resolution with crystallographic studies of Chaetomium thermophilum Raptor at 4.3 angstrom resolution. The structure explains how FKBP-rapamycin and architectural elements of mTORC1 limit access to the recessed active site. Consistent with a role in substrate recognition and delivery, the conserved amino-terminal domain of Raptor is juxtaposed to the kinase active site.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "mTORC1 (mTOR/Raptor/mLST8/FKBP-rapamycin)", "ai_species": "Cryo-EM structure", "ai_effect": "Resolves the architecture of human mTORC1 bound to FKBP-rapamycin", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/AYL2015/" }, { "sid": "LASSILA2026", "title": "Pregnane X receptor-mediated liver growth: a controlled clinical trial in healthy volunteers and identification of the role of AKT-MTOR pathway in mouse.", "authors": "Lassila P; Karpale M; Kummu O et al.", "year": 2026, "journal": "Archives of Toxicology", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Human controlled clinical trial (n=16); mouse (PXR-humanised, PCN)", "peer_reviewed": "Yes", "doi": "10.1007/s00204-026-04526-5", "pmid": "", "pmcid": "", "finding": "One week of rifampicin increased the liver volume-to-body-weight ratio by 2.7% in 16 healthy volunteers, and PXR activation enlarged the liver in male mice through the proliferative AKT-MTOR pathway rather than YAP.\n", "abstract": "Pregnane X receptor (PXR) is a master xenobiotic nuclear receptor. Activation of PXR has been linked to liver growth in mice, usually via interaction with YAP, but this adaptive response had not been observed in humans. The authors investigated the effect of the human PXR agonist rifampicin on liver size in a controlled clinical trial in healthy volunteers. One-week rifampicin treatment caused a 2.7% mean increase in liver volume-to-body weight ratio without affecting liver fat content (n=16). Pxr mice were transduced with adenovirus carrying murine PXR or GFP and treated with pregnenolone-16alpha-carbonitrile (PCN) for 0-4 days. PCN significantly increased liver size in male mice after 1 day and further after 4 days; no significant enlargement occurred in females. 4-day PCN also improved glucose tolerance in males. RNA-sequencing showed upregulation of proliferation genes, and DigiWest protein profiling and immunoblotting revealed increased AKT-MTOR pathway activity in male mice, with no YAP activation.", "ai_intervention": "Rifampicin (human); pregnenolone-16α-carbonitrile (mouse)", "ai_target": "PXR; AKT-MTOR; YAP", "ai_species": "Human; mouse", "ai_effect": "2.7% increase in liver volume-to-body-weight ratio in humans; PXR-driven hepatomegaly and improved glucose tolerance in male mice via AKT-MTOR", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LASSILA2026/" }, { "sid": "BAN2014", "title": "Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls", "authors": "Bannister CA et al.", "year": 2014, "journal": "Diabetes, Obesity and Metabolism", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Humans, retrospective cohort (n=180,926)", "peer_reviewed": "Yes", "doi": "10.1111/dom.12354", "pmid": "25041462", "pmcid": "", "finding": "Diabetic patients started on metformin had longer median survival than matched non-diabetic controls without the drug. Retrospective and observational: consistent with a survival benefit, but confounding by indication and healthy-adherer effects cannot be excluded.\n", "abstract": "Clinical and observational studies have shown an increased risk of cardiovascular events and death associated with sulphonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulphonylureas. The objective of this study was therefore to compare all-cause mortality in diabetic patients treated first-line with either sulphonylurea or metformin monotherapy with that in matched individuals without diabetes.\n\nWe used retrospective observational data from the UK Clinical Practice Research Datalink (CPRD) from 2000. Subjects with type 2 diabetes who progressed to first-line treatment with metformin or sulphonylurea monotherapy were selected and matched to people without diabetes. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables.\n\nWe identified 78,241 subjects treated with metformin, 12,222 treated with sulphonylurea, and 90,463 matched subjects without diabetes. This resulted in a total, censored follow-up period of 503,384 years. There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy [survival time ratio (STR) = 1.0], adjusted median survival time was 15% lower (STR = 0.85, 95% CI 0.81-0.90) in matched individuals without diabetes and 38% lower (0.62, 0.58-0.66) in diabetic patients treated with sulphonylurea monotherapy.\n\nPatients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulphonylurea had markedly reduced survival compared with both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulphonylurea remains a concern.", "ai_intervention": "Metformin (vs sulphonylurea) monotherapy", "ai_target": "AMPK / mTOR (indirect)", "ai_species": "Human – retrospective cohort (n=180,926)", "ai_effect": "Metformin-treated diabetics had lower all-cause mortality than sulphonylurea users and even matched non-diabetic controls", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BAN2014/" }, { "sid": "KAR2017", "title": "Cryo-EM structure of Saccharomyces cerevisiae target of rapamycin complex 2", "authors": "Karuppasamy M; Schaffitzel C et al.", "year": 2017, "journal": "Nature communications", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.1038/s41467-017-01862-0", "pmid": "29170376", "pmcid": "PMC5700991", "finding": "Cryo-EM structure of yeast TORC2 reveals its overall architecture and rapamycin insensitivity.\n", "abstract": "The target of rapamycin (TOR) kinase assembles into two distinct multiprotein complexes, conserved across eukaryote evolution. In contrast to TOR complex 1 (TORC1), TORC2 kinase activity is not inhibited by the macrolide rapamycin. Here, we present the structure of Saccharomyces cerevisiae TORC2 determined by electron cryo-microscopy. TORC2 contains six subunits assembling into a 1.4 MDa rhombohedron. Tor2 and Lst8 form the common core of both TOR complexes. Avo3/Rictor is unique to TORC2, but interacts with the same HEAT repeats of Tor2 that are engaged by Kog1/Raptor in mammalian TORC1, explaining the mutual exclusivity of these two proteins. Density, which we conclude is Avo3, occludes the FKBP12-rapamycin-binding site of Tor2's FRB domain rendering TORC2 rapamycin insensitive and recessing the kinase active site. Although mobile, Avo1/hSin1 further restricts access to the active site as its conserved-region-in-the-middle (CRIM) domain is positioned along an edge of the TORC2 active-site-cleft, consistent with a role for CRIM in substrate recruitment.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "TORC2 (Tor2/Lst8/Avo)", "ai_species": "Cryo-EM structure (S. cerevisiae)", "ai_effect": "Cryo-EM structure of yeast TORC2, a 1.4-MDa rhombohedron of six subunits", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KAR2017/" }, { "sid": "BAB2025", "title": "Restriction of individual branched-chain amino acids has distinct effects on the development and progression of Alzheimer's disease in 3xTg mice", "authors": "Babygirija R; Lamming DW et al.", "year": 2026, "journal": "Advanced Science", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (Alzheimer's disease model)", "peer_reviewed": "Yes", "doi": "10.1002/advs.202515220", "pmid": "41817439", "pmcid": "PMC13248761", "finding": "UPDATE (was bioRxiv preprint at seed time, peer-reviewed and published in Advanced Science March 2026). Restricting individual branched-chain amino acids has distinct, sex-specific effects on cognition and AD pathology in 3xTg mice; restriction of isoleucine and valine (but not leucine) promotes metabolic health. Note: the different BCAAs act differentially on mTORC1, which is why single-amino-acid restriction matters.\n", "abstract": "Dietary protein regulates metabolic health and aging, with many benefits of a low protein diet resulting from reduced consumption of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Each BCAA has distinct physiological and molecular effects, and while restriction of protein or all three BCAAs improves cognition in mouse models of Alzheimer's disease (AD), the role of each individual BCAA on AD is unknown. Here, we investigate the impact of restricting leucine, isoleucine, or valine on metabolism, AD pathology, molecular signaling, and cognition in male and female 3xTg AD mice. Mice were fed BCAA-restricted diets for nine months starting at six months of age. Restriction of either isoleucine or valine, but not leucine, improved metabolic health. We observed distinct, BCAA-specific effects on AD pathology, molecular signaling, and gene expression in both sexes as well as shared molecular responses in males. Restricting any BCAA improved short-term memory in males, with isoleucine having the strongest effect, while valine restriction led to the greatest cognitive benefits for females. These findings suggest that targeted BCAA restriction, particularly of isoleucine or valine, may form the basis of a novel sex-specific approach to prevent or delay AD.", "ai_intervention": "Dietary (restriction of individual BCAAs: Leu/Ile/Val)", "ai_target": "BCAAs / mTORC1", "ai_species": "Mouse (3xTg Alzheimer's model)", "ai_effect": "Individual BCAAs have distinct effects on Alzheimer's progression; restriction (notably isoleucine) improves outcomes", "ai_dose": "Diets with 67% reduction of isoleucine, leucine, or valine, started at 6 months of age; duration was 9 months for body composition, 3 months for metabolic tests.", "ai_samplesize": "3xTg and NTg mice of both sexes; n=5-14 per diet group per sex, varying by experiment.", "ai_effectsize": "ValR diet significantly increased energy expenditure in 3xTg females (p<0.05); IleR increased energy expenditure in 3xTg males (p<0.05) and improved glucose tolerance in both sexes (p<0.05).", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BAB2025/" }, { "sid": "CHE2008", "title": "TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species", "authors": "Chen C; Liu Yu; Liu R; Ikenoue T; Guan KL; Liu Yang; Zheng P", "year": 2008, "journal": "Journal of Experimental Medicine", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (conditional Tsc1 knockout)", "peer_reviewed": "Yes", "doi": "10.1084/jem.20081297", "pmid": "18809716", "pmcid": "PMC2556783", "finding": "Showed why blood stem cells must keep mTOR LOW. Deleting TSC1 (which unleashes mTOR) drove resting stem cells into rapid division, flooded them with reactive oxygen species, and burned out their ability to self-renew. An antioxidant rescued them. A key link between mTOR, stem-cell exhaustion, and tissue aging.\n", "abstract": "The tuberous sclerosis complex (TSC)-mammalian target of rapamycin (mTOR) pathway is a key regulator of cellular metabolism. We used conditional deletion of Tsc1 to address how quiescence is associated with the function of hematopoietic stem cells (HSCs). We demonstrate that Tsc1 deletion in the HSCs drives them from quiescence into rapid cycling, with increased mitochondrial biogenesis and elevated levels of reactive oxygen species (ROS). Importantly, this deletion dramatically reduced both hematopoiesis and self-renewal of HSCs, as revealed by serial and competitive bone marrow transplantation. In vivo treatment with an ROS antagonist restored HSC numbers and functions. These data demonstrated that the TSC-mTOR pathway maintains the quiescence and function of HSCs by repressing ROS production. The detrimental effect of up-regulated ROS in metabolically active HSCs may explain the well-documented association between quiescence and the \"stemness\" of HSCs.", "ai_intervention": "Genetic (Tsc1 conditional knockout)", "ai_target": "TSC-mTOR / mitochondrial biogenesis / ROS", "ai_species": "Mouse (conditional Tsc1 KO)", "ai_effect": "TSC-mTOR maintains hematopoietic stem cell quiescence and function by repressing mitochondrial biogenesis and ROS", "ai_dose": "Mice (6 wk old) treated with polyinosine-polycytidine (pIpC) every other day for 2 wk to induce Tsc1 deletion.", "ai_samplesize": "Variable, e.g., n=3 to n=10 mice per group depending on the experiment.", "ai_effectsize": "Tsc1 deletion reduced quiescent LT-HSCs from ~70% to <15% and increased BrdU incorporation nearly fourfold (from 13% to ~60%); resulted in an ~50% reduction in white blood cell counts (P = 0.001).", "ai_limitations": "It is unlikely that the HSCs in the spleen are fully functional because HSCs have reduced self-renewal when their niche in BM is disrupted.", "atlas_url": "https://mtor-atlas.org/study/CHE2008/" }, { "sid": "DEM2014", "title": "Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2", "authors": "Demetriades C; Teleman AA et al.", "year": 2014, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2014.01.024", "pmid": "24529380", "pmcid": "PMC4346203", "finding": "Amino-acid starvation recruits TSC2 to the lysosome to inhibit Rheb and TORC1.\n", "abstract": "TOR complex 1 (TORC1) is a potent anabolic regulator of cellular growth and metabolism. When cells have sufficient amino acids, TORC1 is active due to its lysosomal localization mediated via the Rag GTPases. Upon amino acid removal, the Rag GTPases release TORC1, causing it to become cytoplasmic and inactive. We show here that, upon amino acid removal, the Rag GTPases also recruit TSC2 to the lysosome, where it can act on Rheb. Only when both the Rag GTPases and Rheb are inactive is TORC1 fully released from the lysosome. Upon amino acid withdrawal, cells lacking TSC2 fail to completely release TORC1 from the lysosome, fail to completely inactivate TORC1, and fail to adjust physiologically to amino acid starvation. These data suggest that regulation of TSC2 subcellular localization may be a general mechanism to control its activity and place TSC2 in the amino-acid-sensing pathway to TORC1.", "ai_intervention": "Biochemical/genetic (Rag / TSC2)", "ai_target": "TORC1 / Rag GTPases / TSC2", "ai_species": "Mammalian cells", "ai_effect": "Upon amino-acid starvation the Rag GTPases recruit TSC2 to the lysosome to inactivate TORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DEM2014/" }, { "sid": "PEREZ2026", "title": "A cross-species drug-discovery platform to accelerate the identification of lifespan-extending interventions", "authors": "Perez K; Schoenfeldt L; Phelps GB; Parras A; Morin J; Pinto C; Guilmot S; Oliveira T; Silveira M; Dolfi L; Ocampo A", "year": 2026, "journal": "Cell Reports", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Five model organisms: S. cerevisiae, C. elegans, D. melanogaster, killifish, mice", "peer_reviewed": "Yes", "doi": "10.1016/j.celrep.2026.117897", "pmid": "42671914", "pmcid": "", "finding": "An integrated high-throughput lifespan-screening platform spanning yeast, nematodes, flies, killifish and mice, evaluating >400 compounds across thousands of conditions using automated imaging and deep-learning death detection. Cross-species integration identifies geroprotectors active in multiple species and shows convergence on known and novel conserved longevity pathways. Methodological infrastructure for the question the Atlas keeps running into: which single-species lifespan results actually generalise. Note the abstract does not name individual hit compounds, so the specific standing of rapamycin/mTOR in this screen cannot be read off the abstract alone.\n", "abstract": "We develop an integrated, high-throughput platform to evaluate pharmacological lifespan-extending interventions across five model organisms spanning unicellular to mammalian biology including yeast, nematodes, fruit flies, killifish, and mice. By combining automated imaging, miniaturized assays, and deep-learning-based death detection, we evaluate over 400 compounds across thousands of conditions. In S. cerevisiae, a miniaturized PI/flow cytometry CLS assay enables scalable screening and identifies key assay confounders, while in C. elegans and D. melanogaster, compact imaging platforms coupled to YOLO-based detection provide a no-transfer, high-throughput survival scoring, and capture compound-, diet-, and sex-dependent effects. In killifish, we develop an in-house drug-pellet formulation for standardized oral delivery in large cohorts, and in mice we combine longitudinal lifespan studies with home-cage activity monitoring to assess late-life interventions. Cross-species integration identifies multi-species geroprotectors and reveals convergence on known and novel conserved longevity pathways, illustrating how this scalable framework can prioritize interventions with high translational potential.", "ai_intervention": ">400 small-molecule compounds screened for lifespan extension", "ai_target": "Conserved longevity pathways (cross-species geroprotector screen)", "ai_species": "Yeast, C. elegans, D. melanogaster, killifish, mouse", "ai_effect": "Cross-species screening identifies multi-species geroprotectors and reveals convergence on conserved longevity pathways", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PEREZ2026/" }, { "sid": "SAN2010", "title": "Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids", "authors": "Sancak Y; Bar-Peled L; Zoncu R; Markhard AL; Nada S; Sabatini DM", "year": 2010, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells + Drosophila", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2010.02.024", "pmid": "20381137", "pmcid": "PMC3024592", "finding": "Established WHERE mTORC1 gets switched on: the lysosome surface. Identified Ragulator as the lysosomal dock that recruits the Rag GTPases and drags mTORC1 to the membrane where its activator Rheb lives. Amino acids work by controlling this translocation.\n", "abstract": "The mTORC1 kinase promotes growth in response to growth factors, energy levels, and amino acids, and its activity is often deregulated in disease. The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb. We show that amino acids induce the movement of mTORC1 to lysosomal membranes, where the Rag proteins reside. A complex encoded by the MAPKSP1, ROBLD3, and c11orf59 genes, which we term Ragulator, interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation. Constitutive targeting of mTORC1 to the lysosomal surface is sufficient to render the mTORC1 pathway amino acid insensitive and independent of Rag and Ragulator, but not Rheb, function. Thus, Rag-Ragulator-mediated translocation of mTORC1 to lysosomal membranes is the key event in amino acid signaling to mTORC1.", "ai_intervention": "Biochemical/genetic (Ragulator-Rag)", "ai_target": "Ragulator / Rag / mTORC1 / Rheb", "ai_species": "Human cells + Drosophila", "ai_effect": "The Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAN2010/" }, { "sid": "ZON2011", "title": "mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase", "authors": "Zoncu R; Bar-Peled L; Efeyan A; Wang S; Sancak Y; Sabatini DM", "year": 2011, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells + cell-free reconstitution", "peer_reviewed": "Yes", "doi": "10.1126/science.1207056", "pmid": "22053050", "pmcid": "PMC3211112", "finding": "Showed amino acid sensing starts INSIDE the lysosome: amino acids accumulate in the lumen and the v-ATPase relays that signal outward ('inside-out') to Ragulator-Rag. A surprising twist on where the cell measures its nutrient status.\n", "abstract": "The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that is stimulated by amino acids. Amino acids activate the Rag guanosine triphosphatases (GTPases), which promote the translocation of mTORC1 to the lysosomal surface, the site of mTORC1 activation. We found that the vacuolar H(+)-adenosine triphosphatase ATPase (v-ATPase) is necessary for amino acids to activate mTORC1. The v-ATPase engages in extensive amino acid-sensitive interactions with the Ragulator, a scaffolding complex that anchors the Rag GTPases to the lysosome. In a cell-free system, ATP hydrolysis by the v-ATPase was necessary for amino acids to regulate the v-ATPase-Ragulator interaction and promote mTORC1 translocation. Results obtained in vitro and in human cells suggest that amino acid signaling begins within the lysosomal lumen. These results identify the v-ATPase as a component of the mTOR pathway and delineate a lysosome-associated machinery for amino acid sensing.", "ai_intervention": "Biochemical/genetic (v-ATPase)", "ai_target": "v-ATPase / Rag-Ragulator / mTORC1", "ai_species": "Human cells + cell-free reconstitution", "ai_effect": "mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZON2011/" }, { "sid": "ZHANG2026C", "title": "Anti-breast cancer effects of the Xingxiao Pill are associated with inhibition of the ErbB3/PI3K/AKT/mTOR pathway, modulation of amino acid metabolism, and promotion of apoptosis.", "authors": "Zhang Jingyue; Cheng J; Cao F et al.", "year": 2026, "journal": "Journal of Ethnopharmacology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (4T1 subcutaneous model); breast cancer cell lines", "peer_reviewed": "Yes", "doi": "10.1016/j.jep.2026.122321", "pmid": "", "pmcid": "", "finding": "Xingxiao Pill inhibited 4T1 breast cancer growth in vitro and in vivo by suppressing ErbB3/PI3K/AKT/mTOR signalling and reshaping amino acid metabolism; cinnamic acid and palmitic acid were identified as constituents that bind mTOR.\n", "abstract": "The Xingxiao Pill (XXP) is a traditional Chinese medicine formula used in tumour therapy. XXP exhibited proliferation-inhibiting activity against eight breast cancer cell lines and both proliferation-inhibiting and apoptosis-promoting activity against 4T1 cells in vitro and in a 4T1 subcutaneous tumour model in vivo. XXP induced mitochondrial apoptosis via the cytochrome C/caspase-9/caspase-3/PARP cascade. Integrated metabolomic and transcriptomic analyses with WGCNA revealed that XXP reshaped amino acid metabolism through a gene module enriched in ErbB3/PI3K/AKT/mTOR signalling; western blotting showed reduced ErbB3 and PI3K and decreased AKT/mTOR phosphorylation with unchanged total protein. Seven bioactive components were identified by UPLC-MS; cinnamic acid, palmitic acid, eugenol, 11-keto-β-boswellic acid and asiatic acid inhibited 4T1 proliferation, and cinnamic acid and palmitic acid were identified as potential mTOR binders.", "ai_intervention": "Xingxiao Pill (TCM formula); cinnamic acid; palmitic acid", "ai_target": "ErbB3/PI3K/AKT/mTOR; amino acid metabolism", "ai_species": "Mouse", "ai_effect": "Inhibited proliferation and induced caspase-mediated apoptosis; reduced AKT/mTOR phosphorylation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZHANG2026C/" }, { "sid": "ROG2019", "title": "Structural basis for the docking of mTORC1 on the lysosomal surface", "authors": "Rogala KB; Sabatini DM et al.", "year": 2019, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.1126/science.aay0166", "pmid": "31601708", "pmcid": "PMC7176403", "finding": "Structure shows how mTORC1 docks onto the Rag-Ragulator lysosomal scaffold.