mTOR
Serine/threonine kinase; central regulator of cell growth and metabolism; direct target of rapamycin.
The kinase at the centre of everything. The central enzyme this whole Atlas is about - short for 'mechanistic target of rapamycin.' It's a master switch that senses nutrients and growth signals and decides whether a cell should grow, build new proteins, and skip its cleanup routines, or hold back and recycle.
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.
TL;DR. mTOR appears in 124 curated studies in Oliver's mTOR Atlas: 12 in people (2 syntheses of human data, 10 human studies); 47 in animal models; 46 at the molecular level (cells, biochemistry, structure); 17 reviews; 1 preprint, not peer-reviewed; 1 registered trial without results yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| mTOR required-for mTORC2 mechanism: complex-assembly · this link in full · on the map table | mTORC2 is built from the very same mTOR enzyme as mTORC1 – it's the partner proteins around it that make the two complexes different. Holds under: Cryo-EM structures of the complex from human cells and yeast (CHE2018, SCA2020, STU2018, KAR2017). Structural evidence shows how the complex is built, not how often or where it forms in living tissue. plausible in people, not shown directly · settled in the literature | M | CHE2018, SCA2020, STU2018, KAR2017 |
| DEPTOR inhibits mTOR mechanism: binding · this link in full · on the map table | DEPTOR sits on mTOR and dampens both complexes; some cancer cells (myeloma) make extra DEPTOR and come to depend on that damping. Holds under: One study in human cancer cell lines (PET2009), centred on myeloma. Not replicated in this corpus and not shown in other cell types, in animals or in patients. plausible in people, not shown directly · settled in the literature | M | PET2009 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| S | Synthesis of human data | 2 |
| H | Human study | 10 |
| A | Animal model | 47 |
| M | Molecular — cells, biochemistry, structure | 46 |
| PP | Preprint, not peer-reviewed | 1 |
| RT | Registered trial, no results yet | 1 |
| R | Review — secondary literature, not a new result | 17 |
Human studies in the Atlas
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | S | Therapeutic reversal of cellular senescence: A systematic review of senolytics, senomorphics and anti-ageing therapies in human clinical trials TRI2026 A PRISMA-guided systematic review of six completed human clinical studies that met its eligibility criteria, testing drugs that clear or calm senescent ("zombie") cells -- senolytics such as dasatinib+quercetin, plus senomorphic and mTOR-targeting approaches. It reported limited and heterogeneous results, a mixture of biomarker and functional outcomes, with mostly mild side effects, and judged the evidence too thin (small samples, short follow-up) to call any of it an established therapy yet. Six INCLUDED studies is not a census of every completed human senotherapeutic trial: inclusion depends on the review's search date and eligibility criteria, and those have to be stated before any field-wide coverage conclusion is drawn. Useful mainly as a rare systematic look at where human senescence-targeting trials, mTOR inhibitors included, stand -- not as proof that any one drug works. |
| 2024 | S | Targeting ageing with rapamycin and its derivatives in humans: a systematic review LEE2024 Described by its authors as 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. |
| 2026 | H | Pregnane X receptor-mediated liver growth: a controlled clinical trial in healthy volunteers and identification of the role of AKT-MTOR pathway in mouse. LASSILA2026 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, accompanied by increased AKT-MTOR pathway activity, without YAP activation. |
| 2025 | H | Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results MOE2025 The authors describe PEARL as the longest trial of rapamycin for healthy ageing so far: 48 weeks, once a week, ages 50 to 85, 114 people finished (40 on 5 mg, 35 on 10 mg, 39 on placebo). The question the trial was built to answer was visceral fat on a DXA scan, and that did not change. Most of what gets quoted comes from secondary results. Lean mass rose in women on 10 mg, and these women also reported less pain, but pain came from a questionnaire the authors did not list as an endpoint, and only eight women were in the 10 mg group, hence the very wide interval (odds ratio 28, 95% CI 2.4 to 324). Side effects were similar to placebo, with more stomach complaints on rapamycin. Bone density was the one signal pointing the wrong way: in the 5 mg group the odds of an improvement in bone mineral density were lower than on placebo (odds ratio 0.24, 95% CI 0.06 to 0.93, p = 0.04), but 10 mg showed no change (odds ratio 1.00) and the comparisons between groups were not significant. Boundary: the capsules were compounded, and the authors found they reached about a third of the blood level of the commercial drug, so 10 mg here is closer to 3 mg of generic sirolimus. Dosing was self-reported, and the group was about two thirds men and health-conscious. |
