mTOR
Serine/threonine kinase; central regulator of cell growth and metabolism; direct target of rapamycin.
The kinase at the centre of everything.
PIKK-family kinase. The same catalytic subunit in two complexes with different partners, locations, substrates and drug sensitivities – the complex, not the kinase, is the unit of biology.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| S | Synthesis of human data | 1 |
| H | Human study | 9 |
| A | Animal model | 24 |
| M | Molecular — cells, biochemistry, structure | 18 |
| R | Review — secondary literature, not a new result | 12 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2024 | S | Targeting ageing with rapamycin and its derivatives in humans: a systematic review LEE2024 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. |
| 2025 | H | Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results MOE2025 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. |
| 2021 | H | Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials MAN2021 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. |
| 2014 | H | Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib WAG2014 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. |
| 2013 | H | 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 FRA2013 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. |
| 2011 | H | Efficacy and safety of sirolimus in lymphangioleiomyomatosis (MILES) MCC2011 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. |
| 2010 | H | Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis KRU2010 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). |
| 2008 | H | Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis BIS2008 Sirolimus shrinks renal angiomyolipomas in tuberous sclerosis / lymphangioleiomyomatosis. |
| 2007 | H | Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma HUD2007 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. |
| 2000 | H | Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study KAH2000 The trial that established rapamycin (sirolimus) as an immunosuppressant in kidney transplant patients - its original, still-standard clinical use. |
| 2026 | A | Urolithin A activates mitophagy via the AMPK-mTOR axis and modulates the gut-ceramide axis to ameliorate cardiac remodeling in HFpEF SONH2026 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. |
| 2026 | A | Age-associated decline of Lamtor5 drives immunosenescence and systemic aging via cGAS-mediated paracrine inflammation. LV2026 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. |
| 2026 | A | LKB1/AMPK deficiency aggravates mitochondrial DNA leakage via mTOR-dependent mitophagy damage in liver injury sensitized by trichloroethylene. ZHU2026 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. |
| 2026 | A | Testosterone propionate maintains autophagic flux and mitochondrial integrity via regulation of the LC3B/p62/Beclin-1/mTOR axis in induced liver fibrosis. VER2026 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. |
| 2026 | A | Notoginsenoside R1 Alleviates Acetaminophen-Induced Liver Injury via MAPK/mTOR-Mediated Autophagy. LIS2026 Notoginsenoside R1 alleviates acetaminophen-induced acute liver injury by activating protective autophagy through MAPK/mTOR pathway modulation, reducing hepatocyte death and oxidative damage. |
| 2026 | A | Deubiquitinase USP7 stabilizes the histone demethylase KDM5B and promotes the progression of renal fibrosis through the TSC1/mTOR axis LV2026S 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. |
| 2026 | A | Diet-dependent, beneficial and adverse effects of rapamycin on life span of Drosophila melanogaster JAC2026 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. |
| 2026 | A | mTOR inhibition augments antitumor immune effector response by reprogramming the TP53-mutant, immune-cold HNSCC tumor microenvironment NAT2026 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. |
| 2026 | A | Survival and Homeostasis of Alveolar Macrophages in Vivo Depend on mTOR Signaling HEN2026 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. |
| 2017 | A | A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs URF2017 A short 10-week course of low-dose rapamycin improved heart function measures in healthy pet dogs with no clinical side effects. |
| 2016 | A | Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice BIT2016 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. |
| 2014 | A | Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome FOK2014 Rapamycin-fed mice show extended lifespan with major changes in the liver transcriptome. |
| 2014 | A | Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction MIL2014 Rapamycin's lifespan extension in mice is dose-dependent and greater in females. |
| 2013 | A | Late-life rapamycin treatment reverses age-related heart dysfunction FLY2013 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. |
| 2013 | A | Rapamycin extends murine lifespan but has limited effects on aging NEF2013 Rapamycin extends murine lifespan but has only limited effects on classic aging phenotypes. |
| 2012 | A | Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice HAL2012 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. |
| 2012 | A | Rapamycin slows aging in mice WIL2012 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. |
| 2011 | A | Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice MIL2011 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. |
| 2010 | A | mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists LIX2010 Ketamine's rapid antidepressant action requires mTOR-dependent synaptogenesis in prefrontal cortex. |
| 2009 | A | mTOR regulates memory CD8 T-cell differentiation ARA2009 mTOR is a key regulator of memory CD8 T-cell differentiation; rapamycin enhances memory responses. |
| 2009 | A | mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging CAS2009 Wnt-induced mTOR activation drives epidermal stem-cell senescence; rapamycin rescues it. |