\n", "abstract": "The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and growth factors. Nutrients promote its translocation to the lysosomal surface, where its Raptor subunit interacts with the Rag guanosine triphosphatase (GTPase)-Ragulator complex. Nutrients switch the heterodimeric Rag GTPases among four different nucleotide-binding states, only one of which (RagA/B GTP-RagC/D GDP) permits mTORC1 association. We used cryo-electron microscopy to determine the structure of the supercomplex of Raptor with Rag-Ragulator at a resolution of 3.2 angstroms. Our findings indicate that the Raptor alpha-solenoid directly detects the nucleotide state of RagA while the Raptor claw threads between the GTPase domains to detect that of RagC. Mutations that disrupted Rag-Raptor binding inhibited mTORC1 lysosomal localization and signaling. By comparison with a structure of mTORC1 bound to its activator Rheb, we developed a model of active mTORC1 docked on the lysosome.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "mTORC1 / Raptor / Rag-Ragulator", "ai_species": "Cryo-EM structure", "ai_effect": "Structure reveals how mTORC1 (via Raptor) docks on the Rag-Ragulator at the lysosomal surface", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ROG2019/" }, { "sid": "WOLF2017", "title": "The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway", "authors": "Wolfson RL; Sabatini DM et al.", "year": 2017, "journal": "Cell metabolism", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2017.07.001", "pmid": "28768171", "pmcid": "PMC5560103", "finding": "Review of the newly discovered amino-acid sensors feeding into mTORC1.\n", "abstract": "The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that responds to a diverse set of environmental inputs, including amino acids. Over the past 10 years, a number of proteins have been identified that help transmit amino acid availability to mTORC1. However, amino acid sensors for this pathway have only recently been discovered. Here, we review these recent advances and highlight the variety of unexplored questions that emerge from the identification of these sensors.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1 amino-acid sensors", "ai_species": "Review", "ai_effect": "Reviews the recently discovered amino-acid sensors for the mTORC1 pathway", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WOLF2017/" }, { "sid": "LIX2010", "title": "mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists", "authors": "Li N; Duman RS et al.", "year": 2010, "journal": "Science", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Rat", "peer_reviewed": "Yes", "doi": "10.1126/science.1190287", "pmid": "20724638", "pmcid": "PMC3116441", "finding": "Ketamine's rapid antidepressant action requires mTOR-dependent synaptogenesis in prefrontal cortex.\n", "abstract": "The rapid antidepressant response after ketamine administration in treatment-resistant depressed patients suggests a possible new approach for treating mood disorders compared to the weeks or months required for standard medications. However, the mechanisms underlying this action of ketamine [a glutamate N-methyl-D-aspartic acid (NMDA) receptor antagonist] have not been identified. We observed that ketamine rapidly activated the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signaling proteins and increased number and function of new spine synapses in the prefrontal cortex of rats. Moreover, blockade of mTOR signaling completely blocked ketamine induction of synaptogenesis and behavioral responses in models of depression. Our results demonstrate that these effects of ketamine are opposite to the synaptic deficits that result from exposure to stress and could contribute to the fast antidepressant actions of ketamine.", "ai_intervention": "Ketamine (NMDA-receptor antagonist)", "ai_target": "mTOR", "ai_species": "Rat", "ai_effect": "mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists (ketamine)", "ai_dose": "Ketamine 5-10 mg/kg (systemic); Ro 25-6981 10 mg/kg (systemic); Rapamycin, U0126, LY294002 (ICV infusion)", "ai_samplesize": "", "ai_effectsize": "Ketamine (5-10 mg/kg) rapidly activated mTOR signaling, increased synaptic proteins (PSD95, GluR1, synapsin I), increased spine density, significantly increased EPSC frequency and amplitude, and produced rapid antidepressant effects in FST, LH, and NSFT. These effects were blocked by rapamycin. Ro 25-6981 (10 mg/kg) showed similar effects.", "ai_limitations": "The mechanisms underlying the induction of mTOR signaling are unclear. Ketamine is a psychotomimetic drug with abuse potential, and a more selective agent would be desirable for clinical antidepressant use.", "atlas_url": "https://mtor-atlas.org/study/LIX2010/" }, { "sid": "POW2011", "title": "Regulation of immune responses by mTOR", "authors": "Powell JD; Horton MR et al.", "year": 2011, "journal": "Annual review of immunology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1146/annurev-immunol-020711-075024", "pmid": "22136167", "pmcid": "PMC3616892", "finding": "Review of mTOR as an integrator of immune-cell metabolism and differentiation.\n", "abstract": "mTOR is an evolutionarily conserved serine/threonine kinase that plays a central role in integrating environmental cues in the form of growth factors, amino acids, and energy. In the study of the immune system, mTOR is emerging as a critical regulator of immune function because of its role in sensing and integrating cues from the immune microenvironment. With the greater appreciation of cellular metabolism as an important regulator of immune cell function, mTOR is proving to be a vital link between immune function and metabolism. In this review, we discuss the ability of mTOR to direct the adaptive immune response. Specifically, we focus on the role of mTOR in promoting differentiation, activation, and function in T cells, B cells, and antigen-presenting cells.", "ai_intervention": "Not applicable (review)", "ai_target": "mTOR (immune)", "ai_species": "Review", "ai_effect": "Reviews mTOR as a central regulator of immune responses", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/POW2011/" }, { "sid": "ZIN2011", "title": "Activation of mTORC2 by association with the ribosome", "authors": "Zinzalla V; Hall MN et al.", "year": 2011, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2011.02.014", "pmid": "21376236", "pmcid": "", "finding": "mTORC2 is activated by direct association with the ribosome downstream of PI3K.\n", "abstract": "The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of growth. Mammalian TOR complex 2 (mTORC2) regulates AGC kinase family members and is implicated in various disorders, including cancer and diabetes. Here, we investigated the upstream regulation of mTORC2. A genetic screen in yeast and subsequent studies in mammalian cells revealed that ribosomes, but not protein synthesis, are required for mTORC2 signaling. Active mTORC2 was physically associated with the ribosome, and insulin-stimulated PI3K signaling promoted mTORC2-ribosome binding, suggesting that ribosomes activate mTORC2 directly. Findings with melanoma and colon cancer cells suggest that mTORC2-ribosome association is important in oncogenic PI3K signaling. Thus, TORC2-ribosome interaction is a likely conserved mechanism of TORC2 activation that is physiologically relevant in both normal and cancer cells. As ribosome content determines growth capacity of a cell, this mechanism of TORC2 regulation ensures that TORC2 is active only in growing cells.", "ai_intervention": "Genetic/biochemical (mTORC2 / ribosome)", "ai_target": "mTORC2 / ribosome / Akt", "ai_species": "Mammalian cells", "ai_effect": "mTORC2 is activated by direct association with the ribosome (PI3K-dependent)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZIN2011/" }, { "sid": "PEN2017", "title": "SZT2 dictates GATOR control of mTORC1 signalling", "authors": "Peng M; Li MO et al.", "year": 2017, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/nature21378", "pmid": "28199315", "pmcid": "PMC5570594", "finding": "SZT2 organizes GATOR1/GATOR2 to dictate amino-acid control of mTORC1.\n", "abstract": "Mechanistic target of rapamycin complex 1 (TORC1) integrates nutrient signals to control cell growth and organismal homeostasis across eukaryotes. The evolutionarily conserved GATOR complex regulates mTORC1 signalling through Rag GTPases, and GATOR1 displays GTPase activating protein (GAP) activity for RAGA and RAGB (RAGA/B) and GATOR2 has been proposed to be an inhibitor of GATOR1. Furthermore, the metazoan-specific SESN proteins function as guanine nucleotide dissociation inhibitors (GDIs) for RAGA/B, and interact with GATOR2 with unknown effects. Here we show that SZT2 (seizure threshold 2), a metazoan-specific protein mutated in epilepsy, recruits a fraction of mammalian GATOR1 and GATOR2 to form a SZT2-orchestrated GATOR (SOG) complex with an essential role in GATOR- and SESN-dependent nutrient sensing and mTORC1 regulation. The interaction of SZT2 with GATOR1 and GATOR2 was synergistic, and an intact SOG complex was required for its localization at the lysosome. SZT2 deficiency resulted in constitutive mTORC1 signalling in cells under nutrient-deprived conditions and neonatal lethality in mice, which was associated with failure to inactivate mTORC1 during fasting. Hyperactivation of mTORC1 in SZT2-deficient cells could be partially corrected by overexpression of the GATOR1 component DEPDC5, and by the lysosome-targeted GATOR2 component WDR59 or lysosome-targeted SESN2. These findings demonstrate that SZT2 has a central role in dictating GATOR-dependent nutrient sensing by promoting lysosomal localization of SOG, and reveal an unexpected function of lysosome-located GATOR2 in suppressing mTORC1 signalling through SESN recruitment.", "ai_intervention": "Genetic/biochemical (SZT2 / KICSTOR)", "ai_target": "SZT2 / GATOR / Rag / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "SZT2 dictates GATOR control of mTORC1 signalling", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PEN2017/" }, { "sid": "SHA2004", "title": "Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies", "authors": "Shah OJ; Wang Zhiyong; Hunter T", "year": 2004, "journal": "Current Biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cub.2004.08.026", "pmid": "15380067", "pmcid": "", "finding": "The companion paper to Harrington 2004, published two months later. In cultured mammalian cells, constitutive Rheb/mTOR/S6K activity depletes IRS1 and IRS2, producing cellular insulin resistance and impaired survival signalling. Together the two papers establish the S6K1 -> IRS negative feedback arm.\n", "abstract": "Tuberous sclerosis is a largely benign tumor syndrome derived from the acquisition of somatic lesions in genes encoding the tumor suppressor products, TSC1 or TSC2. Loss of function of the TSC1-TSC2 complex, which acts as a Rheb GAP, yields constitutive, unrestrained signaling from the cell growth machinery comprised of Rheb, mTOR, and S6K. We demonstrate herein that constitutive activation of the Rheb/mTOR/S6K cassette, whether by genetic deletion of TSC1 or TSC2 or by ectopic expression of Rheb, is sufficient to induce insulin resistance. This is the result of downregulation of the insulin receptor substrates, IRS1 and IRS2, which become limiting for signal transmission from the insulin receptor to PI3K. Downstream of PI3K, the survival kinase, Akt, is completely refractory to activation by IRS-dependent growth factor pathways such as insulin or IGF-I in TSC1- or TSC2-deficient cells but not to activation by IRS-independent pathways such as those utilized by PDGF. The antiapoptotic program induced by IGF-I but not PDGF is severely compromised in TSC2 null cells. Our results suggest that inappropriate activation of the Rheb/mTOR/S6K pathway imposes a negative feedback program to attenuate IRS-dependent processes such as cell survival.", "ai_intervention": "", "ai_target": "TSC/Rheb/mTOR/S6K -> IRS1/2", "ai_species": "Mammalian cells", "ai_effect": "Constitutive mTOR/S6K signalling depletes IRS1/2 and causes cellular insulin resistance", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SHA2004/" }, { "sid": "TAN2024", "title": "Targeting mTOR restores tau-induced metabolic, mitochondrial, and cognitive deficits in a tauopathy mouse model", "authors": "Tang Z; Guo M; Ding Y; Wen Y; Li B; Xiao Y; Ni R; Guan Z; Qi XL", "year": 2024, "journal": "bioRxiv (preprint)", "tier": "Preprint", "pyramid": "Preprint", "category": "Preprint", "model": "Mouse (Tau3E-overexpressing, hippocampal CA3)", "peer_reviewed": "No", "doi": "10.1101/2024.11.24.625068", "pmid": "", "pmcid": "", "finding": "In mice engineered to overexpress a phosphomimetic tau variant, one week of rapamycin reversed tau-driven mitochondrial dysfunction and rescued cognitive performance in the Morris water maze - extends the mTOR-autophagy-neurodegeneration link (already seen with Huntington's) to a direct tau-phosphorylation mechanism relevant to Alzheimer's.\n", "abstract": "Aim: Hyperphosphorylated tau plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Whether mammalian target of rapamycin (mTOR) directly interacts with the Tau protein at Ser214, Ser356 and Thr231 is not clear. This study aimed to investigate whether mTOR-regulated tau phosphorylation disrupts mitochondrial dynamics and function and whether rapamycin, an mTOR inhibitor, can modulate tau phosphorylation levels and attenuate AD-related alterations. Methods: Adeno-associated virus (AAV) vectors were used to intracranially deliver the TauS214E/T231E/S356E (Tau3E) variant into 2-month-old C57BL/6 mice. The mice were intraperitoneally administered the mTOR inhibitor rapamycin for one week, followed by assessment via the Morris water maze test. Western blot, immunofluorescence staining and flow cytometry measured mTOR, p70S6K and tau expression, mitochondrial dynamics and reactive oxygen species (ROS) in HT22 cells and Tau3E-overexpressing mice, as well as postmortem brain tissue from AD patients. Results: p-mTOR-S2448 colocalized with p-Tau-Ser214, p-Tau-Ser356 and p-Tau-Thr231 in the hippocampal CA3 region of AD patients. HT22 cells and mice overexpressing Tau3E showed elevated p-mTOR, p-p70S6K and ROS, mitochondrial fragmentation, and increased p-Tau at the three sites; rapamycin partially mitigated the cognitive and molecular alterations. Conclusion: The study reveals a causal link between tau phosphorylation at Ser214/Ser356/Thr231 and mTOR upregulation with downstream ROS, mitochondrial dysfunction and cognitive impairment; rapamycin (i.p.) alleviates the impairment, reduces p-Tau and restores mitochondrial homeostasis, neuronal loss and cognition in mice. (Preprint abstract; source: bioRxiv.)", "ai_intervention": "Rapamycin (mTOR inhibition)", "ai_target": "mTOR / Tau (Ser214/Ser356/Thr231)", "ai_species": "Mouse (tauopathy, Tau3E CA3)", "ai_effect": "Targeting mTOR restores tau-induced metabolic, mitochondrial and cognitive deficits in a tauopathy model", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/TAN2024/" }, { "sid": "HUD2007", "title": "Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma", "authors": "Hudes G et al.", "year": 2007, "journal": "New England Journal of Medicine", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, phase III RCT (n=626)", "peer_reviewed": "Yes", "doi": "10.1056/NEJMoa066838", "pmid": "17538086", "pmcid": "", "finding": "Temsirolimus alone extended median overall survival to 10.9 months versus 7.3 months with interferon alfa in poor-prognosis metastatic kidney cancer; rash, hyperglycemia, and hyperlipidemia were more common with temsirolimus.\n", "abstract": "Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease.\n\nIn this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group.\n\nPatients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02).\n\nAs compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].).", "ai_intervention": "Temsirolimus (± interferon alfa)", "ai_target": "mTOR", "ai_species": "Human – phase III RCT (n=626, poor-prognosis RCC)", "ai_effect": "Temsirolimus improved overall survival vs interferon alfa in poor-prognosis metastatic renal-cell carcinoma", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HUD2007/" }, { "sid": "THO2012", "title": "A unifying model for mTORC1-mediated regulation of mRNA translation", "authors": "Thoreen CC; Chantranupong L; Keys HR; Wang T; Gray NS; Sabatini DM", "year": 2012, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse cells (ribosome profiling)", "peer_reviewed": "Yes", "doi": "10.1038/nature11083", "pmid": "22552098", "pmcid": "PMC3347774", "finding": "Used ribosome profiling with the complete inhibitor Torin1 to address a long-standing debate: in these cells, mTORC1's translational control runs largely through the 4E-BP family acting on a specific class of mRNAs (TOP motifs). Losing just the 4E-BPs makes translation resistant to mTOR inhibition - naming them the master effectors.\n", "abstract": "The mTOR complex 1 (mTORC1) kinase nucleates a pathway that promotes cell growth and proliferation and is the target of rapamycin, a drug with many clinical uses. mTORC1 regulates messenger RNA translation, but the overall translational program is poorly defined and no unifying model exists to explain how mTORC1 differentially controls the translation of specific mRNAs. Here we use high-resolution transcriptome-scale ribosome profiling to monitor translation in mouse cells acutely treated with the mTOR inhibitor Torin 1, which, unlike rapamycin, fully inhibits mTORC1 (ref. 2). Our data reveal a surprisingly simple model of the mRNA features and mechanisms that confer mTORC1-dependent translation control. The subset of mRNAs that are specifically regulated by mTORC1 consists almost entirely of transcripts with established 5' terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1 and Ybx1, with previously unrecognized TOP or related TOP-like motifs that we identified. We find no evidence to support proposals that mTORC1 preferentially regulates mRNAs with increased 5' untranslated region length or complexity. mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown. Remarkably, loss of just the 4E-BP family of translational repressors, arguably the best characterized mTORC1 substrates, is sufficient to render TOP and TOP-like mRNA translation resistant to Torin 1. The 4E-BPs inhibit translation initiation by interfering with the interaction between the cap-binding protein eIF4E and eIF4G1. Loss of this interaction diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much more than other mRNAs, explaining why mTOR inhibition selectively suppresses their translation. Our results clarify the translational program controlled by mTORC1 and identify 4E-BPs and eIF4G1 as its master effectors.", "ai_intervention": "Ribosome profiling (Torin1)", "ai_target": "mTORC1 / 4E-BP / TOP mRNAs", "ai_species": "Mouse cells", "ai_effect": "Proposes a unifying model: mTORC1 controls translation of TOP mRNAs via 4E-BP", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/THO2012/" }, { "sid": "WUL2006", "title": "TOR signaling in growth and metabolism", "authors": "Wullschleger S; Hall MN et al.", "year": 2006, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2006.01.016", "pmid": "16469695", "pmcid": "", "finding": "Landmark review synthesizing TOR signalling in growth and metabolism across organisms.\n", "abstract": "The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. Here, highlighting contributions from studies in model organisms, we review mammalian TOR complexes and the signaling branches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1), which is sensitive to rapamycin, and TORC2, which is not. The physiological consequences of mammalian TORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.", "ai_intervention": "Not applicable (review)", "ai_target": "TORC1 / TORC2", "ai_species": "Review", "ai_effect": "Reviews TOR complexes and the signaling branches they mediate in growth and metabolism", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WUL2006/" }, { "sid": "URF2017", "title": "A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs", "authors": "Urfer SR; Kaeberlein M et al.", "year": 2017, "journal": "GeroScience", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Companion dogs (client-owned, RCT)", "peer_reviewed": "Yes", "doi": "10.1007/s11357-017-9972-z", "pmid": "28374166", "pmcid": "PMC5411365", "finding": "A short 10-week course of low-dose rapamycin improved heart function measures in healthy pet dogs with no clinical side effects.\n", "abstract": "Age is the single greatest risk factor for most causes of morbidity and mortality in humans and their companion animals. As opposed to other model organisms used to study aging, dogs share the human environment, are subject to similar risk factors, receive comparable medical care, and develop many of the same age-related diseases humans do. In this study, 24 middle-aged healthy dogs received either placebo or a non-immunosuppressive dose of rapamycin for 10 weeks. All dogs received clinical and hematological exams before, during, and after the trial and echocardiography before and after the trial. Our results showed no clinical side effects in the rapamycin-treated group compared to dogs receiving the placebo. Echocardiography suggested improvement in both diastolic and systolic age-related measures of heart function (E/A ratio, fractional shortening, and ejection fraction) in the rapamycin-treated dogs. Hematological values remained within the normal range for all parameters studied; however, the mean corpuscular volume (MCV) was decreased in rapamycin-treated dogs. Based on these results, we will test rapamycin on a larger dog cohort for a longer period of time in order to validate its effects on cardiac function and to determine whether it can significantly improve healthspan and reduce mortality in companion dogs.", "ai_intervention": "Rapamycin (short-term)", "ai_target": "mTOR", "ai_species": "Companion dogs (client-owned RCT, n=24)", "ai_effect": "Short-term rapamycin was well tolerated in middle-aged dogs, with signs of improved cardiac function", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/URF2017/" }, { "sid": "JUN2015", "title": "Amino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9", "authors": "Jung J; Behrends C et al.", "year": 2015, "journal": "Molecular and cellular biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1128/MCB.00125-15", "pmid": "25963655", "pmcid": "PMC4475919", "finding": "SLC38A9, a lysosomal membrane protein, mediates amino-acid-dependent mTORC1 activation.