| 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 This paper reports two trials of RTB101, a drug that blocks mTOR, taken once a day for 16 weeks by adults over 65. In the phase 2b trial (652 people), fewer people on 10 mg had a lab-confirmed respiratory infection than on placebo (19% against 28%), but that result comes from a pooled analysis the authors did not correct for multiple testing, and the corrected analysis did not reach significance. The phase 3 trial (1,024 people) used a different main endpoint, set with the FDA: symptoms with or without a lab test. It found no difference (26% against 25%, p = 0.65), although blood tests still showed more antiviral genes switched on in both trials. In phase 2b, twice-daily dosing and a combination with everolimus did not reach significance, which the authors read as a hint that on-off inhibition may beat constant inhibition. Those numbers are "data not shown" in the paper. Boundary: RTB101 is not rapamycin or everolimus, the phase 3 group was healthier (no COPD, no smokers), and that trial was too small to test the lab-confirmed endpoint. The only everolimus arm (RTB101 plus everolimus 0.1 mg daily) was a combination and did not reach significance, which is why this paper is listed against the everolimus and immune function link on the pathway map. It cannot show what everolimus alone does. |
| 2014 | H | Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib WAG2014 Two concurrent activating MTOR mutations are 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 MILES was a 12-month placebo-controlled trial of sirolimus in 89 women with lymphangioleiomyomatosis (LAM), a rare lung disease driven by overactive mTOR. On placebo, lung function (FEV1) fell by about 12 ml a month. On sirolimus it held steady (+1 ml a month), a 153 ml difference over the year. In the next year nobody took the drug, and the sirolimus group's decline resumed in parallel with placebo, so the benefit lasted only while the drug was taken. Walking distance and gas-transfer capacity did not improve. Boundary: patients had fairly advanced disease (average FEV1 about 48% of predicted), many dropped out of the observation year, and mouth ulcers and rashes may have revealed who was on the drug. Sirolimus was held at a blood level of 5 to 15 ng/ml, so this was continuous dosing, not intermittent. |
| 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 | Astragaloside IV Mitigates Tacrolimus-Induced Chronic Nephrotoxicity by Regulating the mTOR-TFEB-GADD45α 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 | 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; restoring Lamtor5 in aged mice rescued immunosenescence and attenuated systemic ageing 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. |
| 2026 | A | High-concentration hydrogen mitigates cognitive impairment in a murine model of Sepsis-associated encephalopathy by enhancing oligodendrocyte maturation and myelination in the mPFC YU2026 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. |
| 2026 | A | Chronic Kidney Disease Risk Posed by 1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl) Benzene (EDPrB): An AOP of mTOR-Mediated Autophagy Dysregulation. MIAO2026 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. |
| 2026 | A | Forsythoside A Alleviates Hypertensive Nephropathy by Promoting Mitophagy and Inhibiting Ferroptosis via ASCL1-CCNB1/mTOR Pathway. CUI2026 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. |
| 2026 | A | Corilagin attenuates osteoarthritis progression by coordinating NF-κB inhibition with PI3K/AKT/mTOR-associated autophagy restoration. ZHOU2026B 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. |
| 2026 | A | Impaired mTOR/SREBP1-Mediated Lipogenesis as a Mechanism of Hepatic Glycogen Accumulation in a Carnivorous Fish Model, Largemouth Bass (Micropterus salmoides) TAO2026 mTOR/SREBP1 signaling governs hepatic glucose partitioning; the insulin-responsive mTOR/SREBP1 axis promotes lipogenesis versus glycogen accumulation. In this model -- a carnivorous fish -- impairment of the axis is associated with hepatic glycogen overload mimicking glucose intolerance. |
| 2026 | A | Early-life exposure to polypropylene microplastics and DEHP induces ASD-relevant neurodevelopmental alterations involving mTOR-regulated autophagy impairment YANG2026 PP-MPs and DEHP activate mTOR and impair autophagy, inducing ASD-like neurodevelopmental deficits in mice; rapamycin rescues autophagic flux and social/behavioral phenotypes. |
| 2026 | A | Pungenin Promotes Hair Growth in Mouse Models of Androgenic Alopecia Through Transcriptional Regulation of the PI3K/AKT/mTOR Axis. ZHAI2026 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. |
| 2026 | A | Dioscorea polystachya Turcz. attenuates male reproductive aging through modulation of mTOR-Beclin-1-mediated autophagy in Leydig and Sertoli cells ZHANG2026B 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. |
| 2026 | A | Aberrant excitatory neuronal ERBB4 promotes Alzheimer's disease pathology LEE2026 Ectopic ERBB4 in excitatory neurons is one of the earliest changes in AD mouse models and is necessary for synapse loss, reactive gliosis, amyloid plaque deposition and cognitive deficits in AD mice, and its overexpression in wild-type excitatory neurons is sufficient to reproduce synapse loss, gliosis and cognitive deficits (but not amyloid plaques); these effects require mTOR signalling downstream of ERBB4. |