| 2009 | A | Rapamycin fed late in life extends lifespan in genetically heterogeneous mice HAR2009 Rapamycin fed from 600 days of age extended median lifespan by 9-14% in both sexes. |
| 2005 | A | Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients KAE2005 A systematic screen of 564 yeast gene deletions found TOR and Sch9 pathway genes as the strongest lifespan-extending hits. |
| 2003 | A | Genetics: influence of TOR kinase on lifespan in C. elegans VEL2003 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. |
| 2026 | M | Astragaloside IV Mitigates Tacrolimus-Induced Chronic Nephrotoxicity by Regulating the mTOR-TFEB-GADD45alpha Pathway GAO2026 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. |
| 2026 | M | Molecular and metabolic dysregulation of lung cancer in developing anti-tumor activity by gambogic acid mediated mTOR signaling: in vitro and computational study. BO2026 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. |
| 2026 | M | GPR143, a novel immunohistochemical marker for renal tumors with FLCN/TSC/MTOR-TFE alterations. LI2026 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. |
| 2026 | M | Rapamycin co-exposure fails to reduce cisplatin-induced damage in GC6-spg spermatogonial cell line. JIB2026 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. |
| 2026 | R | Nutrient-sensing pathways in adult stem cells: Orchestrating homeostasis, aging, and disease XIA2026 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. |
| 2026 | M | Fluorescent protein ticker tape (FPTT): Multiplexed recording of transcriptional dynamics in living cells and in vivo WANG2026C Engineered a multiplexed fluorescent-protein 'ticker tape' biosensor platform (self-assembling protein fibers + multispectral fluorescent proteins) for longitudinal, single-cell recording of signaling-pathway transcriptional histories (mTOR, NF-κB, STAT3, NFAT, cAMP). Applying the mTOR-FPTT reporter, the authors independently observed cell-cycle-dependent OSCILLATING mTOR activity dynamics -- a new, orthogonal tool corroborating that mTOR signaling is patterned over time rather than static, consistent with JOS2024's cell-cycle oscillation finding. |
| 2025 | R | What is the clinical evidence to support off-label rapamycin therapy in healthy adults? HAN2025 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. |
| 2020 | M | AIMTOR, a BRET biosensor for live imaging, reveals subcellular mTOR signaling and dysfunctions BOU2020 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. |
| 2020 | R | mTOR at the nexus of nutrition, growth, ageing and disease LIU2020 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. |
| 2018 | R | mTOR signalling and cellular metabolism are mutual determinants in cancer MOS2018 Review of mTOR and cellular metabolism as mutual determinants in cancer. |
| 2017 | R | mTOR Signaling in Growth, Metabolism, and Disease SAX2017 Comprehensive synthesis of mTORC1/mTORC2 signaling, growth regulation, metabolism, and disease relevance. |
| 2017 | R | Twenty-five years of mTOR: Uncovering the link from nutrients to growth SAB2017 Sabatini's 25-year synthesis linking nutrient sensing to growth through mTOR. |
| 2016 | R | mTOR Signaling Confers Resistance to Targeted Cancer Drugs GUR2016 Review of how mTOR signalling confers resistance to targeted cancer therapies. |
| 2016 | R | The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging KEN2016 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. |
| 2016 | M | Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor ROD2016 RapaLink-1, a third-generation bivalent inhibitor, overcomes mTOR resistance mutations. |
| 2014 | M | A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity GRA2014 A spectrum of cancer-associated MTOR mutations are hyperactivating and predict rapamycin sensitivity. |
| 2013 | M | mTOR kinase structure, mechanism and regulation YAN2013 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. |
| 2013 | R | mTOR is a key modulator of ageing and age-related disease JOH2013 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. |
| 2011 | R | Regulation of immune responses by mTOR POW2011 Review of mTOR as an integrator of immune-cell metabolism and differentiation. |
| 2009 | M | The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment DEL2009 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. |
| 2009 | M | Rapamycin decelerates cellular senescence DEM2009 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. |
| 2007 | R | Defining the role of mTOR in cancer GUE2007 Comprehensive review arguing mTOR signaling is commonly deregulated in human cancers, laying out the rationale for rapalog trials in oncology. |
| 2006 | R | Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition BLA2006 Proposes the 'hyperfunction theory' of aging: TOR signaling, useful in youth, stays switched on into old age and becomes actively damaging. |
| 2004 | M | Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton SAR2004 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. |
| 2003 | M | GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR KIM2003 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. |
| 2002 | M | mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery KIM2002 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. |
| 2002 | M | Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action HARA2002 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. |
| 1996 | M | Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP CHO1996 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. |
| 1994 | M | RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs SAB1994 Discovery of the protein RAFT1 (today's mTOR) as the direct target of the FKBP12-rapamycin complex; founding paper of the entire mTOR field. |
| 1991 | M | Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast HEI1991 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. |