\n", "abstract": "The serine/threonine kinase mTORC1 regulates cellular homeostasis in response to many cues, such as nutrient status and energy level. Amino acids induce mTORC1 activation on lysosomes via the small Rag GTPases and the Ragulator complex, thereby controlling protein translation and cell growth. Here, we identify the human 11-pass transmembrane protein SLC38A9 as a novel component of the Rag-Ragulator complex. SLC38A9 localizes with Rag-Ragulator complex components on lysosomes and associates with Rag GTPases in an amino acid-sensitive and nucleotide binding state-dependent manner. Depletion of SLC38A9 inhibits mTORC1 activity in the presence of amino acids and in response to amino acid replenishment following starvation. Conversely, SLC38A9 overexpression causes RHEB (Ras homolog enriched in brain) GTPase-dependent hyperactivation of mTORC1 and partly sustains mTORC1 activity upon amino acid deprivation. Intriguingly, during amino acid starvation mTOR is retained at the lysosome upon SLC38A9 depletion but fails to be activated. Together, the findings of our study reveal SLC38A9 as a Rag-Ragulator complex member transducing amino acid availability to mTORC1 activity.", "ai_intervention": "Biochemical/genetic (SLC38A9)", "ai_target": "SLC38A9 / Rag-Ragulator / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "SLC38A9 is a lysosomal component of the Rag-Ragulator that mediates amino-acid-dependent mTORC1 activation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JUN2015/" }, { "sid": "HOW2017", "title": "Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex", "authors": "Howell JJ; Hellberg K; Turner M; Talbott G; Kolar MJ; Ross DS; Hoxhaj G; Saghatelian A; Shaw RJ; Manning BD", "year": 2017, "journal": "Cell Metabolism", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse liver + primary hepatocytes", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2016.12.009", "pmid": "28089566", "pmcid": "PMC5299044", "finding": "Pinned down HOW the diabetes drug metformin - a major longevity candidate - actually reaches mTOR. In the liver, metformin lowers cellular energy, and at low doses this shuts down mTORC1 specifically through AMPK and the TSC complex. Direct mechanistic bridge between a widely-used drug, energy sensing, and the mTOR pathway.\n", "abstract": "Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion. Here we show that metformin robustly inhibits mTORC1 in mouse liver tissue and primary hepatocytes. Using mouse genetics, we find that at the lowest concentrations of metformin that inhibit hepatic mTORC1 signaling, this inhibition is dependent on AMPK and the tuberous sclerosis complex (TSC) protein complex (TSC complex). Finally, we show that metformin profoundly inhibits hepatocyte protein synthesis in a manner that is largely dependent on its ability to suppress mTORC1 signaling.", "ai_intervention": "Metformin (dose-dependent)", "ai_target": "AMPK / TSC / Rag / mTORC1", "ai_species": "Mouse liver + primary hepatocytes", "ai_effect": "Metformin inhibits hepatic mTORC1 via dose-dependent AMPK- and TSC-complex-dependent mechanisms", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HOW2017/" }, { "sid": "HAN2025", "title": "What is the clinical evidence to support off-label rapamycin therapy in healthy adults?", "authors": "Hands JM; Lustgarten MS; Frame LA; Rosen B", "year": 2025, "journal": "Aging (Albany NY)", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Narrative review + PhenoAge modeling of one cohort", "peer_reviewed": "Yes", "doi": "10.18632/aging.206300", "pmid": "40778880", "pmcid": "PMC12422820", "finding": "A deliberately cautious review of low-dose rapamycin in healthy adults, and re-models one cohort using the PhenoAge biological-aging clock. Verdict: despite strong animal lifespan data, human evidence does NOT yet prove rapamycin delays aging in healthy people. A valuable counterweight to longevity-community hype - it holds the human evidence to a strict standard rather than over-reading promising signals.\n", "abstract": "Low dose rapamycin therapy has been proposed as a longevity candidate in healthy aging adults. We present a review of the evidence for low dose rapamycin and rapalog therapies in healthy human adults and model the findings of one cohort study using the PhenoAge model. Despite the preclinical evidence supporting the use of sirolimus to enhance mean and maximal lifespan, the data in humans have yet to establish that rapamycin, or its analogues, is a proven seno-therapeutic that can delay aging in healthy older adults. Rapamycin and rapalogs warrant further study with larger cohorts to better establish their contribution to human aging.", "ai_intervention": "Not applicable (narrative review + PhenoAge modeling)", "ai_target": "mTOR", "ai_species": "Narrative review (+ modeling of one cohort)", "ai_effect": "Reviews the limited human evidence for off-label low-dose rapamycin in healthy adults; benefit not yet established", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HAN2025/" }, { "sid": "BRO1994", "title": "A mammalian protein targeted by G1-arresting rapamycin-receptor complex", "authors": "Brown EJ; Schreiber SL et al.", "year": 1994, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Bovine brain; in vitro", "peer_reviewed": "Yes", "doi": "10.1038/369756a0", "pmid": "8008069", "pmcid": "", "finding": "Purified FRAP (mTOR) as the mammalian FKBP12-rapamycin target homologous to yeast TOR1/2.\n", "abstract": "The structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways. FKBP12-rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma, liver and T cells as well as in yeast, and interferes with mitogenic signalling pathways that are involved in G1 progression, namely with activation of the protein p70S6k (refs 5, 11-13) and cyclin-dependent kinases. Here we isolate a mammalian FKBP-rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly, these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases.", "ai_intervention": "Biochemical (FKBP12-rapamycin complex)", "ai_target": "mTOR (FRAP) / FKBP12", "ai_species": "Bovine brain; in vitro", "ai_effect": "Identifies the mammalian FKBP12-rapamycin target protein that controls G1 cell-cycle progression", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BRO1994/" }, { "sid": "SHE2018", "title": "Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes", "authors": "Shen K; Sabatini DM et al.", "year": 2018, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.1038/nature26158", "pmid": "29590090", "pmcid": "PMC5975964", "finding": "Cryo-EM structures of GATOR1 and GATOR1-Rag complexes reveal GAP and inhibitory-clamp mechanisms.\n", "abstract": "Nutrients, such as amino acids and glucose, signal through the Rag GTPases to activate mTORC1. The GATOR1 protein complex-comprising DEPDC5, NPRL2 and NPRL3-regulates the Rag GTPases as a GTPase-activating protein (GAP) for RAGA; loss of GATOR1 desensitizes mTORC1 signalling to nutrient starvation. GATOR1 components have no sequence homology to other proteins, so the function of GATOR1 at the molecular level is currently unknown. Here we used cryo-electron microscopy to solve structures of GATOR1 and GATOR1-Rag GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 links DEPDC5 and NPRL3, and DEPDC5 contacts the Rag GTPase heterodimer. Biochemical analyses reveal that our GATOR1-Rag GTPases structure is inhibitory, and that at least two binding modes must exist between the Rag GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2-NPRL3 heterodimer and RAGA execute GAP activity. These data reveal the structure of a component of the nutrient-sensing mTORC1 pathway and a non-canonical interaction between a GAP and its substrate GTPase.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "GATOR1 (DEPDC5/NPRL2/NPRL3) / RagA / mTORC1", "ai_species": "Cryo-EM structure", "ai_effect": "Cryo-EM structures of GATOR1 and GATOR1-Rag reveal its GAP activity and inhibitory-clamp mechanism", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SHE2018/" }, { "sid": "FIN2002", "title": "Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E", "authors": "Fingar DC; Blenis J et al.", "year": 2002, "journal": "Genes & development", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1101/gad.995802", "pmid": "12080086", "pmcid": "PMC186342", "finding": "mTOR controls mammalian cell size through its downstream translational targets S6K1 and 4E-BP1/eIF4E.\n", "abstract": "The coordinated action of cell cycle progression and cell growth (an increase in cell size and cell mass) is critical for sustained cellular proliferation, yet the biochemical signals that control cell growth are poorly defined, particularly in mammalian systems. We find that cell growth and cell cycle progression are separable processes in mammalian cells and that growth to appropriate cell size requires mTOR- and PI3K-dependent signals. Expression of a rapamycin-resistant mutant of mTOR rescues the reduced cell size phenotype induced by rapamycin in a kinase-dependent manner, showing the evolutionarily conserved role of mTOR in control of cell growth. Expression of S6K1 mutants that possess partial rapamycin-resistant activity or overexpression of eIF4E individually and additively partially rescues the rapamycin-induced decrease in cell size. In the absence of rapamycin, overexpression of S6K1 or eIF4E increases cell size, and, when coexpressed, they cooperate to increase cell size further. Expression of a phosphorylation site-defective mutant of 4EBP1 that constitutively binds the eIF4E-Cap complex to inhibit translation initiation reduces cell size and blocks eIF4E effects on cell size. These data show that mTOR signals downstream to at least two independent targets, S6K1 and 4EBP1/eIF4E, that function in translational control to regulate mammalian cell size.", "ai_intervention": "Genetic/pharmacologic (mTOR/S6K1/4EBP1)", "ai_target": "mTOR / S6K1 / 4EBP1-eIF4E", "ai_species": "Mammalian cells", "ai_effect": "Mammalian cell size is controlled by mTOR through its downstream targets S6K1 and 4EBP1/eIF4E", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/FIN2002/" }, { "sid": "ALS2026", "title": "Disruption of the insulin/IGF-1 signaling pathway in Caenorhabditis elegans dramatically increases male longevity and enhances reproductive health late in life", "authors": "Al-Saadi RS; Lewack HB; Phillips PC", "year": 2026, "journal": "Aging (Albany NY)", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "C. elegans (males; auxin-inducible degron degradation of DAF-2/IGF-1 receptor)", "peer_reviewed": "Yes", "doi": "10.18632/aging.206411", "pmid": "42641111", "pmcid": "", "finding": "Ubiquitous auxin-inducible degradation of the DAF-2/IGF-1 receptor in C. elegans males increases median lifespan by more than 440% — among the largest lifespan extensions reported for a single intervention — and prolongs male reproductive function late in life. Notably, degrading DAF-2 specifically in the male germline shortened lifespan, the opposite of its effect in hermaphrodites, underlining that pro-longevity nutrient-sensing interventions can act in a sex- and tissue-dependent way.\n", "abstract": "Males and females are known to have dramatically different health and lifespan trajectories, but the underlying basis for these differences is yet to be fully elucidated. In the nematode model system, most aging studies have been conducted with hermaphrodites, and little is known about male-specific responses to pro-longevity mutations. Several previous studies have used the auxin-inducible degron system to degrade the DAF-2/IGF-1 receptor in hermaphrodites, finding that both ubiquitous and tissue-specific degradation can extend lifespan. Here we show that ubiquitous degradation of DAF-2 in male C. elegans increases median lifespan by more than 440%, one of the longest lifespan extensions by a single intervention to date. Conversely, degrading DAF-2 in the male germline decreased lifespan, opposite of its effect in hermaphrodites. Using male mating and reproductive success as a meaningful ecological and neurophysiological measure of healthspan, we found that ubiquitous degradation of DAF-2 greatly prolongs reproductive health, likely by prolonging function of the male intromittent organ in the tail. This work provides further evidence for the importance of studying sex differences in aging and highlights the utility of using C. elegans males to understand the underlying basis of enhanced lifespan and healthspan.", "ai_intervention": "", "ai_target": "", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ALS2026/" }, { "sid": "GUIB2026", "title": "Maternal Sirolimus Therapy for Fetal Extensive Lymphatic Cystic Malformation: Selection Criteria, Management, and Outcomes in a Series of Six Cases", "authors": "Guibaud L; Bordas-Fournel M; Cabet S; Le Vaillant C; Bruel A; Lefran‡ois T; Megier C; Benachi A; Sohier M; Gallois Y; Somon T; Jouannic J-M; Canaud G; Guilhem A; Atallah A; Fraissenon A", "year": 2026, "journal": "Prenatal Diagnosis", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "", "peer_reviewed": "Yes", "doi": "10.1002/pd.70230", "pmid": "42607031", "pmcid": "", "finding": "Maternal rapamycin (sirolimus) therapy for extensive fetal lymphatic malformations. Prenatal mTOR inhibition feasible with partial/marked lesion regression in 5/6 newborns; transplacental transfer observed. Observational case series (n=6); confounding by indication not excluded.\n", "abstract": "", "ai_intervention": "", "ai_target": "", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GUIB2026/" }, { "sid": "KIM2002", "title": "mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery", "authors": "Kim DH; Sarbassov DD; Ali SM; King JE; Latek RR; Erdjument-Bromage H; Tempst P; Sabatini DM", "year": 2002, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human/rodent cell lines (biochemistry)", "peer_reviewed": "Yes", "doi": "10.1016/s0092-8674(02)00808-5", "pmid": "12150925", "pmcid": "", "finding": "Discovery of Raptor as the defining partner of mTOR in mTORC1. This is the paper that gives mTORC1 its identity: Raptor is the scaffold that lets mTOR find and phosphorylate its targets (S6K1), and the complex is stabilized under starvation. Companion paper to Hara 2002.\n", "abstract": "mTOR/RAFT1/FRAP is the target of the immunosuppressive drug rapamycin and the central component of a nutrient- and hormone-sensitive signaling pathway that regulates cell growth. We report that mTOR forms a stoichiometric complex with raptor, an evolutionarily conserved protein with at least two roles in the mTOR pathway. Raptor has a positive role in nutrient-stimulated signaling to the downstream effector S6K1, maintenance of cell size, and mTOR protein expression. The association of raptor with mTOR also negatively regulates the mTOR kinase activity. Conditions that repress the pathway, such as nutrient deprivation and mitochondrial uncoupling, stabilize the mTOR-raptor association and inhibit mTOR kinase activity. We propose that raptor is a missing component of the mTOR pathway that through its association with mTOR regulates cell size in response to nutrient levels.", "ai_intervention": "Biochemical/genetic (raptor)", "ai_target": "mTOR / raptor", "ai_species": "Human/rodent cell lines (biochemistry)", "ai_effect": "mTOR forms a nutrient-sensitive complex with raptor that signals to the cell-growth machinery", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KIM2002/" }, { "sid": "CHO1996", "title": "Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP", "authors": "Choi J; Chen J; Schreiber SL; Clardy J", "year": 1996, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "X-ray crystallography (structural biology)", "peer_reviewed": "Yes", "doi": "10.1126/science.273.5272.239", "pmid": "8662507", "pmcid": "", "finding": "The crystal structure that showed HOW rapamycin works at the atomic level: one rapamycin molecule glues two proteins together - FKBP12 and mTOR's FRB domain - by plugging into two hydrophobic pockets at once. A textbook example of a small molecule acting as 'molecular glue' to force protein dimerization.\n", "abstract": "Rapamycin, a potent immunosuppressive agent, binds two proteins: the FK506-binding protein (FKBP12) and the FKBP-rapamycin-associated protein (FRAP). A crystal structure of the ternary complex of human FKBP12, rapamycin, and the FKBP12-rapamycin-binding (FRB) domain of human FRAP at a resolution of 2.7 angstroms revealed the two proteins bound together as a result of the ability of rapamycin to occupy two different hydrophobic binding pockets simultaneously. The structure shows extensive interactions between rapamycin and both proteins, but fewer interactions between the proteins. The structure of the FRB domain of FRAP clarifies both rapamycin-independent and -dependent effects observed for mutants of FRAP and its homologs in the family of proteins related to the ataxia-telangiectasia mutant gene product, and it illustrates how a small cell-permeable molecule can mediate protein dimerization.", "ai_intervention": "Structural (X-ray crystallography)", "ai_target": "FKBP12 / rapamycin / FRAP (FRB domain)", "ai_species": "X-ray crystallography", "ai_effect": "2.7-Å ternary structure of FKBP12-rapamycin bound to the FRB domain of human FRAP/mTOR", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHO1996/" }, { "sid": "ZON2010", "title": "mTOR: from growth signal integration to cancer, diabetes and ageing", "authors": "Zoncu R; Sabatini DM et al.", "year": 2010, "journal": "Nature reviews. Molecular cell biology", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1038/nrm3025", "pmid": "21157483", "pmcid": "PMC3390257", "finding": "Authoritative review of mTOR from growth-signal integration to disease.\n", "abstract": "In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1 / mTORC2", "ai_species": "Review", "ai_effect": "Reviews TOR signaling from growth-signal integration to cancer, diabetes and ageing", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZON2010/" }, { "sid": "PET2011", "title": "mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway", "authors": "Peterson TR; Sabatini DM et al.", "year": 2011, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2011.06.034", "pmid": "21816276", "pmcid": "PMC3336367", "finding": "mTORC1 controls lipin-1 nuclear localization to regulate SREBP and lipid synthesis.\n", "abstract": "The nutrient- and growth factor-responsive kinase mTOR complex 1 (mTORC1) regulates many processes that control growth, including protein synthesis, autophagy, and lipogenesis. Through unknown mechanisms, mTORC1 promotes the function of SREBP, a master regulator of lipo- and sterolgenic gene transcription. Here, we demonstrate that mTORC1 regulates SREBP by controlling the nuclear entry of lipin 1, a phosphatidic acid phosphatase. Dephosphorylated, nuclear, catalytically active lipin 1 promotes nuclear remodeling and mediates the effects of mTORC1 on SREBP target gene, SREBP promoter activity, and nuclear SREBP protein abundance. Inhibition of mTORC1 in the liver significantly impairs SREBP function and makes mice resistant, in a lipin 1-dependent fashion, to the hepatic steatosis and hypercholesterolemia induced by a high-fat and -cholesterol diet. These findings establish lipin 1 as a key component of the mTORC1-SREBP pathway.", "ai_intervention": "Genetic/pharmacologic (mTORC1/lipin1)", "ai_target": "mTORC1 / lipin1 / SREBP", "ai_species": "Mammalian cells", "ai_effect": "mTORC1 controls lipin1 nuclear entry to regulate the SREBP lipogenic transcription program", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PET2011/" }, { "sid": "DEL2009", "title": "The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment", "authors": "Delgoffe GM; Powell JD et al.", "year": 2009, "journal": "Immunity", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse (T cells)", "peer_reviewed": "Yes", "doi": "10.1016/j.immuni.2009.04.014", "pmid": "19538929", "pmcid": "PMC2768135", "finding": "T cells lacking mTOR fail to become normal effector cells and default toward regulatory T cells, showing mTOR is a master switch for immune cell fate.\n", "abstract": "Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2 production upon initial stimulation. However, such cells failed to differentiate into T helper 1 (Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased STAT transcription factor activation and failure to upregulate lineage-specific transcription factors. Under normally activating conditions, T cells lacking mTOR differentiated into Foxp3(+) regulatory T cells. This was associated with hyperactive Smad3 activation in the absence of exogenous TGF-beta. Surprisingly, T cells selectively deficient in TORC1 do not divert to a regulatory T cell pathway, implicating both TORC1 and TORC2 in preventing the generation of regulatory T cells. Overall, our studies suggest that mTOR kinase signaling regulates decisions between effector and regulatory T cell lineage commitment.", "ai_intervention": "Genetic (mTOR-deficient T cells)", "ai_target": "mTOR", "ai_species": "Mouse (T cells)", "ai_effect": "mTOR is required for effector T-cell differentiation; its loss biases cells toward the regulatory T-cell lineage", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DEL2009/" }, { "sid": "CHR2009", "title": "AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity", "authors": "Chresta CM; Pass M et al.", "year": 2009, "journal": "Cancer research", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cancer cells; xenograft", "peer_reviewed": "Yes", "doi": "10.1158/0008-5472.CAN-09-1751", "pmid": "20028854", "pmcid": "", "finding": "AZD8055, an ATP-competitive mTOR kinase inhibitor, blocks both mTORC1 and mTORC2 (rapamycin-resistant outputs).\n", "abstract": "The mammalian target of rapamycin (mTOR) kinase forms two multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, cell survival, and autophagy. Allosteric inhibitors of mTORC1, such as rapamycin, have been extensively used to study tumor cell growth, proliferation, and autophagy but have shown only limited clinical utility. Here, we describe AZD8055, a novel ATP-competitive inhibitor of mTOR kinase activity, with an IC50 of 0.8 nmol/L. AZD8055 showed excellent selectivity (approximately 1,000-fold) against all class I phosphatidylinositol 3-kinase (PI3K) isoforms and other members of the PI3K-like kinase family. Furthermore, there was no significant activity against a panel of 260 kinases at concentrations up to 10 micromol/L. AZD8055 inhibits the phosphorylation of mTORC1 substrates p70S6K and 4E-BP1 as well as phosphorylation of the mTORC2 substrate AKT and downstream proteins. The rapamycin-resistant T37/46 phosphorylation sites on 4E-BP1 were fully inhibited by AZD8055, resulting in significant inhibition of cap-dependent translation. In vitro, AZD8055 potently inhibits proliferation and induces autophagy in H838 and A549 cells. In vivo, AZD8055 induces a dose-dependent pharmacodynamic effect on phosphorylated S6 and phosphorylated AKT at plasma concentrations leading to tumor growth inhibition. Notably, AZD8055 results in significant growth inhibition and/or regression in xenografts, representing a broad range of human tumor types. AZD8055 is currently in phase I clinical trials.", "ai_intervention": "AZD8055 (ATP-competitive mTOR inhibitor)", "ai_target": "mTORC1 & mTORC2", "ai_species": "Cancer cells; xenograft", "ai_effect": "AZD8055 is a potent, selective, orally bioavailable ATP-competitive mTOR inhibitor with antitumor activity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHR2009/" }, { "sid": "GAR2008", "title": "mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1)", "authors": "Garcia-Martinez JM; Alessi DR et al.", "year": 2008, "journal": "The Biochemical journal", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1042/BJ20081668", "pmid": "18925875", "pmcid": "", "finding": "mTORC2 controls hydrophobic-motif phosphorylation and activity of SGK1 in addition to Akt.