| 2026 | A | Rapamycin Attenuates Age-Related Changes in Marmoset Submandibular Gland: A Non-Human Primate Model of Human Oral Aging. ABD2026 In the aging marmoset submandibular gland the authors found fewer mucous and serous acinar units, expansion of ductal and collagen-rich stromal compartments, more extracellular matrix remodeling, dysregulated lipid metabolism, and more apoptotic and senescent cells. Chronic oral rapamycin was associated with partial preservation of acinar structure and with less fibrosis, lipid accumulation and fewer apoptotic and senescent cells, giving a tissue picture closer to that of younger animals. Boundary: histological and immunofluorescence associations in one tissue of a short-lived primate; the abstract gives no dose or group sizes, does not show that gland function improved, and reports no lifespan outcome. |
| 2023 | A | A masked, placebo-controlled, randomized clinical trial evaluating safety and the effect on cardiac function of low-dose rapamycin in 17 healthy client-owned dogs BAR2023 In 17 healthy pet dogs, 6 months of low-dose rapamycin (0.025 mg/kg, three times a week) caused no clinically significant adverse events. Echocardiography, however, showed NO statistically significant difference from placebo at 6 or 12 months, so the heart benefit hinted at in the earlier 10-week trial (URF2017) was not reproduced. Owners did report perceived positive changes in behavior or health more often in the rapamycin group (26.8% vs 8.1% of bi-weekly surveys), but that is a subjective, owner-reported outcome. A small safety-focused trial, not designed to test lifespan. |
| 2021 | A | DNA methylation age analysis of rapamycin in common marmosets. HOR2021 The authors built two epigenetic clocks for common marmoset blood from DNA methylation data; the human-marmoset clock for relative age correlated moderately well with age in vervet monkeys and rhesus macaques. In a separate marmoset cohort they tested whether rapamycin would change epigenetic age. The clocks did not detect a significant effect of rapamycin on the epigenetic age of marmoset blood. Boundary: a null result on one biomarker (DNA methylation age in blood). It does not show that rapamycin has no effect on aging in marmosets, only that these clocks did not register one; the abstract gives no dose, duration or group size. |
| 2018 | A | mTOR signaling regulates central and peripheral circadian clock function RAM2018 mTOR sets how fast and how strongly the circadian clock ticks. Inhibiting mTOR lengthened the clock period and flattened its amplitude; activating it shortened the period and raised the amplitude, in cells, in ex vivo brain (SCN) and liver clocks, and in mTOR heterozygous mice, whose locomotor rhythm ran longer. The study starts from the observation that mTOR activity itself oscillates over 24 hours in many tissues. |
| 2018 | A | Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets. SIL2018 In middle-aged marmosets given daily rapamycin, 9 months of treatment produced only minor changes in cellular blood counts, so hematological side effects are not likely outcomes of long-term rapamycin in relatively healthy middle-aged animals. Trough blood concentrations of rapamycin were significantly lower in females than in males, yet both sexes changed little. At baseline, males and females differed little in morphology or in markers of blood cell counts, metabolism and inflammation. Boundary: healthy middle-aged marmosets, 9 months, hematology and clinical laboratory markers only; it says nothing about efficacy or lifespan, and the abstract does not give the dose or group sizes. |
| 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 in healthy pet dogs caused no clinical side effects, and echocardiography suggested improved measures of heart function. |
| 2017 | A | Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy LIP2017 In mouse models of tuberous sclerosis, where mTOR is stuck on, the circadian clock ran abnormally: poor timekeeping in constant conditions and exaggerated responses to phase resetting. mTOR raised BMAL1 levels by changing its translation, degradation and location; genetically lowering BMAL1 rescued the behavioural rhythm defects. Constant, unpatterned mTOR activity disturbs a rhythm downstream. |
| 2016 | A | Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice BIT2016 Mice got rapamycin for only 3 months, starting at 20 to 21 months of age, and were then taken off it. A high injected dose (8 mg/kg a day) raised the males' remaining life expectancy after treatment by 60% (p = 0.02), which is a 16% longer median lifespan counted from birth. In females the same dose did not extend life (p = 0.26), and all 16 treated females examined had aggressive blood-cell tumours of the lymphoma type, against 6 of 12 controls, while other tumour types became rarer. A lower dose in the diet (126 ppm; the injected dose was estimated to equal about 378 ppm) raised post-treatment life expectancy by 42% in both sexes together and median lifespan by 13%, improved grip strength and rotarod performance, and changed the gut bacteria (more segmented filamentous bacteria). Boundary: mice only. The tumour counts come from small groups (12 to 16 per arm), side effects such as cataracts or testis changes were not tested at the dietary dose, and 'life expectancy' is counted from the end of treatment, so it makes the gain look larger than the change in total lifespan. |