\n", "abstract": "SGK1 (serum- and glucocorticoid-induced protein kinase 1) is a member of the AGC (protein kinase A/protein kinase G/protein kinase C) family of protein kinases and is activated by agonists including growth factors. SGK1 regulates diverse effects of extracellular agonists by phosphorylating regulatory proteins that control cellular processes such as ion transport and growth. Like other AGC family kinases, activation of SGK1 is triggered by phosphorylation of a threonine residue within the T-loop of the kinase domain and a serine residue lying within the C-terminal hydrophobic motif (Ser(422) in SGK1). PDK1 phosphorylates the T-loop of SGK1. The identity of the hydrophobic motif kinase is unclear. Recent work has established that mTORC1 phosphorylates the hydrophobic motif of S6K, whereas mTORC2 phosphorylates the hydrophobic motif of Akt. In the present study we demonstrate that SGK1 hydrophobic motif phosphorylation and activity is ablated in knockout fibroblasts possessing mTORC1 activity, but lacking the mTORC2 subunits rictor, Sin1 or mLST8. Furthermore, phosphorylation of NDRG1, a physiological substrate of SGK1, was also abolished in rictor-, Sin1- or mLST8-deficient fibroblasts. mTORC2 immunoprecipitated from wild-type, but not from mLST8- or rictor-knockout cells, phosphorylated SGK1 at Ser(422). Consistent with mTORC1 not regulating SGK1, immunoprecipitated mTORC1 failed to phosphorylate SGK1 at Ser(422). Moreover, rapamycin treatment of HEK-293, MCF-7 or HeLa cells suppressed phosphorylation of S6K, without affecting SGK1 phosphorylation or activation. The findings indicate that mTORC2, but not mTORC1, plays a vital role in controlling the hydrophobic motif phosphorylation and activity of SGK1, and that NDRG1 phosphorylation represents an excellent biomarker for mTORC2 activity.", "ai_intervention": "Genetic/biochemical (mTORC2/SGK1)", "ai_target": "mTORC2 / SGK1", "ai_species": "Mammalian cells", "ai_effect": "mTORC2 controls the hydrophobic-motif phosphorylation and activation of SGK1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GAR2008/" }, { "sid": "PYO2013", "title": "Overexpression of Atg5 in mice activates autophagy and extends lifespan", "authors": "Pyo JO; Jung YK et al.", "year": 2013, "journal": "Nature Communications", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (Atg5-overexpressing transgenic)", "peer_reviewed": "Yes", "doi": "10.1038/ncomms3300", "pmid": "23939249", "pmcid": "PMC3753544", "finding": "Mice engineered with extra copies of the autophagy gene Atg5 lived 17% longer and were leaner and more insulin-sensitive.\n", "abstract": "Autophagy has been implicated in the ageing process, but whether autophagy activation extends lifespan in mammals is unknown. Here we show that ubiquitous overexpression of Atg5, a protein essential for autophagosome formation, extends median lifespan of mice by 17.2%. We demonstrate that moderate overexpression of Atg5 in mice enhances autophagy, and that Atg5 transgenic mice showed anti-ageing phenotypes, including leanness, increased insulin sensitivity and improved motor function. Furthermore, mouse embryonic fibroblasts cultured from Atg5 transgenic mice are more tolerant to oxidative damage and cell death induced by oxidative stress, and this tolerance was reversible by treatment with an autophagy inhibitor. Our observations suggest that the leanness and lifespan extension in Atg5 transgenic mice may be the result of increased autophagic activity.", "ai_intervention": "Genetic (Atg5 overexpression)", "ai_target": "Autophagy (Atg5)", "ai_species": "Mouse (Atg5-overexpressing transgenic)", "ai_effect": "Ubiquitous Atg5 overexpression enhances autophagy and extends median mouse lifespan by ~17%", "ai_dose": "Atg5 cDNA inserted into pCAGGS vector driven by cytomegalovirus enhancer and chicken β-actin promoter, expressed ubiquitously in transgenic mice.", "ai_samplesize": "n=65 for WT mice and n=70 for Atg5 Tg mice (line 25, combined sex); n=25 for WT and n=30 for other Atg5 Tg lines (43, 47, 471).", "ai_effectsize": "Median lifespan of Atg5 Tg mice (line 25) was 119 days (~17%) longer than WT (P <0.001); maximum lifespan was 900±34 days for Atg5 Tg vs 781±22 days for WT (P <0.01).", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PYO2013/" }, { "sid": "MEL2003", "title": "Autophagy genes are essential for dauer development and life-span extension in C. elegans", "authors": "Melendez A; Levine B et al.", "year": 2003, "journal": "Science", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Caenorhabditis elegans", "peer_reviewed": "Yes", "doi": "10.1126/science.1087782", "pmid": "12958363", "pmcid": "", "finding": "Worms lacking the autophagy gene bec-1 lost the lifespan-extending benefit of reduced insulin-like signaling - autophagy is mechanistically required for longevity, not just correlated.\n", "abstract": "Both dauer formation (a stage of developmental arrest) and adult life-span in Caenorhabditis elegans are negatively regulated by insulin-like signaling, but little is known about cellular pathways that mediate these processes. Autophagy, through the sequestration and delivery of cargo to the lysosomes, is the major route for degrading long-lived proteins and cytoplasmic organelles in eukaryotic cells. Using nematodes with a loss-of-function mutation in the insulin-like signaling pathway, we show that bec-1, the C. elegans ortholog of the yeast and mammalian autophagy gene APG6/VPS30/beclin1, is essential for normal dauer morphogenesis and life-span extension. Dauer formation is associated with increased autophagy and also requires C. elegans orthologs of the yeast autophagy genes APG1, APG7, APG8, and AUT10. Thus, autophagy is a cellular pathway essential for dauer development and life-span extension in C. elegans.", "ai_intervention": "Genetic (autophagy-gene RNAi)", "ai_target": "Autophagy / insulin-IGF (daf-2)", "ai_species": "C. elegans", "ai_effect": "Autophagy genes are essential for dauer development and for lifespan extension in insulin/IGF (daf-2) mutants", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MEL2003/" }, { "sid": "PRI1992", "title": "Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase", "authors": "Price DJ; Bierer BE et al.", "year": 1992, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells; in vitro", "peer_reviewed": "Yes", "doi": "10.1126/science.1380182", "pmid": "1380182", "pmcid": "", "finding": "Rapamycin induces dephosphorylation/inactivation of the 70 kDa S6 kinase, defining an early readout of TOR signalling.\n", "abstract": "The immunosuppressant rapamycin inhibited proliferation of the H4IIEC hepatoma cell line. Rapamycin, but not its structural analog FK506, also inhibited the basal and insulin-stimulated activity of the p70 ribosomal protein S6 kinase. By contrast, insulin stimulation of the p85 Rsk S6 kinase and mitogen-activated protein (MAP) kinase activity were unaffected by drug. Rapamycin treatment of COS cells transfected with recombinant p70 S6 kinase completely inhibited the appearance of the hyperphosphorylated form of p70 S6 kinase concomitant with the inhibition of enzyme activity toward 40S subunits. Thus, rapamycin inhibits a signal transduction element that is necessary for the activation of p70 S6 kinase and mitogenesis but unnecessary for activation of p85 Rsk S6 kinase or MAP kinase.", "ai_intervention": "Rapamycin (vs FK506)", "ai_target": "p70 S6 kinase", "ai_species": "Mammalian cells; in vitro", "ai_effect": "Rapamycin (not FK506) inhibits basal and insulin-stimulated p70 S6 kinase activity", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PRI1992/" }, { "sid": "MEN2014", "title": "Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome", "authors": "Menon S; Manning BD et al.", "year": 2014, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2013.11.049", "pmid": "24529379", "pmcid": "PMC4030681", "finding": "Spatial control of the TSC complex integrates insulin and nutrient inputs at the lysosome.\n", "abstract": "mTORC1 promotes cell growth in response to nutrients and growth factors. Insulin activates mTORC1 through the PI3K-Akt pathway, which inhibits the TSC1-TSC2-TBC1D7 complex (the TSC complex) to turn on Rheb, an essential activator of mTORC1. However, the mechanistic basis of how this pathway integrates with nutrient-sensing pathways is unknown. We demonstrate that insulin stimulates acute dissociation of the TSC complex from the lysosomal surface, where subpopulations of Rheb and mTORC1 reside. The TSC complex associates with the lysosome in a Rheb-dependent manner, and its dissociation in response to insulin requires Akt-mediated TSC2 phosphorylation. Loss of the PTEN tumor suppressor results in constitutive activation of mTORC1 through the Akt-dependent dissociation of the TSC complex from the lysosome. These findings provide a unifying mechanism by which independent pathways affecting the spatial recruitment of mTORC1 and the TSC complex to Rheb at the lysosomal surface serve to integrate diverse growth signals.", "ai_intervention": "Genetic/biochemical (TSC complex/Rheb)", "ai_target": "TSC complex / Rheb / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "Insulin drives lysosomal dissociation of the TSC complex, integrating insulin and nutrient regulation of mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MEN2014/" }, { "sid": "SEN2010", "title": "mTORC1 controls fasting-induced ketogenesis and its modulation by ageing", "authors": "Sengupta S; Sabatini DM et al.", "year": 2010, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mouse/cells", "peer_reviewed": "Yes", "doi": "10.1038/nature09584", "pmid": "21179166", "pmcid": "", "finding": "mTORC1 controls fasting-induced hepatic ketogenesis via PPARalpha, and this is blunted with age.\n", "abstract": "The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of a mammalian pathway that coordinates cell growth with the availability of nutrients, energy and growth factors. Progress has been made in the identification of mTORC1 pathway components and in understanding their functions in cells, but there is relatively little known about the role of the pathway in vivo. Specifically, we have little knowledge regarding the role mTORC1 has in liver physiology. In fasted animals, the liver performs numerous functions that maintain whole-body homeostasis, including the production of ketone bodies for peripheral tissues to use as energy sources. Here we show that mTORC1 controls ketogenesis in mice in response to fasting. We find that liver-specific loss of TSC1, an mTORC1 inhibitor, leads to a fasting-resistant increase in liver size, and to a pronounced defect in ketone body production and ketogenic gene expression on fasting. The loss of raptor, an essential mTORC1 component, has the opposite effects. In addition, we find that the inhibition of mTORC1 is required for the fasting-induced activation of PPARalpha, the master transcriptional activator of ketogenic genes, and that suppression of NCoR1, a co-repressor of PPARalpha, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signalling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis, which correlates with an increase in mTORC1 signalling. Moreover, we show that the suppressive effects of mTORC1 activation and ageing on PPARalpha activity and ketone production are not additive, and that mTORC1 inhibition is sufficient to prevent the ageing-induced defect in ketogenesis. Thus, our findings reveal that mTORC1 is a key regulator of PPARalpha function and hepatic ketogenesis and suggest a role for mTORC1 activity in promoting the ageing of the liver.", "ai_intervention": "Genetic (raptor liver knockout)", "ai_target": "mTORC1 / PPARα / ketogenesis", "ai_species": "Mouse/cells", "ai_effect": "mTORC1 controls fasting-induced ketogenesis (via PPARα); this control is blunted with ageing", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SEN2010/" }, { "sid": "VAN2007", "title": "Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40", "authors": "Vander Haar E; Kim DH et al.", "year": 2007, "journal": "Nature cell biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1038/ncb1547", "pmid": "17277771", "pmcid": "", "finding": "Insulin signals to mTORC1 through Akt phosphorylation of the inhibitor PRAS40.\n", "abstract": "Insulin stimulates protein synthesis and cell growth by activation of the protein kinases Akt (also known as protein kinase B, PKB) and mammalian target of rapamycin (mTOR). It was reported that Akt activates mTOR by phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2). However, in recent studies the physiological requirement of Akt phosphorylation of TSC2 for mTOR activation has been questioned. Here, we identify PRAS40 (proline-rich Akt/PKB substrate 40 kDa) as a novel mTOR binding partner that mediates Akt signals to mTOR. PRAS40 binds the mTOR kinase domain and its interaction with mTOR is induced under conditions that inhibit mTOR signalling, such as nutrient or serum deprivation or mitochondrial metabolic inhibition. Binding of PRAS40 inhibits mTOR activity and suppresses constitutive activation of mTOR in cells lacking TSC2. PRAS40 silencing inactivates insulin-receptor substrate-1 (IRS-1) and Akt, and uncouples the response of mTOR to Akt signals. Furthermore, PRAS40 phosphorylation by Akt and association with 14-3-3, a cytosolic anchor protein, are crucial for insulin to stimulate mTOR. These findings identify PRAS40 as an important regulator of insulin sensitivity of the Akt-mTOR pathway and a potential target for the treatment of cancers, insulin resistance and hamartoma syndromes.", "ai_intervention": "Biochemical/genetic (PRAS40/Akt)", "ai_target": "mTORC1 / PRAS40 / Akt", "ai_species": "Mammalian cells", "ai_effect": "Insulin signals to mTOR via Akt phosphorylation of PRAS40, relieving its inhibition of mTORC1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/VAN2007/" }, { "sid": "FAN2026", "title": "mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency", "authors": "Fan W; Liu H; Yang L; Sinha N; Catipovic M; Dong D; Easawaran H; Green R; Laiho M", "year": 2026, "journal": "Genes & Development", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cancer cell lines (functional genomics/CRISPR screens)", "peer_reviewed": "Yes", "doi": "10.1101/gad.353708.126", "pmid": "42575690", "pmcid": "", "finding": "mTORC1 inhibition does not restore ribosome biogenesis but redistributes limited ribosomes away from highly-translated 5'TOP mRNAs toward survival-essential transcripts, defining a 'translational fitness' mechanism that lets cancer cells survive ribosome biogenesis deficiency.\n", "abstract": "Ribosome biogenesis is a resource-consuming process that facilitates rapid growth and feeds uncontrolled, cancerous traits. Constraining ribosome biogenesis and protein translation has become a tenable therapeutic strategy for cancer. Yet, we do not know how cells that rely on high metabolic activity adapt and sustain their growth when deprived of their translational capacity. Conversely, stem cells and treatment-resistant cells persist under low metabolic states challenging their eradication. These are critical questions in cancer therapies. To delineate survival mechanisms that allow cancer cells to adapt to ribosome biogenesis defects, we conducted functional genomics screens during inhibition of RNA polymerase I. We identified that inactivation of mTOR enabled cell survival despite severe translational suppression. This was paradoxical as activation of mTOR is considered oncogenic by boosting ribosome biogenesis and cellular translational programs. We show that mTORC1 inhibition does neither restore rRNA synthesis nor ribosome biogenesis, but redistributes limited ribosomes from highly translated 5'TOP mRNAs to survival-essential transcripts. This mTOR inactivation-mediated prioritization of translational resources represents a minimal requirement for cell survival when translational capacity is compromised, which we term 'translational fitness.' Our findings redefine the role of mTOR in cell survival and highlight the need for strategic targeting of translation regulation in cancer therapy.", "ai_intervention": "Functional genomics/CRISPR screens under RNA Pol I inhibition; mTOR inactivation (genetic/pharmacologic)", "ai_target": "mTORC1 / ribosome biogenesis / 5'TOP mRNA translation", "ai_species": "Human cancer cell lines", "ai_effect": "mTOR inactivation redistributes limited ribosomes from 5'TOP mRNAs to survival-essential transcripts, enabling adaptive survival ('translational fitness') under ribosome biogenesis deficiency", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/FAN2026/" }, { "sid": "GIN2026", "title": "Inferring feedback regulation from static snapshots of a single signal", "authors": "Ginzberg M; Tan C; Patel N; Kafri R", "year": 2026, "journal": "Biochemistry and Biophysics Reports", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human/mammalian cultured cells (fixed-cell single-cell imaging, ergodic rate analysis)", "peer_reviewed": "Yes", "doi": "10.1016/j.bbrep.2026.102747", "pmid": "42643853", "pmcid": "PMC13505498", "finding": "Introduces AoF (Assay of Feedback), a perturbation-free single-cell imaging method that reconstructs how a signal CHANGES OVER TIME from fixed-cell snapshots, using DNA content and Geminin to order cells along the cell cycle. Applied to Akt phosphorylation, it uncovers a negative feedback loop that is active only in a narrow window at the G1/S transition; biochemistry points to mTORC1/S6K1-dependent inhibitory phosphorylation of IRS1 as the likely source, though the authors state this edge is not uniquely established. Directly relevant to the question of whether mTOR pathway activity is better described as a time-varying pattern than a fixed level.\n", "abstract": "Direct measurement of feedback regulation remains difficult because it usually relies on pathway perturbations and prior knowledge of circuit topology. We introduce AoF (Assay of Feedback), a single-cell imaging framework that combines fixed-cell measurements of a target (together with DNA and Geminin as cell-cycle ordering markers) with ergodic rate analysis to reconstruct target dynamics in steady-state proliferating populations and quantify how a target's inferred rate of change depends on its own level. AoF therefore estimates feedback sign, magnitude, and state dependence from snapshot data without resolving surrounding circuitry. As a proof of concept, we applied AoF to map Akt phosphorylation across the cell cycle, unmasking a highly localized negative feedback loop restricted to the G1/S transition. Biochemical experiments point to an mTORC1/S6K1-dependent inhibitory phosphorylation of IRS1, which would stabilize Akt activation during early S phase, as the likeliest source of this snapshot-derived signature, but they do not establish that edge uniquely. AoF provides a rapid, scalable, and perturbation-free methodology to map context-specific feedback control.", "ai_intervention": "None (observational imaging assay); mTORC1/S6K1 inhibition used in supporting biochemistry", "ai_target": "AKT phosphorylation; mTORC1-S6K1-IRS1 negative feedback", "ai_species": "Cultured mammalian cells", "ai_effect": "Reveals cell-cycle-localized negative feedback on AKT at G1/S, attributed to mTORC1/S6K1-IRS1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GIN2026/" }, { "sid": "CON2021", "title": "Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction", "authors": "Condon KJ; Sabatini DM et al.", "year": 2021, "journal": "Proceedings of the National Academy of Sciences of the United States of America", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "CRISPR screen; cells", "peer_reviewed": "Yes", "doi": "10.1073/pnas.2022120118", "pmid": "33483422", "pmcid": "PMC7848693", "finding": "Genome-wide CRISPR screens reveal AMPK and HRI relay mitochondrial dysfunction to mTORC1.\n", "abstract": "In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 growth control pathway. Because the full complement of these proteins has not been systematically identified, we developed a FACS-based CRISPR-Cas9 genetic screening strategy to pinpoint genes that regulate mTORC1 activity. Along with almost all known positive components of the mTORC1 pathway, we identified many genes that impact mTORC1 activity. Using the genome-wide screening data, we generated a focused sublibrary targeting hundreds of genes and carried out epistasis screens in cells lacking nutrient- and stress-responsive mTORC1 modulators, including GATOR1, AMPK, GCN2, and ATF4. From these data, we pinpointed mitochondrial function as a particularly important input into mTORC1 signaling. We find that the kinases AMPK and HRI signal, with varying kinetics, mitochondrial distress to mTORC1, and that HRI acts through the ATF4-dependent up-regulation of both Sestrin2 and Redd1. Loss of both AMPK and HRI is sufficient to render mTORC1 signaling largely resistant to mitochondrial dysfunction induced by the ATP synthase inhibitor oligomycin as well as the electron transport chain inhibitors piericidin and antimycin. Taken together, our data reveal a catalog of genes that impact the mTORC1 pathway and clarify the multifaceted ways in which mTORC1 senses mitochondrial dysfunction.", "ai_intervention": "Genome-wide CRISPR-Cas9 screen", "ai_target": "mTORC1 (mitochondrial-dysfunction sensing)", "ai_species": "CRISPR screen; cells", "ai_effect": "CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CON2021/" }, { "sid": "HAR1998", "title": "Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism", "authors": "Hara K; Avruch J et al.", "year": 1998, "journal": "The Journal of biological chemistry", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "CHO cells; in vitro", "peer_reviewed": "Yes", "doi": "10.1074/jbc.273.23.14484", "pmid": "9603962", "pmcid": "", "finding": "Amino acid sufficiency signals through mTOR to p70 S6K and 4E-BP1 via a common effector, first linking nutrients to mTOR.\n", "abstract": "The present study identifies the operation of a signal tranduction pathway in mammalian cells that provides a checkpoint control, linking amino acid sufficiency to the control of peptide chain initiation. Withdrawal of amino acids from the nutrient medium of CHO-IR cells results in a rapid deactivation of p70 S6 kinase and dephosphorylation of eIF-4E BP1, which become unresponsive to all agonists. Readdition of the amino acid mixture quickly restores the phosphorylation and responsiveness of p70 and eIF-4E BP1 to insulin. Increasing the ambient amino acids to twice that usually employed increases basal p70 activity to the maximal level otherwise attained in the presence of insulin and abrogates further stimulation by insulin. Withdrawal of most individual amino acids also inhibits p70, although with differing potency. Amino acid withdrawal from CHO-IR cells does not significantly alter insulin stimulation of tyrosine phosphorylation, phosphotyrosine-associated phosphatidylinositol 3-kinase activity, c-Akt/protein kinase B activity, or mitogen-activated protein kinase activity. The selective inhibition of p70 and eIF-4E BP1 phosphorylation by amino acid withdrawal resembles the response to rapamycin, which prevents p70 reactivation by amino acids, indicating that mTOR is required for the response to amino acids. A p70 deletion mutant, p70Delta2-46/DeltaCT104, that is resistant to inhibition by rapamycin (but sensitive to wortmannin) is also resistant to inhibition by amino acid withdrawal, indicating that amino acid sufficiency and mTOR signal to p70 through a common effector, which could be mTOR itself, or an mTOR-controlled downstream element, such as a protein phosphatase.", "ai_intervention": "Biochemical (amino-acid withdrawal)", "ai_target": "mTOR / p70 S6K / 4E-BP1", "ai_species": "CHO cells; in vitro", "ai_effect": "Amino-acid sufficiency and mTOR regulate p70 S6K and 4E-BP1 through a common effector mechanism", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HAR1998/" }, { "sid": "GAO2026B", "title": "Tumor fat composition predicts response to everolimus and supports low-dose therapy in TSC-associated renal angiomyolipomas: a multicenter prospective study", "authors": "Gao K; Zhang X et al.", "year": 2026, "journal": "Frontiers in oncology", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Human (TSC-associated renal angiomyolipoma patients, multicenter prospective cohort, n=183)", "peer_reviewed": "Yes", "doi": "10.3389/fonc.2026.1893155", "pmid": "42558341", "pmcid": "PMC13437317", "finding": "In a multicenter prospective cohort of 183 TSC-associated renal angiomyolipoma patients, everolimus reduced tumor volume by >=50% in 44% of patients at 3 months and 83% at 6 months; fat-poor lesions responded significantly better than fat-rich ones. A low-dose everolimus regimen showed comparable efficacy to standard dose with fewer adverse events (notably less oral mucositis), though tumor regrowth occurred after treatment discontinuation.\n", "abstract": "Renal angiomyolipomas associated with tuberous sclerosis complex (TSC-RAML) may lead to progressive renal damage and hemorrhage. Everolimus is recommended as first-line therapy, but predictors of treatment response and optimal dosing strategies remain unclear. In this multicenter prospective cohort study across multiple centers in China, 183 consecutive patients with TSC-RAML were enrolled, with three prespecified analytical subsets: standard-dose everolimus efficacy, CT-based tumor fat-composition analysis, and exploratory dose-comparison analysis. A >=50% reduction in tumor volume occurred in 44% (34/78) of patients at 3 months and 83% (60/72) at 6 months. Tumor reduction was significantly greater in fat-poor than fat-rich lesions. No significant difference in response was observed between standard- and low-dose groups. Oral mucositis was the most common adverse event but occurred less frequently in the low-dose group (P=.002). Tumor regrowth was observed after treatment discontinuation. Limitations include the nonrandomized design and open-label treatment administration.", "ai_intervention": "Everolimus, standard-dose vs low-dose; CT-based tumor fat composition analysis", "ai_target": "mTOR (via everolimus)", "ai_species": "Human (TSC-RAML patients, n=183, multicenter China cohort)", "ai_effect": "Everolimus reduces TSC-associated renal angiomyolipoma tumor volume, more effectively in fat-poor lesions; low-dose regimen shows comparable efficacy with better tolerability", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GAO2026B/" }, { "sid": "WAN2011", "title": "The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation", "authors": "Wang R; Green DR et al.", "year": 2011, "journal": "Immunity", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1016/j.immuni.2011.09.021", "pmid": "22195744", "pmcid": "PMC3248798", "finding": "The transcription factor Myc drives metabolic reprogramming of activated T cells downstream of mTOR.\n", "abstract": "To fulfill the bioenergetic and biosynthetic demand of proliferation, T cells reprogram their metabolic pathways from fatty acid beta-oxidation and pyruvate oxidation via the TCA cycle to the glycolytic, pentose-phosphate, and glutaminolytic pathways. Two of the top-ranked candidate transcription factors potentially responsible for the activation-induced T cell metabolic transcriptome, HIF1alpha and Myc, were induced upon T cell activation, but only the acute deletion of Myc markedly inhibited activation-induced glycolysis and glutaminolysis in T cells. Glutamine deprivation compromised activation-induced T cell growth and proliferation, and this was partially replaced by nucleotides and polyamines, implicating glutamine as an important source for biosynthetic precursors in active T cells. Metabolic tracer analysis revealed a Myc-dependent metabolic pathway linking glutaminolysis to the biosynthesis of polyamines. Therefore, a Myc-dependent global metabolic transcriptome drives metabolic reprogramming in activated, primary T lymphocytes. This may represent a general mechanism for metabolic reprogramming under patho-physiological conditions.", "ai_intervention": "Genetic (Myc)", "ai_target": "Myc (mTOR-linked metabolism)", "ai_species": "Mouse T cells", "ai_effect": "Myc controls the metabolic reprogramming (glycolysis, glutaminolysis) upon T-lymphocyte activation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/WAN2011/" }, { "sid": "YAN2017", "title": "Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40", "authors": "Yang H; Pavletich NP et al.", "year": 2017, "journal": "Nature", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.1038/nature25023", "pmid": "29236692", "pmcid": "PMC5750076", "finding": "Structures reveal how RHEB allosterically activates and PRAS40 inhibits mTORC1.\n", "abstract": "The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 angstrom cryo-electron microscopy structure of mTORC1 and the 3.4 angstrom structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "mTORC1 / RHEB / PRAS40", "ai_species": "Cryo-EM structure", "ai_effect": "Structures reveal how RHEB allosterically activates mTORC1 and how PRAS40 inhibits it", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/YAN2017/" }, { "sid": "SAR2005", "title": "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex", "authors": "Sarbassov DD et al.", "year": 2005, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells; Drosophila", "peer_reviewed": "Yes", "doi": "10.1126/science.1106148", "pmid": "15718470", "pmcid": "", "finding": "The rictor-mTOR complex (mTORC2) directly phosphorylates Akt/PKB on Ser473, regulating cell survival.\n", "abstract": "Deregulation of Akt/protein kinase B (PKB) is implicated in the pathogenesis of cancer and diabetes. Akt/PKB activation requires the phosphorylation of Thr308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and Ser473 within the carboxyl-terminal hydrophobic motif by an unknown kinase. We show that in Drosophila and human cells the target of rapamycin (TOR) kinase and its associated protein rictor are necessary for Ser473 phosphorylation and that a reduction in rictor or mammalian TOR (mTOR) expression inhibited an Akt/PKB effector. The rictor-mTOR complex directly phosphorylated Akt/PKB on Ser473 in vitro and facilitated Thr308 phosphorylation by PDK1. Rictor-mTOR may serve as a drug target in tumors that have lost the expression of PTEN, a tumor suppressor that opposes Akt/PKB activation.", "ai_intervention": "Genetic/biochemical (rictor-mTOR)", "ai_target": "mTORC2 (rictor) / Akt Ser473", "ai_species": "Human cells; Drosophila", "ai_effect": "The rictor-mTOR complex (mTORC2) phosphorylates Akt/PKB at Ser473", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SAR2005/" }, { "sid": "PET2013", "title": "Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases", "authors": "Petit CS; Ferguson SM et al.", "year": 2013, "journal": "The Journal of cell biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1083/jcb.201307084", "pmid": "24081491", "pmcid": "PMC3787382", "finding": "Amino acids recruit folliculin to lysosomes to support Rag-dependent mTORC1 activation.\n", "abstract": "Birt-Hogg-Dube syndrome, a human disease characterized by fibrofolliculomas (hair follicle tumors) as well as a strong predisposition toward the development of pneumothorax, pulmonary cysts, and renal carcinoma, arises from loss-of-function mutations in the folliculin (FLCN) gene. In this study, we show that FLCN regulates lysosome function by promoting the mTORC1-dependent phosphorylation and cytoplasmic sequestration of transcription factor EB (TFEB). Our results indicate that FLCN is specifically required for the amino acid-stimulated recruitment of mTORC1 to lysosomes by Rag GTPases. We further demonstrated that FLCN itself was selectively recruited to the surface of lysosomes after amino acid depletion and directly bound to RagA via its GTPase domain. FLCN-interacting protein 1 (FNIP1) promotes both the lysosome recruitment and Rag interactions of FLCN. These new findings define the lysosome as a site of action for FLCN and indicate a critical role for FLCN in the amino acid-dependent activation of mTOR via its direct interaction with the RagA/B GTPases.", "ai_intervention": "Genetic/biochemical (FLCN)", "ai_target": "FLCN / Rag GTPases / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "Amino-acid-stimulated recruitment of folliculin (FLCN) to lysosomes supports Rag GTPase activation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PET2013/" }, { "sid": "BRU1997", "title": "Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin", "authors": "Brunn GJ; Abraham RT et al.", "year": 1997, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "HEK293; in vitro", "peer_reviewed": "Yes", "doi": "10.1126/science.277.5322.99", "pmid": "9204908", "pmcid": "", "finding": "mTOR directly phosphorylates 4E-BP1 (PHAS-I), releasing eIF4E and establishing mTOR's role in translational control.\n", "abstract": "The immunosuppressant rapamycin interferes with G1-phase progression in lymphoid and other cell types by inhibiting the function of the mammalian target of rapamycin (mTOR). mTOR was determined to be a terminal kinase in a signaling pathway that couples mitogenic stimulation to the phosphorylation of the eukaryotic initiation factor (eIF)-4E-binding protein, PHAS-I. The rapamycin-sensitive protein kinase activity of mTOR was required for phosphorylation of PHAS-I in insulin-stimulated human embryonic kidney cells. mTOR phosphorylated PHAS-I on serine and threonine residues in vitro, and these modifications inhibited the binding of PHAS-I to eIF-4E. These studies define a role for mTOR in translational control and offer further insights into the mechanism whereby rapamycin inhibits G1-phase progression in mammalian cells.", "ai_intervention": "Biochemical (mTOR/PHAS-I)", "ai_target": "mTOR / PHAS-I (4E-BP1) / eIF4E", "ai_species": "HEK293; in vitro", "ai_effect": "mTOR is a terminal kinase phosphorylating the translational repressor PHAS-I (4E-BP1)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BRU1997/" }, { "sid": "SET2011", "title": "TFEB links autophagy to lysosomal biogenesis", "authors": "Settembre C; Di Malta C; Polito VA; Garcia Arencibia M; Vetrini F; Erdin S; et al.; Ballabio A", "year": 2011, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human/mouse cells", "peer_reviewed": "Yes", "doi": "10.1126/science.1204592", "pmid": "21617040", "pmcid": "PMC3638014", "finding": "Established TFEB as the single master switch that coordinates the WHOLE recycling program - it turns on both autophagosome and lysosome genes at once during starvation. This is the transcription factor that the mTORC1 pathway keeps switched off when nutrients are plentiful (mechanism pinned down by companion papers).\n", "abstract": "Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion, and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB were regulated by serine phosphorylation mediated by the extracellular signal-regulated kinase 2, whose activity was tuned by the levels of extracellular nutrients. Thus, a mitogen-activated protein kinase-dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles.", "ai_intervention": "Genetic (TFEB)", "ai_target": "TFEB / autophagy-lysosome", "ai_species": "Human/mouse cells", "ai_effect": "TFEB drives a transcriptional program that links autophagy to lysosomal biogenesis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SET2011/" }, { "sid": "ARA2009", "title": "mTOR regulates memory CD8 T-cell differentiation", "authors": "Araki K; Ahmed R et al.", "year": 2009, "journal": "Nature", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1038/nature08155", "pmid": "19543266", "pmcid": "PMC2710807", "finding": "mTOR is a key regulator of memory CD8 T-cell differentiation; rapamycin enhances memory responses.\n", "abstract": "Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor or FKBP12 in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.", "ai_intervention": "Rapamycin (mTOR modulation)", "ai_target": "mTOR", "ai_species": "Mouse", "ai_effect": "mTOR regulates memory CD8 T-cell differentiation; rapamycin enhances memory T-cell quantity and quality", "ai_dose": "Rapamycin administered continuously (day -1~35), during expansion (days -1~8), or contraction (days 8~35) post-infection; specific quantitative dose not stated.", "ai_samplesize": "", "ai_effectsize": "Rapamycin enhanced LCMV-specific CD8 T cell responses, decreased T cell contraction, and improved functional qualities of memory CD8 T cells. Memory T cell numbers remained 10-fold higher even 165 days after stopping drug treatment, and rapamycin treatment during contraction resulted in significantly higher numbers of functional memory cells (p <0.0001~0.0022).", "ai_limitations": "mTOR knockdown does not completely mimic rapamycin treatment.", "atlas_url": "https://mtor-atlas.org/study/ARA2009/" }, { "sid": "FU2026", "title": "tRNA-derived fragment tRF-17-8SPOL52 induces resistance to bortezomib in multiple myeloma via autophagy activation.", "authors": "Fu Y; Qiao Z; Xiao Y; Liang T; Xu C", "year": 2026, "journal": "Biochimica et biophysica acta. Molecular basis of disease", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human (myeloma cell lines + patient samples)", "peer_reviewed": "Yes", "doi": "10.1016/j.bbadis.2026.168396", "pmid": "", "pmcid": "", "finding": "tRF-17-8SPOL52 tsRNA is upregulated in relapsed/refractory myeloma and drives bortezomib resistance by suppressing RUBCN (a negative autophagy regulator), thereby activating autophagy flux.\n", "abstract": "Drug resistance limits the long-term survival of patients with multiple myeloma. The role of tRNA-derived fragments (tsRNAs) in bortezomib resistance in myeloma remains unknown. tRF-17-8SPOL52 was identified as the most highly expressed tsRNA in relapsed/refractory myeloma. tRF-17-8SPOL52 promoted bortezomib resistance in vitro and in vivo. Ago-RIP-sequencing and dual-luciferase reporter assay showed that tRF-17-8SPOL52 negatively regulated RUBCN. The regulation of RUBCN by tRF-17-8SPOL52 was Ago-dependent. Further research showed increased autophagy induced by tRF-17-8SPOL52, identifying autophagy activation as the mechanism of bortezomib resistance in multiple myeloma.", "ai_intervention": "tRF-17-8SPOL52 (tsRNA)", "ai_target": "RUBCN / autophagy", "ai_species": "Human (myeloma)", "ai_effect": "Activates autophagy via RUBCN suppression, inducing bortezomib resistance", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/FU2026/" }, { "sid": "BLA2006", "title": "Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition", "authors": "Blagosklonny MV", "year": 2006, "journal": "Cell Cycle", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Theoretical / review article", "peer_reviewed": "Yes", "doi": "10.4161/cc.5.18.3288", "pmid": "17012837", "pmcid": "", "finding": "Proposes the 'hyperfunction theory' of aging: TOR signaling, useful in youth, stays switched on into old age and becomes actively damaging.\n", "abstract": "While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient- and mitogen-sensing pathway, which promotes cell growth, even though cell cycle is blocked. Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And, in humans, cell hypertrophy, hyper-function and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macula-degeneration, Alzheimer's and Parkinson's diseases. Finally, I discuss that extended life span will reveal new causes for aging (e.g., ROS, 'wear and tear', Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first.", "ai_intervention": "Not applicable (theoretical/review; proposes rapamycin)", "ai_target": "mTOR", "ai_species": "Theoretical / review article", "ai_effect": "Proposes aging as a quasi-programmed, hyperfunctional mTOR-driven process that rapamycin could pharmacologically slow", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BLA2006/" }, { "sid": "ZHU2026", "title": "LKB1/AMPK deficiency aggravates mitochondrial DNA leakage via mTOR-dependent mitophagy damage in liver injury sensitized by trichloroethylene.", "authors": "Zhu L, Wan C, Li Z, Fan X, Liu Z", "year": 2026, "journal": "Chemico-Biological Interactions", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1016/j.cbi.2026.112261", "pmid": "42462870", "pmcid": "", "finding": "LKB1/AMPK deficiency exacerbates trichloroethylene-induced liver injury by impairing mTOR-regulated mitophagy and causing mitochondrial DNA leakage; rapamycin and AMPK activation are protective, nominating the LKB1/AMPK/mTOR axis as a candidate therapeutic target in mice; no human data.\n", "abstract": "In a TCE-sensitized mouse liver injury model, LKB1/AMPK deficiency aggravated mTOR-dependent impairment of mitophagy, causing mitochondrial DNA leakage and exacerbated immune-mediated liver damage. Rapamycin treatment, LKB1 overexpression, and AICAR (AMPK activator) each rescued mitophagy and reduced liver injury.", "ai_intervention": "Rapamycin; AICAR; LKB1 overexpression", "ai_target": "LKB1/AMPK/mTOR axis; mitophagy", "ai_species": "Mouse", "ai_effect": "Rapamycin and AMPK activation restore mTOR-dependent mitophagy; LKB1/AMPK deficiency worsens mitochondrial DNA leakage and liver injury", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZHU2026/" }, { "sid": "KIM2012", "title": "SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling", "authors": "Kim YM; Kim DH et al.", "year": 2012, "journal": "Molecular cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.molcel.2012.04.007", "pmid": "22575674", "pmcid": "PMC3389276", "finding": "SH3BP4 negatively regulates amino-acid-Rag-GTPase-mTORC1 signalling.\n", "abstract": "Amino acids stimulate cell growth and suppress autophagy through activation of mTORC1. The activation of mTORC1 by amino acids is mediated by Rag guanosine triphosphatase (GTPase) heterodimers on the lysosome. The molecular mechanism by which amino acids regulate the Rag GTPase heterodimers remains to be elucidated. Here, we identify SH3 domain-binding protein 4 (SH3BP4) as a binding protein and a negative regulator of Rag GTPase complex. SH3BP4 binds to the inactive Rag GTPase complex through its Src homology 3 (SH3) domain under conditions of amino acid starvation and inhibits the formation of active Rag GTPase complex. As a consequence, the binding abrogates the interaction of mTORC1 with Rag GTPase complex and the recruitment of mTORC1 to the lysosome, thus inhibiting amino acid-induced mTORC1 activation and cell growth and promoting autophagy. These results demonstrate that SH3BP4 is a negative regulator of the Rag GTPase complex and amino acid-dependent mTORC1 signaling.", "ai_intervention": "Biochemical/genetic (SH3BP4)", "ai_target": "SH3BP4 / Rag GTPase / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "SH3BP4 is a negative regulator of amino-acid-Rag-GTPase-mTORC1 signaling", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KIM2012/" }, { "sid": "GU2017", "title": "SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway", "authors": "Gu X; Orozco JM; Saxton RA; Condon KJ; Liu GY; Krawczyk PA; Scaria SM; Harper JW; Gygi SP; Sabatini DM", "year": 2017, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cells (biochemistry)", "peer_reviewed": "Yes", "doi": "10.1126/science.aao3265", "pmid": "29123071", "pmcid": "PMC5747364", "finding": "Extended nutrient sensing beyond amino acids to METABOLITES: SAMTOR reads S-adenosylmethionine (SAM), the cell's methyl-donor currency, linking methionine and one-carbon metabolism to mTORC1. Relevant to why methionine restriction affects aging.\n", "abstract": "mTOR complex 1 (mTORC1) regulates cell growth and metabolism in response to multiple environmental cues. Nutrients signal via the Rag guanosine triphosphatases (GTPases) to promote the localization of mTORC1 to the lysosomal surface, its site of activation. We identified SAMTOR, a previously uncharacterized protein, which inhibits mTORC1 signaling by interacting with GATOR1, the GTPase activating protein (GAP) for RagA/B. We found that the methyl donor-adenosylmethionine (SAM) disrupts the SAMTOR-GATOR1 complex by binding directly to SAMTOR with a dissociation constant of approximately 7 μM. In cells, methionine starvation reduces SAM levels below this dissociation constant and promotes the association of SAMTOR with GATOR1, thereby inhibiting mTORC1 signaling in a SAMTOR-dependent fashion. Methionine-induced activation of mTORC1 requires the SAM binding capacity of SAMTOR. Thus, SAMTOR is a SAM sensor that links methionine and one-carbon metabolism to mTORC1 signaling.", "ai_intervention": "Biochemical/genetic (SAMTOR)", "ai_target": "SAMTOR / GATOR1 / mTORC1 (SAM/methionine)", "ai_species": "Human cells (biochemistry)", "ai_effect": "SAMTOR is an S-adenosylmethionine sensor that inhibits mTORC1 by interacting with GATOR1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GU2017/" }, { "sid": "HOS2009", "title": "Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy", "authors": "Hosokawa N; Hara T; Kaizuka T; Kishi C; Takamura A; Miura Y; et al.; Mizushima N", "year": 2009, "journal": "Molecular Biology of the Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1091/mbc.e08-12-1248", "pmid": "19211835", "pmcid": "PMC2663915", "finding": "Showed the DIRECT brake mTORC1 uses on autophagy: when nutrients are plentiful, mTORC1 physically joins the ULK1-Atg13-FIP200 complex (the autophagy-starter kinase) and phosphorylates ULK1 to keep it off. Starvation or rapamycin releases this brake and autophagy begins.\n", "abstract": "Autophagy is an intracellular degradation system, by which cytoplasmic contents are degraded in lysosomes. Autophagy is dynamically induced by nutrient depletion to provide necessary amino acids within cells, thus helping them adapt to starvation. Although it has been suggested that mTOR is a major negative regulator of autophagy, how it controls autophagy has not yet been determined. Here, we report a novel mammalian autophagy factor, Atg13, which forms a stable approximately 3-MDa protein complex with ULK1 and FIP200. Atg13 localizes on the autophagic isolation membrane and is essential for autophagosome formation. In contrast to yeast counterparts, formation of the ULK1-Atg13-FIP200 complex is not altered by nutrient conditions. Importantly, mTORC1 is incorporated into the ULK1-Atg13-FIP200 complex through ULK1 in a nutrient-dependent manner and mTOR phosphorylates ULK1 and Atg13. ULK1 is dephosphorylated by rapamycin treatment or starvation. These data suggest that mTORC1 suppresses autophagy through direct regulation of the approximately 3-MDa ULK1-Atg13-FIP200 complex.", "ai_intervention": "Genetic/biochemical (mTORC1/ULK1-Atg13-FIP200)", "ai_target": "mTORC1 / ULK1-Atg13-FIP200", "ai_species": "Mammalian cells", "ai_effect": "Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex controls autophagy induction", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HOS2009/" }, { "sid": "YUX2011", "title": "Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling", "authors": "Yu Yonghao; Blenis J et al.", "year": 2011, "journal": "Science", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1126/science.1199484", "pmid": "21659605", "pmcid": "PMC3195509", "finding": "Phosphoproteomics identify Grb10 as an mTORC1 substrate driving negative feedback on insulin/PI3K.\n", "abstract": "The evolutionarily conserved serine-threonine kinase mammalian target of rapamycin (mTOR) plays a critical role in regulating many pathophysiological processes. Functional characterization of the mTOR signaling pathways, however, has been hampered by the paucity of known substrates. We used large-scale quantitative phosphoproteomics experiments to define the signaling networks downstream of mTORC1 and mTORC2. Characterization of one mTORC1 substrate, the growth factor receptor-bound protein 10 (Grb10), showed that mTORC1-mediated phosphorylation stabilized Grb10, leading to feedback inhibition of the phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated, mitogen-activated protein kinase (ERK-MAPK) pathways. Grb10 expression is frequently down-regulated in various cancers, and loss of Grb10 and loss of the well-established tumor suppressor phosphatase PTEN appear to be mutually exclusive events, suggesting that Grb10 might be a tumor suppressor regulated by mTORC1.", "ai_intervention": "Phosphoproteomics (mTORC1/Grb10)", "ai_target": "mTORC1 / Grb10 / insulin signaling", "ai_species": "Mammalian cells", "ai_effect": "Grb10 is an mTORC1 substrate that negatively feeds back on insulin/IGF signaling", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/YUX2011/" }, { "sid": "PAN2013", "title": "Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1", "authors": "Panchaud N; De Virgilio C et al.", "year": 2013, "journal": "Science signaling", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Yeast", "peer_reviewed": "Yes", "doi": "10.1126/scisignal.2004112", "pmid": "23716719", "pmcid": "", "finding": "The SEACIT complex is a GAP for the Rag/Gtr GTPases mediating amino-acid inhibition of TORC1.\n", "abstract": "The Rag family of guanosine triphosphatases (GTPases) regulates eukaryotic cell growth in response to amino acids by activating the target of rapamycin complex 1 (TORC1). In humans, this pathway is often deregulated in cancer. In yeast, amino acids promote binding of GTP (guanosine 5'-triphosphate) to the Rag family GTPase Gtr1, which, in combination with a GDP (guanosine diphosphate)-bound Gtr2, forms the active, TORC1-stimulating GTPase heterodimer. We identified Iml1, which functioned in a complex with Npr2 and Npr3, as a GAP (GTPase-activating protein) for Gtr1. Upon amino acid deprivation, Iml1 transiently interacted with Gtr1 at the vacuolar membrane to stimulate its intrinsic GTPase activity and consequently decrease the activity of TORC1. Our results delineate a potentially conserved mechanism by which the Iml1, Npr2, and Npr3 orthologous proteins in humans may suppress tumor formation.", "ai_intervention": "Biochemical/genetic (SEACIT/GAP for Gtr1)", "ai_target": "TORC1 / Gtr1 (Rag) / SEACIT", "ai_species": "Yeast", "ai_effect": "Amino-acid deprivation inhibits TORC1 through a GAP complex (SEACIT) for the Rag-family GTPase Gtr1", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PAN2013/" }, { "sid": "PLEDGER2026", "title": "Translational repression of 5' TOP mRNAs in chronically activated CD8+ T cells.", "authors": "Pledger ES; Ambavaram N; Ferguson L; Cate JHD", "year": 2026, "journal": "RNA biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human (CD8+ T cells in vitro)", "peer_reviewed": "Yes", "doi": "10.1080/15476286.2026.2715355", "pmid": "", "pmcid": "", "finding": "Ribosome profiling of exhausted human CD8+ T cells reveals marked repression of 5'TOP mRNAs despite elevated mTOR activity, uncovering an mTOR-independent translational control mechanism in T cell exhaustion.\n", "abstract": "T cell exhaustion is a dysfunctional state that arises during chronic infections and cancer, characterized by impaired effector functions and sustained expression of inhibitory receptors. We performed ribosome profiling and RNA sequencing on chronically activated human CD8+ T cells to globally assess translational control during a model of T cell exhaustion. Our analyses reveal a marked repression of 5' terminal oligopyrimidine (TOP) mRNAs during chronic activation. Unexpectedly, we demonstrate that this translational repression occurs despite evidence of elevated mTOR activity. These findings uncover a previously unknown layer of translational control in exhausted T cells.", "ai_intervention": "Chronic T cell activation", "ai_target": "mTOR / 5'TOP mRNA translation", "ai_species": "Human", "ai_effect": "5'TOP mRNAs repressed despite elevated mTOR activity in exhausted CD8+ T cells", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PLEDGER2026/" }, { "sid": "LIANG2026", "title": "LINP1 suppresses radiation-induced cellular senescence in keratinocytes by modulating the mTOR-p53 axis", "authors": "Liang X; Hou M; Liu Yaru; Yang Y; Zhang C; Zhang Z; Zhou L", "year": 2026, "journal": "Molecular and Cellular Biochemistry", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human keratinocytes; ex vivo human skin explants", "peer_reviewed": "Yes", "doi": "10.1007/s11010-026-05682-z", "pmid": "", "pmcid": "", "finding": "LncRNA LINP1 binds the FAT domain of mTOR, reduces mTOR-p53 interaction and p53 Ser15 phosphorylation, thereby suppressing radiation-induced cellular senescence in keratinocytes and human skin.\n", "abstract": "LINP1 is a markedly upregulated lncRNA following ionizing radiation (IR). LINP1 promotes cell survival and limits radiation-induced DNA damage accumulation. Mechanistically, LINP1 attenuates radiation-induced cellular senescence through modulation of the mTOR-p53 signaling axis: LINP1 associates with the FAT domain of mTOR, attenuates the interaction between mTOR and p53, thereby reducing p53 Ser15 phosphorylation and downstream senescence-associated signaling. Validation in ex vivo human skin explants demonstrates that LINP1 depletion exacerbates radiation-induced tissue damage, persistent DNA damage accumulation, and senescence-associated phenotypes.", "ai_intervention": "LINP1 overexpression/knockdown; ionizing radiation", "ai_target": "mTOR FAT domain; mTOR-p53 interaction; p53 Ser15 phosphorylation; cellular senescence", "ai_species": "Human", "ai_effect": "LINP1 directly binds mTOR FAT domain to reduce mTOR-p53 interaction, decrease p53 activation, and suppress radiation-induced senescence", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LIANG2026/" }, { "sid": "MIL2014", "title": "Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction", "authors": "Miller RA; Strong R et al.", "year": 2014, "journal": "Aging cell", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1111/acel.12194", "pmid": "24341993", "pmcid": "PMC4032600", "finding": "Rapamycin's lifespan extension in mice is dose-dependent and greater in females.\n", "abstract": "Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females) when tested at a dose threefold higher than that used in our previous studies; maximal longevity was also increased in both sexes. Rapamycin increased lifespan more in females than in males at each dose evaluated, perhaps reflecting sexual dimorphism in blood levels of this drug. Some of the endocrine and metabolic changes seen in diet-restricted mice are not seen in mice exposed to rapamycin, and the pattern of expression of hepatic genes involved in xenobiotic metabolism is also quite distinct in rapamycin-treated and diet-restricted mice, suggesting that these two interventions for extending mouse lifespan differ in many respects.", "ai_intervention": "Rapamycin (dose-response)", "ai_target": "mTOR", "ai_species": "Mouse (genetically heterogeneous)", "ai_effect": "Rapamycin extends lifespan 23-26% in a dose- and sex-dependent way, metabolically distinct from dietary restriction", "ai_dose": "Rapamycin in food at 4.7, 14, or 42 ppm, administered from 9 months of age until death.", "ai_samplesize": "Pooled data from 3 sites: 300 control males, 156 males per rapamycin dose group; 280 control females, 136 females per rapamycin dose group.", "ai_effectsize": "Highest dose (42 ppm) increased median lifespan by 23% in males (P<0.0001) and 26% in females (P<0.0001); all three doses extended lifespan in females, and the two highest doses extended lifespan in males.", "ai_limitations": "Lower statistical power for site-independent analyses; Gompertz parameter estimates should be interpreted with caution due to small data sets, low statistical power, and no adjustment for site-to-site variation; increased fighting (11-22% cages removed) in highest dose male group with unknown cause.", "atlas_url": "https://mtor-atlas.org/study/MIL2014/" }, { "sid": "POR2008", "title": "SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth", "authors": "Porstmann T; Schulze A et al.", "year": 2008, "journal": "Cell metabolism", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2008.07.007", "pmid": "18762023", "pmcid": "PMC2593919", "finding": "mTORC1 activates SREBP to drive lipogenesis supporting Akt-dependent cell growth.\n", "abstract": "Cell growth (accumulation of mass) needs to be coordinated with metabolic processes that are required for the synthesis of macromolecules. The PI3-kinase/Akt signaling pathway induces cell growth via activation of complex 1 of the target of rapamycin (TORC1). Here we show that Akt-dependent lipogenesis requires mTORC1 activity. Furthermore, nuclear accumulation of the mature form of the sterol responsive element binding protein (SREBP1) and expression of SREBP target genes was blocked by the mTORC1 inhibitor rapamycin. We also show that silencing of SREBP blocks Akt-dependent lipogenesis and attenuates the increase in cell size in response to Akt activation in vitro. Silencing of dSREBP in flies caused a reduction in cell and organ size and blocked the induction of cell growth by dPI3K. Our results suggest that the PI3K/Akt/TOR pathway regulates protein and lipid biosynthesis in an orchestrated manner and that both processes are required for cell growth.", "ai_intervention": "Genetic/pharmacologic (mTORC1/SREBP)", "ai_target": "mTORC1 / SREBP / Akt", "ai_species": "Mammalian cells", "ai_effect": "SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth (lipogenesis)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/POR2008/" }, { "sid": "GAN2009", "title": "ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy", "authors": "Ganley IG; Jiang X et al.", "year": 2009, "journal": "The Journal of biological chemistry", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1074/jbc.M900573200", "pmid": "19258318", "pmcid": "PMC2673298", "finding": "The ULK1-ATG13-FIP200 complex transmits mTOR signalling to initiate autophagy.\n", "abstract": "Autophagy is a degradative process that recycles long-lived and faulty cellular components. It is linked to many diseases and is required for normal development. ULK1, a mammalian serine/threonine protein kinase, plays a key role in the initial stages of autophagy, though the exact molecular mechanism is unknown. Here we report identification of a novel protein complex containing ULK1 and two additional protein factors, FIP200 and ATG13, all of which are essential for starvation-induced autophagy. Both FIP200 and ATG13 are critical for correct localization of ULK1 to the pre-autophagosome and stability of ULK1 protein. Additionally, we demonstrate by using both cellular experiments and a de novo in vitro reconstituted reaction that FIP200 and ATG13 can enhance ULK1 kinase activity individually but both are required for maximal stimulation. Further, we show that ATG13 and ULK1 are phosphorylated by the mTOR pathway in a nutrient starvation-regulated manner, indicating that the ULK1.ATG13.FIP200 complex acts as a node for integrating incoming autophagy signals into autophagosome biogenesis.", "ai_intervention": "Genetic/biochemical (ULK1-ATG13-FIP200)", "ai_target": "mTOR / ULK1-ATG13-FIP200", "ai_species": "Mammalian cells", "ai_effect": "The ULK1-ATG13-FIP200 complex mediates mTOR signaling and is essential for autophagy", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GAN2009/" }, { "sid": "SUN2026", "title": "Favorable response to second-line sirolimus regardless of status in acquired pure red cell aplasia: A retrospective study from a single center.", "authors": "Sun Z; Jia X; Shen Y et al.", "year": 2026, "journal": "Therapeutic Advances in Hematology", "tier": "B - Human", "pyramid": "3 - Human Observational", "category": "Human", "model": "Human (single-centre retrospective, n=58)", "peer_reviewed": "Yes", "doi": "10.1177/20406207261483341", "pmid": "", "pmcid": "", "finding": "Second-line sirolimus achieved a 54.5% overall response rate in ciclosporin-refractory acquired pure red cell aplasia (64.3% in secondary disease) versus 25.0% for first-line ciclosporin, with responses independent of mutation status.\n", "abstract": "Cyclosporine A (CsA) is standard first-line treatment for acquired pure red cell aplasia (PRCA), but outcomes vary and salvage strategies for CsA-refractory patients are poorly defined. Retrospective single-centre comparative study of patients treated 2021-2025: 36 received first-line CsA and 22 switched to sirolimus for lack of response or intolerance. The ORR for first-line CsA was 25.0% (9/36), significantly higher in primary cases (42.1%) than secondary (5.9%). In the salvage sirolimus group ORR was 54.5%, with efficacy in both primary (37.5%) and secondary (64.3%) cases. Median time to response did not differ significantly (3.0 vs 1.5 months). No responses to CsA were seen in patients harbouring mutations (0/6), whereas sirolimus elicited responses in both mutated (3/6) and wild-type (4/5) patients, indicating efficacy irrespective of mutation status.", "ai_intervention": "Sirolimus (second-line salvage)", "ai_target": "mTOR", "ai_species": "Human", "ai_effect": "54.5% ORR in CsA-refractory PRCA; sustained remission in responders; effective regardless of STAT3/5b mutation status", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/SUN2026/" }, { "sid": "BRU2004", "title": "Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex", "authors": "Brugarolas J; Kaelin WG et al.", "year": 2004, "journal": "Genes & development", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1101/gad.1256804", "pmid": "15545625", "pmcid": "PMC534650", "finding": "Hypoxia inhibits mTOR via REDD1-dependent activation of the TSC1/2 complex.\n", "abstract": "Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is modulated by a variety of signals. Energy depletion and hypoxia result in mTOR inhibition. While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known. Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801. Disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 blocks the effects of hypoxia on mTOR, as measured by changes in the mTOR targets S6K and 4E-BP1, and results in abnormal accumulation of Hypoxia-inducible factor (HIF). In contrast to energy depletion, mTOR inhibition by hypoxia does not require AMPK or LKB1. Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene. Disruption of REDD1 abrogates the hypoxia-induced inhibition of mTOR, and REDD1 overexpression is sufficient to down-regulate S6K phosphorylation in a TSC1/TSC2-dependent manner. Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia.", "ai_intervention": "Genetic (REDD1 / TSC1-TSC2)", "ai_target": "mTOR / REDD1 / TSC1-TSC2", "ai_species": "Mammalian cells", "ai_effect": "Hypoxia inhibits mTOR via REDD1 acting through the TSC1/TSC2 tumor-suppressor complex", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/BRU2004/" }, { "sid": "DEM2009", "title": "Rapamycin decelerates cellular senescence", "authors": "Demidenko ZN; Zubova SG; Bukreeva EI; Pospelov VA; Pospelova TV; Blagosklonny MV", "year": 2009, "journal": "Cell Cycle", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human + rodent cell lines", "peer_reviewed": "Yes", "doi": "10.4161/cc.8.12.8606", "pmid": "19471117", "pmcid": "", "finding": "Blagosklonny's key experiment behind his 'hyperfunction' theory of aging. When a cell's division is blocked but mTOR keeps driving growth, the cell tips into permanent senescence. Rapamycin uncouples the two - keeping arrested cells reversible instead of senescent. Direct evidence that mTOR actively drives the senescent state, not just passively accompanies it.\n", "abstract": "When the cell cycle is arrested but cellular growth is not, then cells senesce, permanently losing proliferative potential. Here we demonstrated that the duration of cell cycle arrest determines a progressive loss of proliferative capacity. In human and rodent cell lines, rapamycin (an inhibitor of mTOR) dramatically decelerated loss of proliferative potential caused by ectopic p21, p16 and sodium butyrate-induced p21. Thus, when the cell cycle was arrested by these factors in the presence of rapamycin, cells retained the capacity to resume proliferation, once p21, p16 or sodium butyrate were removed. While rapamycin prevented the permanent loss of proliferative potential in arrested cells, it did not force the arrested cells into proliferation. During cell cycle arrest, rapamycin transformed the irreversible arrest into a reversible condition. Our data demonstrate that senescence can be pharmacologically suppressed.", "ai_intervention": "Rapamycin (mTOR inhibition)", "ai_target": "mTOR", "ai_species": "Human + rodent cell lines", "ai_effect": "Rapamycin decelerates cellular senescence (geroconversion) during cell-cycle arrest", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DEM2009/" }, { "sid": "MA2026", "title": "PIP4K2A Attenuates Cerebral Ischemia/Reperfusion Injury by Reducing the TRIB3-p62 Complex Burden and Modulating AKT/mTOR Signaling.", "authors": "Ma B; Yu X; Li M; Zhu H; Dong X; Yu S et al.", "year": 2026, "journal": "Translational stroke research", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse", "peer_reviewed": "Yes", "doi": "10.1007/s12975-026-01474-1", "pmid": "", "pmcid": "", "finding": "PIP4K2A overexpression attenuates cerebral ischemia/reperfusion injury by reducing TRIB3-p62 complex burden and modulating AKT/mTOR signaling to restore autophagic flux, identifying PIP4K2A-AKT/mTOR as a neuroprotective axis in stroke.\n", "abstract": "Ischemic stroke remains a major cause of long-term disability. Impaired autophagic flux worsens neuronal injury after ischemia. This study elucidates the role of PIP4K2A and its regulation of autophagy in cerebral ischemia/reperfusion (I/R) injury using serum proteomics and in vivo stroke models.", "ai_intervention": "PIP4K2A overexpression", "ai_target": "AKT/mTOR / autophagy / TRIB3-p62", "ai_species": "Mouse", "ai_effect": "PIP4K2A restored autophagic flux and reduced neuronal injury via AKT/mTOR modulation in I/R stroke", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MA2026/" }, { "sid": "DUR2012", "title": "Glutaminolysis activates Rag-mTORC1 signaling", "authors": "Duran RV; Hall MN et al.", "year": 2012, "journal": "Molecular cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.molcel.2012.05.043", "pmid": "22749528", "pmcid": "", "finding": "Glutaminolysis activates Rag-mTORC1 signalling through alpha-ketoglutarate production.\n", "abstract": "Amino acids control cell growth via activation of the highly conserved kinase TORC1. Glutamine is a particularly important amino acid in cell growth control and metabolism. However, the role of glutamine in TORC1 activation remains poorly defined. Glutamine is metabolized through glutaminolysis to produce alpha-ketoglutarate. We demonstrate that glutamine in combination with leucine activates mammalian TORC1 (mTORC1) by enhancing glutaminolysis and alpha-ketoglutarate production. Inhibition of glutaminolysis prevented GTP loading of RagB and lysosomal translocation and subsequent activation of mTORC1. Constitutively active Rag heterodimer activated mTORC1 in the absence of glutaminolysis. Conversely, enhanced glutaminolysis or a cell-permeable alpha-ketoglutarate analog stimulated lysosomal translocation and activation of mTORC1. Finally, cell growth and autophagy, two processes controlled by mTORC1, were regulated by glutaminolysis. Thus, mTORC1 senses and is activated by glutamine and leucine via glutaminolysis and alpha-ketoglutarate production upstream of Rag. This may provide an explanation for glutamine addiction in cancer cells.", "ai_intervention": "Biochemical/genetic (glutaminolysis)", "ai_target": "mTORC1 / Rag GTPases (α-ketoglutarate)", "ai_species": "Mammalian cells", "ai_effect": "Glutaminolysis (with leucine) activates Rag-mTORC1 signaling via α-ketoglutarate production", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DUR2012/" }, { "sid": "ZHANG2026B", "title": "Dioscorea polystachya Turcz. attenuates male reproductive aging through modulation of mTOR-Beclin-1-mediated autophagy in Leydig and Sertoli cells", "authors": "Zhang Y; Feng J; Xie T; Zhang X; Pan D; Liu S; Zhao D; Wang S; Liu M; Yu S", "year": 2026, "journal": "Journal of Ethnopharmacology", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Rat (aged model); Mouse Leydig (TM3) and Sertoli (TM4) cells", "peer_reviewed": "Yes", "doi": "10.1016/j.jep.2026.122304", "pmid": "", "pmcid": "", "finding": "Chinese yam protein extract (CYCSE) attenuates male reproductive aging by activating testicular autophagy through the mTOR-Beclin-1 axis in Leydig and Sertoli cells; mTOR activation blocks protective effects.\n", "abstract": "This study investigated the efficacy of Chinese yam protein extract (CYCSE) from Dioscorea polystachya in attenuating aging-related reproductive decline. In aged rats and D-galactose-induced senescent mouse Leydig and Sertoli cells, CYCSE ameliorated testicular histopathology, restored sperm parameters, increased testosterone levels, reduced senescence markers (SA-beta-gal, p16, p21, p53), and mitigated oxidative stress. TEM confirmed restored autophagic flux in senescent cells. Mechanistically, CYCSE restored autophagic activity via the mTOR-Beclin-1 signaling axis. Protective effects were substantially diminished by co-treatment with an mTOR activator, confirming pathway involvement.", "ai_intervention": "Chinese yam protein extract (CYCSE); mTOR activator (control)", "ai_target": "mTOR-Beclin-1 axis; autophagy; Star; Cyp11a1", "ai_species": "Rat; Mouse", "ai_effect": "CYCSE suppresses mTOR to activate autophagy via Beclin-1, reducing senescence markers and restoring reproductive function in aged testicular cells", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZHANG2026B/" }, { "sid": "TEE2003", "title": "Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb", "authors": "Tee AR; Cantley LC et al.", "year": 2003, "journal": "Current Biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cell lines", "peer_reviewed": "Yes", "doi": "10.1016/s0960-9822(03)00506-2", "pmid": "12906785", "pmcid": "", "finding": "TSC1-TSC2 acts as a GTPase-activating protein (GAP) for Rheb; when TSC is inactive, Rheb accumulates in its active GTP-bound form and directly activates mTORC1.\n", "abstract": "Tuberous Sclerosis Complex (TSC) is a genetic disorder that occurs through the loss of heterozygosity of either TSC1 or TSC2, which encode Hamartin or Tuberin, respectively. Tuberin and Hamartin form a tumor suppressor heterodimer that inhibits the mammalian target of rapamycin (mTOR) nutrient signaling input, but how this occurs is unclear.\n\nWe show that the small G protein Rheb (Ras homolog enriched in brain) is a molecular target of TSC1/TSC2 that regulates mTOR signaling. Overexpression of Rheb activates 40S ribosomal protein S6 kinase 1 (S6K1) but not p90 ribosomal S6 kinase 1 (RSK1) or Akt. Furthermore, Rheb induces phosphorylation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1) and causes 4E-BP1 to dissociate from eIF4E. This dissociation is completely sensitive to rapamycin (an mTOR inhibitor) but not wortmannin (a phosphoinositide 3-kinase [PI3K] inhibitor). Rheb also activates S6K1 during amino acid insufficiency via a rapamycin-sensitive mechanism, suggesting that Rheb participates in nutrient signaling through mTOR. Moreover, Rheb does not activate a S6K1 mutant that is unresponsive to mTOR-mediated signals, confirming that Rheb functions upstream of mTOR. Overexpression of the Tuberin-Hamartin heterodimer inhibits Rheb-mediated S6K1 activation, suggesting that Tuberin functions as a Rheb GTPase activating protein (GAP). Supporting this notion, TSC patient-derived Tuberin GAP domain mutants were unable to inactivate Rheb in vivo. Moreover, in vitro studies reveal that Tuberin, when associated with Hamartin, acts as a Rheb GTPase-activating protein. Finally, we show that membrane localization of Rheb is important for its biological activity because a farnesylation-defective mutant of Rheb stimulated S6K1 activation less efficiently.\n\nWe show that Rheb acts as a novel mediator of the nutrient signaling input to mTOR and is the molecular target of TSC1 and TSC2 within mammalian cells.", "ai_intervention": "Biochemical/genetic (TSC1/TSC2)", "ai_target": "TSC1-TSC2 (Hamartin/Tuberin) / Rheb / mTOR", "ai_species": "Human cell lines", "ai_effect": "Tuberin-Hamartin (TSC1-TSC2) control mTOR by acting as a GAP complex toward Rheb", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/TEE2003/" }, { "sid": "STO2003", "title": "Rheb is an essential regulator of S6K in controlling cell growth in Drosophila", "authors": "Stocker H; Hafen E et al.", "year": 2003, "journal": "Nature cell biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Drosophila", "peer_reviewed": "Yes", "doi": "10.1038/ncb995", "pmid": "12766775", "pmcid": "", "finding": "Rheb is an essential regulator of S6K controlling cell growth downstream of TSC in Drosophila.\n", "abstract": "Understanding the mechanisms through which multicellular organisms regulate cell, organ and body growth is of relevance to developmental biology and to research on growth-related diseases such as cancer. Here we describe a new effector in growth control, the small GTPase Rheb (Ras homologue enriched in brain). Mutations in the Drosophila melanogaster Rheb gene were isolated as growth-inhibitors, whereas overexpression of Rheb promoted cell growth. Our genetic and biochemical analyses suggest that Rheb functions downstream of the tumour suppressors Tsc1 (tuberous sclerosis 1)-Tsc2 in the TOR (target of rapamycin) signalling pathway to control growth, and that a major effector of Rheb function is ribosomal S6 kinase (S6K).", "ai_intervention": "Genetic (Rheb mutants/overexpression)", "ai_target": "Rheb / S6K / TOR", "ai_species": "Drosophila", "ai_effect": "Rheb is an essential regulator of S6K controlling cell growth in Drosophila", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/STO2003/" }, { "sid": "LEE2026", "title": "Aberrant excitatory neuronal ERBB4 promotes Alzheimer's disease pathology", "authors": "Lee SY; Park E; Lee HE; Kim S; Yeo Y; Park J; Choi YJ; Lee K; Yoon KJ; Park S; Kim E; Kim JI; Chung WS", "year": 2026, "journal": "Nature", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Mechanism", "model": "Mouse AD models (5xFAD/APP), excitatory-neuron-specific Erbb4 deletion and overexpression; human AD single-nucleus transcriptomics", "peer_reviewed": "Yes", "doi": "10.1038/s41586-026-10964-z", "pmid": "42649291", "pmcid": "", "finding": "Ectopic ERBB4 in excitatory neurons is one of the earliest changes in AD mouse models and is both necessary and sufficient for synapse loss, reactive gliosis, amyloid deposition and cognitive deficits — and these effects require mTOR signalling downstream of ERBB4. Places mTOR as a required mediator in an early neuronal driver of AD pathology, upstream of the glial and amyloid phenotypes.\n", "abstract": "Neuroinflammation and synapse loss are associated with cognitive decline in Alzheimer's disease (AD). Although microglial hyperphagocytic activity has been implicated in synapse loss, the mechanisms underlying these pathologies remain obscure. Here we demonstrate that, during AD progression in mice, astrocytes and microglia increase phagocytic elimination of excitatory synapses while reducing elimination of inhibitory synapses, suggesting that neuroinflammation alone may be dispensable for early AD synapse loss. Instead, single-nucleus RNA-sequencing analysis identified the emergence of early-responsive excitatory neurons (EREN), characterized by expression of ectopic Erb-B2 receptor tyrosine kinase 4 (Erbb4), as one of the earliest major alterations in AD mouse models. Selective Erbb4 deletion in AD excitatory neurons abrogated abnormal neuronal network activities and synapse loss, as well as reactive gliosis, amyloid plaque deposition and cognitive deficits. Conversely, Erbb4 overexpression in wild-type excitatory neurons recapitulated these core AD-like phenotypes without amyloid plaques. Mechanistically, these effects required mammalian target of rapamycin (mTOR) signalling downstream of ERBB4. Subsequent transcriptomic analyses showed that excitatory neuronal Erbb4 is both necessary and sufficient to induce EREN and reactive gliosis. Directed mediation analysis of human AD transcriptomic data further support a model in which excitatory neuronal ERBB4 contributes to a pathogenic cascade that links amyloid pathology to tau propagation and cognitive decline. These findings identify aberrant Erbb4 expression in excitatory neurons as an early driver of AD pathophysiology and a potential therapeutic target across neurodegenerative diseases.", "ai_intervention": "Excitatory-neuron-specific Erbb4 deletion and Erbb4 overexpression; mTOR pathway inhibition", "ai_target": "ERBB4 -> mTOR signalling in excitatory neurons", "ai_species": "Mouse; human transcriptomic data", "ai_effect": "Erbb4 deletion rescued synapse loss, gliosis, amyloid deposition and cognitive deficits; Erbb4 overexpression recapitulated AD-like phenotypes — both requiring mTOR signalling downstream", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LEE2026/" }, { "sid": "HAR2009", "title": "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice", "authors": "Harrison DE et al.", "year": 2009, "journal": "Nature", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (genetically heterogeneous, 3 sites)", "peer_reviewed": "Yes", "doi": "10.1038/nature08221", "pmid": "19587680", "pmcid": "PMC2786175", "finding": "Rapamycin fed from 600 days of age extended median lifespan by 9-14% in both sexes.\n", "abstract": "Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both. To our knowledge, these are the first results to demonstrate a role for mTOR signalling in the regulation of mammalian lifespan, as well as pharmacological extension of lifespan in both genders. These findings have implications for further development of interventions targeting mTOR for the treatment and prevention of age-related diseases.", "ai_intervention": "Rapamycin (late-life feeding)", "ai_target": "mTOR", "ai_species": "Mouse (genetically heterogeneous, 3 sites)", "ai_effect": "Rapamycin fed from 600 days extended median and maximal lifespan in both sexes – first pharmacological lifespan extension in a mammal", "ai_dose": "Dietary encapsulated rapamycin, initiated at 600 days of age (or 270 days in a separate study), resulting in blood levels of 60-70 ng/ml.", "ai_samplesize": "1901 mice (38 still alive at analysis date).", "ai_effectsize": "Pooled mean lifespan increased by 9% for males and 13% for females; life expectancy at 600 days increased by 28% for males and 38% for females (p < 0.0001).", "ai_limitations": "Improved survival among males at UT and UM might reflect pre-treatment nutritional/health differences, not solely rapamycin effects; additional data needed for accurate effect size and maximal longevity for 270-day start.", "atlas_url": "https://mtor-atlas.org/study/HAR2009/" }, { "sid": "REN2026", "title": "Microbiota-associated kynurenic acid drives PD-1 blockade resistance through an ITGA2-mTOR-CTSV axis in gastric cancer.", "authors": "Ren Y; Yu X; Jiang J; Luo J; Zhao C; et al.", "year": 2026, "journal": "Journal for immunotherapy of cancer", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Mechanism", "model": "Mouse + Human (gastric cancer)", "peer_reviewed": "Yes", "doi": "10.1136/jitc-2026-015172", "pmid": "", "pmcid": "", "finding": "Tumor microbiota-derived kynurenic acid drives resistance to PD-1 blockade in gastric cancer by activating the ITGA2-mTOR-CTSV signaling axis, suppressing CD8+ T cell cytotoxic function.\n", "abstract": "The tumor microbiota critically shapes responses to immunotherapy; however, the mechanisms by which specific microbial species drive immune checkpoint blockade (ICB) resistance in gastric cancer (GC) remain poorly defined. Bacterial enrichment was assessed in ICB-unresponsive GC tissues from patients and multiple preclinical models. Orthotopic, subcutaneous, and germ-free mono-colonized mouse models were employed to evaluate the impact on antitumor immunity and PD-1 blockade efficacy. Integrated multi-omics analyses were performed to identify microbiota-derived metabolites, and mechanistic studies investigated their effects on CD8 T-cell function. Kynurenic acid was identified as a key metabolite suppressing CD8+ T cell effector function through the ITGA2-mTOR-CTSV axis.", "ai_intervention": "ITGA2 targeting / anti-PD-1", "ai_target": "mTOR (ITGA2-mTOR-CTSV axis)", "ai_species": "Mouse + Human", "ai_effect": "mTOR-mediated suppression of CD8+ T cells driving immunotherapy resistance", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/REN2026/" }, { "sid": "ZID2009", "title": "4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila", "authors": "Zid BM; Rogers AN; Katewa SD; Vargas MA; Kolipinski MC; Lu TA; Benzer S; Kapahi P", "year": 2009, "journal": "Cell", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Drosophila (fruit fly)", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2009.07.034", "pmid": "19804760", "pmcid": "PMC2759400", "finding": "Connected the dots between diet, mTOR, and lifespan. Dietary restriction lowers mTOR activity, which frees up 4E-BP - and here 4E-BP was shown to be REQUIRED for the lifespan boost, working by selectively boosting translation of mitochondrial genes. A rare case pinning a specific mTOR effector to the longevity benefit of eating less.\n", "abstract": "Dietary restriction (DR) extends lifespan in multiple species. To examine the mechanisms of lifespan extension upon DR, we assayed genome-wide translational changes in Drosophila. A number of nuclear encoded mitochondrial genes, including those in Complex I and IV of the electron transport chain, showed increased ribosomal loading and enhanced overall activity upon DR. We found that various mitochondrial genes possessed shorter and less structured 5'UTRs, which were important for their enhanced mRNA translation. The translational repressor 4E-BP, the eukaryotic translation initiation factor 4E binding protein, was upregulated upon DR and mediated DR dependent changes in mitochondrial activity and lifespan extension. Inhibition of individual mitochondrial subunits from Complex I and IV diminished the lifespan extension obtained upon DR, reflecting the importance of enhanced mitochondrial function during DR. Our results imply that translational regulation of nuclear-encoded mitochondrial gene expression by 4E-BP plays an important role in lifespan extension upon DR. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.", "ai_intervention": "Genetic (4E-BP)", "ai_target": "4E-BP / mitochondria", "ai_species": "Drosophila", "ai_effect": "4E-BP extends lifespan under dietary restriction by enhancing mitochondrial activity", "ai_dose": "Reducing the concentration of yeast or yeast extract in the fly diet while sucrose was constant (Dietary Restriction)", "ai_samplesize": "", "ai_effectsize": "Upon DR, approximately 30% decrease of labeled methionine incorporation into newly synthesized proteins; mitochondrial protein density increased 25% in control flies; 20% upregulation in Complex I activity in DR flies; Cytochrome C oxidase (COX) activity increased 60% in control flies upon DR; 55 genes were differentially translationally downregulated and 201 upregulated upon DR (FDR < 5%)", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ZID2009/" }, { "sid": "JIB2026", "title": "Rapamycin co-exposure fails to reduce cisplatin-induced damage in GC6-spg spermatogonial cell line.", "authors": "Jibrin A, Mitchell RT, Lopes F", "year": 2026, "journal": "Reproduction & Fertility", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Negative_result", "model": "GC6-spg spermatogonial cell line", "peer_reviewed": "Yes", "doi": "10.1530/RAF-26-0044", "pmid": "42455795", "pmcid": "", "finding": "Rapamycin fails to protect spermatogonial stem cells from cisplatin-induced damage in vitro, indicating sex-specific or context-specific limits to rapamycin's cytoprotective role and suggesting male fertility preservation requires alternative strategies.\n", "abstract": "This study assessed whether rapamycin could protect male spermatogonial stem cells (GC6-spg line) from cisplatin-induced cytotoxicity, analogous to its protective role reported in female fertility preservation. Rapamycin co-exposure did not prevent cisplatin-induced cell loss or damage in this spermatogonial cell line, suggesting limited utility for male fertility preservation during cancer treatment.", "ai_intervention": "Rapamycin", "ai_target": "mTOR inhibition; spermatogonial stem cell survival", "ai_species": "Human (cell line)", "ai_effect": "No protective effect — rapamycin does not rescue cisplatin-induced spermatogonial stem cell loss (negative result)", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/JIB2026/" }, { "sid": "KIM2011", "title": "AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1", "authors": "Kim J; Kundu M; Viollet B; Guan KL", "year": 2011, "journal": "Nature Cell Biology", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human/mouse cells", "peer_reviewed": "Yes", "doi": "10.1038/ncb2152", "pmid": "21258367", "pmcid": "PMC3987946", "finding": "Revealed the tug-of-war over ULK1: the energy sensor AMPK phosphorylates ULK1 at activating sites to turn autophagy ON when energy is low, while mTORC1 phosphorylates a different site (Ser757) to keep it OFF and even blocks AMPK from reaching ULK1. Two opposing kinases wired to the same switch.\n", "abstract": "Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.", "ai_intervention": "Genetic/biochemical (AMPK, mTOR, ULK1)", "ai_target": "AMPK / mTOR / ULK1", "ai_species": "Human/mouse cells", "ai_effect": "AMPK and mTOR reciprocally phosphorylate ULK1 to regulate autophagy", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/KIM2011/" }, { "sid": "POU2013", "title": "High-dose resveratrol supplementation in obese men: an investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition", "authors": "Poulsen MM et al.", "year": 2013, "journal": "Diabetes", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Negative_result", "model": "Humans, RCT, obese men (n=24)", "peer_reviewed": "Yes", "doi": "10.2337/db12-0975", "pmid": "23193181", "pmcid": "PMC3609591", "finding": "4 weeks of high-dose resveratrol had no effect on insulin sensitivity, blood pressure, or body composition - directly contradicting the promising rodent data that drove the original hype.\n", "abstract": "Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. In a randomized, placebo-controlled, double-blinded, and parallel-group design, 24 obese but otherwise healthy men were randomly assigned to 4 weeks of resveratrol or placebo treatment. Extensive metabolic examinations including assessment of glucose turnover and insulin sensitivity (hyperinsulinemic euglycemic clamp) were performed before and after the treatment. Insulin sensitivity, the primary outcome measure, deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol supplementation also had no effect on blood pressure; resting energy expenditure; oxidation rates of lipid; ectopic or visceral fat content; or inflammatory and metabolic biomarkers. The lack of effect disagrees with persuasive data obtained from rodent models and raises doubt about the justification of resveratrol as a human nutritional supplement in metabolic disorders.", "ai_intervention": "Resveratrol (high-dose)", "ai_target": "SIRT1 (mTOR-adjacent)", "ai_species": "Human – RCT (obese men, n=24)", "ai_effect": "High-dose resveratrol did NOT improve insulin sensitivity, substrate metabolism or body composition in obese men (negative trial)", "ai_dose": "High-dose resveratrol daily for 4 weeks vs placebo; investigator-initiated randomized double-blind parallel-group trial.", "ai_samplesize": "26 obese men enrolled; 1 dropout (claustrophobia), 1 excluded (rash) -> ~24 analyzed.", "ai_effectsize": "NEGATIVE trial: no significant change in insulin sensitivity, resting energy expenditure, respiratory quotient, glucose/lipid oxidation, inflammatory biomarkers, leptin, or liver function.", "ai_limitations": "Small sample; null result contradicts the SIRT1/CR-mimetic hype for resveratrol.", "atlas_url": "https://mtor-atlas.org/study/POU2013/" }, { "sid": "STU2018", "title": "Architecture of the human mTORC2 core complex", "authors": "Stuttfeld E; Ban N et al.", "year": 2018, "journal": "eLife", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Cryo-EM structure", "peer_reviewed": "Yes", "doi": "10.7554/eLife.33101", "pmid": "29424687", "pmcid": "PMC5837792", "finding": "Architecture of the human mTORC2 core complex (mTOR-Rictor-SIN1-mLST8).\n", "abstract": "The mammalian target of rapamycin (mTOR) is a key protein kinase controlling cellular metabolism and growth. It is part of the two structurally and functionally distinct multiprotein complexes mTORC1 and mTORC2. Dysregulation of mTOR occurs in diabetes, cancer and neurological disease. We report the architecture of human mTORC2 at intermediate resolution, revealing a conserved binding site for accessory proteins on mTOR and explaining the structural basis for the rapamycin insensitivity of the complex.", "ai_intervention": "Structural (cryo-EM)", "ai_target": "mTORC2 core", "ai_species": "Cryo-EM structure", "ai_effect": "Architecture of the human mTORC2 core complex, revealing a conserved accessory-protein binding site", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/STU2018/" }, { "sid": "MA2005", "title": "Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis", "authors": "Ma L; Chen Z; Erdjument-Bromage H; Tempst P; Pandolfi PP", "year": 2005, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2005.02.031", "pmid": "15851026", "pmcid": "", "finding": "The MAPK input to mTORC1. In mammalian cells, ERK phosphorylates TSC2 and inactivates the TSC complex, so growth signalling through Ras/ERK converges on the same brake that Akt releases. This is the third major upstream arm alongside PI3K/Akt and AMPK. Its practical significance is that it offers a route to mTORC1 activation that PI3K inhibitors do not close - though that inference is mechanistic; no human data here.\n", "abstract": "Tuberous sclerosis (TSC) is a tumor syndrome caused by mutation in TSC1 or TSC2 genes. TSC tumorigenesis is not always accompanied by loss of heterozygosity (LOH). Recently, extracellular signal-regulated kinase (Erk) has been found activated in TSC lesions lacking TSC1 or TSC2 LOH. Here, we show that Erk may play a critical role in TSC progression through posttranslational inactivation of TSC2. Erk-dependent phosphorylation leads to TSC1-TSC2 dissociation and markedly impairs TSC2 ability to inhibit mTOR signaling, cell proliferation, and oncogenic transformation. Importantly, expression of an Erk nonphosphorylatable TSC2 mutant in TSC2+/- tumor cells where Erk is constitutively activated blocks tumorigenecity in vivo, while wild-type TSC2 is ineffective. Our findings position the Ras/MAPK pathway upstream of the TSC complex and suggest that Erk may modulate mTOR signaling and contribute to disease progression through phosphorylation and inactivation of TSC2.", "ai_intervention": "", "ai_target": "ERK -> TSC2 (Ser664) -> mTORC1", "ai_species": "Mammalian cells", "ai_effect": "ERK phosphorylates TSC2 and inactivates the TSC complex, activating mTORC1 independently of Akt", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/MA2005/" }, { "sid": "NCT05835999", "title": "Everolimus Aging Study (EVERLAST): Clinical Evaluation of mTORC1 Inhibition for Geroprotection", "authors": "University of Wisconsin, Madison (registered trial)", "year": "", "journal": "ClinicalTrials.gov (registration)", "tier": "Registered trial", "pyramid": "Registered Trial", "category": "Ongoing_Trial", "model": "Humans, RCT (registered, ongoing)", "peer_reviewed": "No", "doi": "NCT05835999", "pmid": "", "pmcid": "", "finding": "Currently active phase 2 trial (NCT05835999) directly testing this Atlas's open dosing hypothesis: whether daily low-dose (0.5mg) versus weekly (5mg) everolimus can improve aging biomarkers and insulin resistance in humans without the metabolic penalty seen with continuous higher-dose rapalog use. No results yet - status ACTIVE_NOT_RECRUITING.\n", "abstract": "The objective of this project is to determine if mTORC1 inhibition by 24 weeks of daily (0.5 mg/day) or weekly (5 mg/week) everolimus can safely improve physiological and molecular hallmarks of aging in humans. Participants who are 55-80 years old and insulin resistant or prediabetic will be randomized to treatment and can expect to be on study for up to approximately 38 weeks; participants aged 18-35 will not receive the intervention and can expect to be on study up to approximately 8 weeks. Pharmacological inhibition of mTOR has repeatedly been shown to extend lifespan and prevent or delay several age-related diseases in diverse model systems, but the risk of serious side effects has prevented long-term use of rapamycin as an anti-aging therapy. Using a double-blinded, randomized, placebo-controlled design, the investigators test the hypothesis that daily low-dose or weekly everolimus improves four inter-related domains of physiological aging (metabolic, cardiac, cognitive and physical function), assess adverse events and blood chemistry, and evaluate mTORC1/mTORC2 signaling, mitochondrial bioenergetics and a multi-omics profile (epigenomics, transcriptomics, proteomics, lipidomics, metabolomics) in blood and/or muscle biopsy. Conditions: Aging, Insulin Resistance. (Registered trial summary; source: ClinicalTrials.gov NCT05835999.)", "ai_intervention": "Everolimus – daily 0.5 mg vs weekly 5 mg, 24 weeks", "ai_target": "mTORC1", "ai_species": "Human – RCT (registered, ongoing; age 55–80, insulin-resistant/prediabetic)", "ai_effect": "No results yet (ACTIVE_NOT_RECRUITING) – tests whether dosing improves aging hallmarks without metabolic penalty", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/NCT05835999/" }, { "sid": "NOJ2003", "title": "The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif", "authors": "Nojima H; Yonezawa K et al.", "year": 2003, "journal": "The Journal of biological chemistry", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "In vitro", "peer_reviewed": "Yes", "doi": "10.1074/jbc.C200665200", "pmid": "12604610", "pmcid": "", "finding": "Raptor binds mTOR substrates via their TOS motifs, acting as the substrate-presenting scaffold of mTORC1.\n", "abstract": "The mammalian target of rapamycin (mTOR) controls multiple cellular functions in response to amino acids and growth factors, in part by regulating the phosphorylation of p70 S6 kinase (p70S6k) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Raptor (regulatory associated protein of mTOR) is a recently identified mTOR binding partner that also binds p70S6k and 4E-BP1 and is essential for TOR signaling in vivo. Herein we demonstrate that raptor binds to p70S6k and 4E-BP1 through their respective TOS (conserved TOR signaling) motifs to be required for amino acid- and mTOR-dependent regulation of these mTOR substrates in vivo. A point mutation of the TOS motif also eliminates all in vitro mTOR-catalyzed 4E-BP1 phosphorylation and abolishes the raptor-dependent component of mTOR-catalyzed p70S6k phosphorylation in vitro. Raptor appears to serve as an mTOR scaffold protein, the binding of which to the TOS motif of mTOR substrates is necessary for effective mTOR-catalyzed phosphorylation in vivo and perhaps for conferring their sensitivity to rapamycin and amino acid sufficiency.", "ai_intervention": "Biochemical (TOS motif)", "ai_target": "mTOR / raptor / p70 S6K / 4E-BP1", "ai_species": "In vitro", "ai_effect": "Raptor binds the mTOR substrates p70 S6K and 4E-BP1 through their TOR-signaling (TOS) motif", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/NOJ2003/" }, { "sid": "DEN2026", "title": "Spalt-related is an inhibitor of mTORC1-mediated growth activated by the integrated stress response", "authors": "Onur Deniz, Ying Liu, Tuuli Kirkinen, Krista Kokki, Kateryna Gaertner, Pau Clavell-Revelles, Jaakko Mattila, Ville Hietakangas", "year": 2026, "journal": "The EMBO Journal", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Mechanism", "model": "Drosophila melanogaster", "peer_reviewed": "Yes", "doi": "10.1038/s44318-026-00858-1", "pmid": "42436355", "pmcid": "", "finding": "Transcription factor Spalt-related (Salr) is a novel mTORC1 inhibitor in Drosophila activated by the integrated stress response, restricting anabolic growth and lipid storage during nutrient stress independently of AKT-FoxO signaling.\n", "abstract": "Anabolic and catabolic processes are coordinated by a conserved regulatory network including mTORC1 and FoxO. Spalt-related (Salr), previously implicated in organogenesis, is identified as a negative regulator of growth and lipid storage in Drosophila. Salr activates catabolic gene expression and restricts mTORC1-mediated cell growth in the fat body. Salr is activated in a slow and sustained manner through the integrated stress response, distinct from transient FoxO activation. Once activated, Salr counters nuclear localization of FoxO.", "ai_intervention": "Integrated stress response activation (genetic)", "ai_target": "mTORC1 / Spalt-related (Salr) / FoxO", "ai_species": "Drosophila melanogaster", "ai_effect": "Inhibition of mTORC1-mediated cell growth; activation of catabolic gene expression; restriction of lipid storage", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/DEN2026/" }, { "sid": "HE2025", "title": "mTORC1, the maestro of cell metabolism and growth", "authors": "He L; Cho S; Blenis J", "year": 2025, "journal": "Genes & Development", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "N/A (narrative review)", "peer_reviewed": "Yes", "doi": "10.1101/gad.352084.124", "pmid": "39572234", "pmcid": "PMC11789495", "finding": "Comprehensive current review of how nutrients and growth signals are integrated by mTORC1 and the metabolic programs it commands, plus the clinical outlook for mTORC1-targeted therapy across cancer, neurodegeneration, obesity, diabetes and aging -- anchor reference for the pathway map.\n", "abstract": "The mechanistic target of rapamycin (mTOR) pathway senses and integrates various environmental and intracellular cues to regulate cell growth and proliferation. As a key conductor of the balance between anabolic and catabolic processes, mTOR complex 1 (mTORC1) orchestrates the symphonic regulation of glycolysis, nucleic acid and lipid metabolism, protein translation and degradation, and gene expression. Dysregulation of the mTOR pathway is linked to numerous human diseases, including cancer, neurodegenerative disorders, obesity, diabetes, and aging. This review provides an in-depth understanding of how nutrients and growth signals are coordinated to influence mTOR signaling and the extensive metabolic rewiring under its command. Additionally, we discuss the use of mTORC1 inhibitors in various aging-associated metabolic diseases and the current and future potential for targeting mTOR in clinical settings. By deciphering the complex landscape of mTORC1 signaling, this review aims to inform novel therapeutic strategies and provide a road map for future research endeavors in this dynamic and rapidly evolving field.", "ai_intervention": "N/A (review)", "ai_target": "mTORC1 pathway (nutrient/growth factor integration)", "ai_species": "N/A", "ai_effect": "Comprehensive review of mTORC1 regulation, metabolic control, and clinical outlook", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HE2025/" }, { "sid": "FRA2013", "title": "Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial", "authors": "Franz DN; Belousova E; Sparagana S; Bebin EM; Frost M; et al.; Jozwiak S", "year": 2013, "journal": "Lancet", "tier": "B - Human", "pyramid": "2 - Human Clinical Trial", "category": "Human", "model": "Humans, phase 3 RCT (n=117, TSC)", "peer_reviewed": "Yes", "doi": "10.1016/S0140-6736(12)61134-9", "pmid": "23158522", "pmcid": "", "finding": "Phase 3 RCT (n=117) in tuberous sclerosis, the disease where mTOR is stuck ON by a genetic fault. Everolimus shrank brain tumors (SEGA) by >=50% in 35% of patients versus 0% on placebo. Because the underlying cause here is direct mTOR overactivation, this is arguably the cleanest randomised human evidence that blocking mTOR works in a genetically defined mTORopathy -- which does not extend to mTOR inhibition in people without such a mutation.\n", "abstract": "Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex.\n\nIn this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828.\n\n117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]).\n\nThese results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis.\n\nNovartis Pharmaceuticals.", "ai_intervention": "Everolimus", "ai_target": "mTOR", "ai_species": "Human – phase 3 RCT (EXIST-1, n=117, TSC)", "ai_effect": "Everolimus reduced subependymal giant cell astrocytoma (SEGA) volume vs placebo in tuberous sclerosis", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/FRA2013/" }, { "sid": "GAN2011", "title": "Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate", "authors": "Gan X; Wu D et al.", "year": 2011, "journal": "The Journal of biological chemistry", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "In vitro; cells", "peer_reviewed": "Yes", "doi": "10.1074/jbc.M110.195016", "pmid": "21310961", "pmcid": "PMC3064154", "finding": "PIP3 directly stimulates mTORC2 kinase activity, linking PI3K to mTORC2.\n", "abstract": "mTORC2 (mammalian target of rapamycin complex 2) plays important roles in signal transduction by regulating an array of downstream effectors, including protein kinase AKT. However, its regulation by upstream regulators remains poorly characterized. Although phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) is known to regulate the phosphorylation of AKT Ser(473), the hydrophobic motif (HM) site, by mTORC2, it is not clear whether PtdIns(3,4,5)P(3) can directly regulate mTORC2 kinase activity. Here, we used two membrane-docked AKT mutant proteins, one with and the other without the pleckstrin homology (PH) domain, as substrates for mTORC2 to dissect the roles of PtdIns(3,4,5)P(3) in AKT HM phosphorylation in cultured cells and in vitro kinase assays. In HEK293T cells, insulin and constitutively active mutants of small GTPase H-Ras and PI3K could induce HM phosphorylation of both AKT mutants, which was blocked by the PI3K inhibitor LY294002. Importantly, PtdIns(3,4,5)P(3) was able to stimulate the phosphorylation of both AKT mutants by immunoprecipitated mTOR2 complexes in an in vitro kinase assay. In both in vivo and in vitro assays, the AKT mutant containing the PH domain appeared to be a better substrate than the one without the PH domain. Therefore, these results suggest that PtdIns(3,4,5)P(3) can regulate HM phosphorylation by mTORC2 via multiple mechanisms. One of the mechanisms is to directly stimulate the kinase activity of mTORC2.", "ai_intervention": "Biochemical (PtdIns(3,4,5)P3)", "ai_target": "mTORC2 / PIP3 / Akt Ser473", "ai_species": "In vitro; cells", "ai_effect": "PtdIns(3,4,5)P3 (PIP3) directly activates mTORC2 kinase activity toward Akt Ser473", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GAN2011/" }, { "sid": "GOB2016", "title": "Amino Acid Sensing by mTORC1: Intracellular Transporters Mark the Spot", "authors": "Goberdhan DC; Harris AL et al.", "year": 2016, "journal": "Cell metabolism", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1016/j.cmet.2016.03.013", "pmid": "27076075", "pmcid": "PMC5067300", "finding": "Review: intracellular amino-acid transporters mark the site of mTORC1 activation.\n", "abstract": "Cell metabolism and growth are matched to nutrient availability via the amino-acid-regulated mechanistic target of rapamycin complex 1 (mTORC1). Transporters have emerged as important amino acid sensors controlling mTOR recruitment and activation at the surface of multiple intracellular compartments. Classically, this has involved late endosomes and lysosomes, but now, in a recent twist, also the Golgi apparatus. Here we propose a model in which specific amino acids in assorted compartments activate different mTORC1 complexes, which may have distinct drug sensitivities and functions. We will discuss the implications of this for mTORC1 function in health and disease.", "ai_intervention": "Not applicable (review)", "ai_target": "mTORC1 / amino-acid transporters", "ai_species": "Review", "ai_effect": "Reviews how intracellular amino-acid transporters mark the sites (lysosome, Golgi) of mTORC1 activation", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/GOB2016/" }, { "sid": "ABR2026", "title": "Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration", "authors": "Abrar F; Martin DDO", "year": 2026, "journal": "Autophagy", "tier": "D - Mechanistic/Review", "pyramid": "Narrative Review", "category": "Review", "model": "Review", "peer_reviewed": "Yes", "doi": "10.1080/15548627.2026.2711593", "pmid": "42560011", "pmcid": "", "finding": "Comprehensive review of how post-translational modifications (phosphorylation, ubiquitination, acetylation, S-acylation, S-nitrosylation) tune SQSTM1/p62's role as the autophagy cargo-receptor hub -- relevant to neurodegenerative disease (Alzheimer's, ALS, Huntington's) where SQSTM1 regulation goes awry.\n", "abstract": "SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. Beyond its structure, post-translational modifications of SQSTM1 dynamically regulate its function within a cell. Post-translational modifications - such as phosphorylation, ubiquitination, acetylation, S-acylation, and S-nitrosylation - are crucial for regulating SQSTM1 function, localization, and interaction with autophagic components, thereby influencing SQSTM1's role in the autophagy pathway. Understanding the role of these protein modifications in modulating autophagy may provide better insight into developing therapeutic strategies for diseases with dysregulated autophagy, such as neurodegenerative diseases. This review discusses the role of these post-translational modifications in controlling SQSTM1's localization and function in autophagy, including its regulation of and by MTORC1 (MTOR complex 1) signaling.", "ai_intervention": "", "ai_target": "SQSTM1/p62 / MTORC1 / autophagy", "ai_species": "", "ai_effect": "", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/ABR2026/" }, { "sid": "HAN2012", "title": "Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway", "authors": "Han JM; Kim S et al.", "year": 2012, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Mammalian cells", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2012.02.044", "pmid": "22424946", "pmcid": "", "finding": "Leucyl-tRNA synthetase acts as an intracellular leucine sensor activating mTORC1 via the Rag pathway.\n", "abstract": "Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly couples intracellular amino acid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1.", "ai_intervention": "Biochemical/genetic (leucyl-tRNA synthetase)", "ai_target": "Leucyl-tRNA synthetase (LRS) / RagD / mTORC1", "ai_species": "Mammalian cells", "ai_effect": "Leucyl-tRNA synthetase acts as an intracellular leucine sensor for the mTORC1 pathway", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/HAN2012/" }, { "sid": "LU2026", "title": "Mathematical Modeling of Dietary Timing- and Protein Quality-Responsive Liver Circadian Clock and its Function on Ribosome Biogenesis", "authors": "Lu L; Levy JL; Anthony TG; Androulakis IP", "year": 2026, "journal": "Physiological Genomics", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Semi-mechanistic computational model of mammalian liver (peripheral clock, mTORC1, GCN2-ISR, ribosome biogenesis)", "peer_reviewed": "Yes", "doi": "10.1152/physiolgenomics.00152.2026", "pmid": "42647400", "pmcid": "", "finding": "Builds a semi-mechanistic model in which liver mTORC1 and GCN2-ISR signalling are driven by RHYTHMS in dietary essential amino acid availability rather than by a fixed nutrient level. Simulations show the two pathways jointly set metabolic entrainability and are required to keep the peripheral clock and ribosome biogenesis synchronised under nutrient stress, and predict individualised recovery trajectories after a transient dietary disruption. A worked example of treating mTORC1 activity as a time-varying pattern whose shape — not just its average — determines the downstream growth output.\n", "abstract": "Independent of the suprachiasmatic nucleus, peripheral clocks can be strongly entrained by dietary signals. Although feeding time has been widely studied, the effects of food quality-particularly nutrient availability and stress-on peripheral circadian entrainment and metabolic regulation remain less understood. We developed a semi-mechanistic mathematical model of peripheral clock synchronization and clock-controlled ribosome biogenesis (RiBi) in response to feeding/fasting cycles and rhythms in dietary essential amino acid (EAA) availability. The model integrates EAA-sensitive signaling through mammalian target of rapamycin complex 1 (mTORC1) and the general control nonderepressible 2 (GCN2)-mediated integrated stress response (ISR), together with ribosomal protein expression as a metabolic endpoint. We used the model to examine circadian entrainment under nutrient stress, adaptation during transitions between feeding schedules with EAA insufficiency, and stress-related mechanisms that may restore circadian and metabolic function. Simulations showed that mTORC1 and GCN2-ISR signaling jointly regulate metabolic entrainability and stress adaptation and are required to maintain circadian synchronization and RiBi dynamics during nutrient stress. The model also predicted that differences in homeostatic adaptation can produce individualized recovery trajectories after transient dietary disruption. Finally, appropriate modulation of GCN2-ISR signaling mitigated disruption-associated RiBi hyperactivation by leveraging dietary EAA rhythms to restore clock function. These findings identify dietary EAA stress and its regulatory pathways as important determinants of peripheral circadian entrainment and metabolic adaptation, supporting the development of personalized nutrition-based strategies.", "ai_intervention": "In silico feeding/fasting schedules and dietary essential amino acid rhythms; simulated GCN2-ISR modulation", "ai_target": "mTORC1 and GCN2-ISR; clock-controlled ribosome biogenesis", "ai_species": "Computational model (mammalian liver)", "ai_effect": "Timing and quality of amino acid intake, not average level, set circadian entrainment and ribosome biogenesis dynamics", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/LU2026/" }, { "sid": "CHE2009", "title": "mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells", "authors": "Chen C; Zheng P et al.", "year": 2009, "journal": "Science signaling", "tier": "C - Animal", "pyramid": "4 - Animal Study", "category": "Animal", "model": "Mouse (HSC)", "peer_reviewed": "Yes", "doi": "10.1126/scisignal.2000559", "pmid": "19934433", "pmcid": "PMC4020596", "finding": "mTOR hyperactivation drives HSC aging; rapamycin restores hematopoietic stem-cell function.\n", "abstract": "Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSCs of young mice mimicked the phenotype of HSCs from aged mice in various ways. These included increased abundance of the messenger RNA encoding the CDK inhibitors p16(Ink4a), p19(Arf), and p21(Cip1); a relative decrease in lymphopoiesis; and impaired capacity to reconstitute the hematopoietic system. In old mice, rapamycin increased life span, restored the self-renewal and hematopoiesis of HSCs, and enabled effective vaccination against a lethal challenge with influenza virus. Together, our data implicate mTOR signaling in HSC aging and show the potential of mTOR inhibitors for restoring hematopoiesis in the elderly.", "ai_intervention": "Genetic (Tsc1 deletion) + rapamycin", "ai_target": "mTOR / TSC1", "ai_species": "Mouse (hematopoietic stem cells)", "ai_effect": "mTOR is elevated in aged HSCs; rapamycin rejuvenates HSC function and immune response", "ai_dose": "4 mg/kg rapamycin by i.p. injection every other day for 6 weeks", "ai_samplesize": "9/12 vehicle-treated old mice succumbed to infection", "ai_effectsize": "Pretreatment with rapamycin increased antigen-specific IgG by approximately 10 times; all rapamycin-treated mice were protected from lethal influenza infection, compared to 75% mortality in vehicle-treated old mice.", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/CHE2009/" }, { "sid": "PET2009", "title": "DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival", "authors": "Peterson TR; Laplante M; Thoreen CC; Sancak Y; Kang SA; Kuehl WM; Gray NS; Sabatini DM", "year": 2009, "journal": "Cell", "tier": "D - Mechanistic/Review", "pyramid": "5 - Mechanistic / In Vitro", "category": "Mechanism", "model": "Human cancer cell lines", "peer_reviewed": "Yes", "doi": "10.1016/j.cell.2009.03.046", "pmid": "19446321", "pmcid": "PMC2758791", "finding": "Identified DEPTOR as a built-in brake on BOTH mTOR complexes. The twist: in some multiple myelomas DEPTOR is overexpressed, which by relieving a feedback loop actually keeps pro-survival Akt signaling ON - a neat example of how an 'inhibitor' can be co-opted by cancer.\n", "abstract": "The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel mTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival.", "ai_intervention": "Genetic/biochemical (DEPTOR)", "ai_target": "DEPTOR / mTORC1 & mTORC2", "ai_species": "Human cancer cell lines", "ai_effect": "DEPTOR is an mTOR inhibitor overexpressed in multiple myeloma and required for myeloma-cell survival", "ai_dose": "", "ai_samplesize": "", "ai_effectsize": "", "ai_limitations": "", "atlas_url": "https://mtor-atlas.org/study/PET2009/" } ]