| 2016 | A | Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. LEL2016 In liver and skeletal muscle from rapamycin-treated marmosets (the earlier pilot cohort), rapamycin was associated with higher expression of PSMB5, a core 20S proteasome subunit, in both tissues but not of PSMB8; proteasome activity itself did not change. Mitochondria-targeted chaperones rose in skeletal muscle but not liver, and autophagy rose in skeletal muscle and adipose tissue but not liver. The authors conclude that only some components of the proteostasis network were upregulated, and in a tissue-specific way. Boundary: tissue samples from a small pilot cohort; the changes are expression-level associations and are not shown to cause any health or lifespan effect. |
| 2015 | A | Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus). ROS2015 Long-term oral encapsulated rapamycin in marmosets had only minor metabolic consequences. Body weight was unchanged overall and fat mass fell only slightly over the first few months. Daily activity counts, blood lipids and glucose metabolism, including oral glucose tolerance, did not change significantly, and adipose tissue showed no difference in metabolic-marker gene expression. In liver, G6Pase activity was suppressed while PCK and GPI activity increased. Boundary: marmoset, oral rapamycin, metabolic endpoints only; the abstract gives neither the dose nor group sizes, and no lifespan result is reported. |
| 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. |
| 2014 | A | The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells MAR2014 This study separated two arms of IL-15 signalling in NK cells by dose: low IL-15 mainly phosphorylated STAT5 (EC50 about 1.5 ng/ml), while higher IL-15 was needed to switch on mTOR (EC50 about 5.3 ng/ml for S6 phosphorylation), and IL-15 was the only one of many tested stimuli that strongly raised pS6. Deleting mTOR in NK cells left bone-marrow numbers normal but blocked the CD11b-low to double-positive transition, cut proliferation about three-fold and left almost no mature NK cells in the periphery, with lower CD71, glucose uptake and about half the surface CD122 and CD132, so the receptor feedback is itself mTOR-dependent. In activation, mTOR-deficient NK cells failed to grow or raise nutrient uptake after poly(I:C) and made about half as much granzyme B, while IFN-gamma production in response to IL-12 plus IL-18 stayed normal. Oral rapamycin lowered pS6 and granzyme B in vivo and made rejection of MHC-class-I-negative target cells significantly less efficient, and mTOR inhibitors also blocked IL-2-driven granzyme B induction in human NK cells. Boundary: mouse genetics and mouse in vivo pharmacology, with the human arm limited to healthy-donor NK cells stimulated in culture; the clinical implication for patients on rapalogs is inference, not a measured patient outcome. |
| 2014 | A | Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset. TAR2014 First description of dosing, pharmacokinetics, biochemical action and tolerability of rapamycin in the common marmoset. Eudragit-encapsulated rapamycin given orally at roughly 1.0 mg/kg/day gave mean trough blood levels of 5.2 ng/mL (range 1.93-10.73), comparable to rodent studies and within the human therapeutic range. In long-term animals (6 of 8) the phospho-rpS6 to total rpS6 ratio fell after 2 weeks, and rapamycin was detectable in liver and adipose tissue with reduced mTOR signalling there. There was no evidence of clinical anemia, fibrotic lung changes or mouth ulcers, and the death rate in the 14-month study was as expected for the animals' ages. Boundary: small cohort (6 of 8 long-term animals showed the pS6 drop), a 3-week and a 14-month study, pharmacology and tolerability only; no lifespan or healthspan outcome was measured, and nothing here is tested in people. |
| 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) female mice for 3 months improved aged heart function, reversing or attenuating age-related cardiac changes, with RNA-seq changes suggesting 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. |
| 2013 | A | Circadian regulation of mTOR by the ubiquitin pathway in renal cell carcinoma OKA2013 In mouse kidney tumours, active phosphorylated mTOR and total mTOR protein followed a 24-hour rhythm, set by the clock through the ubiquitin ligase Fbxw7. Giving everolimus when mTOR was high improved survival compared with other dosing times. Same drug, same dose - the clock time of dosing changed the outcome. |
| 2013 | A | Increased mammalian lifespan and a segmental and tissue-specific slowing of aging after genetic reduction of mTOR expression WUX2013 Genetically reduced mTOR increases mouse lifespan with tissue-specific slowing of aging. |
| 2012 | A | Chronic inhibition of mammalian target of rapamycin 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 and maximal lifespan in both sexes; age at 90% mortality rose 14% in females and 9% in males. |
| 2008 | A | A role for autophagy in the extension of lifespan by dietary restriction in C. elegans HAN2008 Makes autophagy a necessary step between dietary restriction and a longer life, not a side effect of it: blocking autophagy genes abolishes the lifespan extension produced both by dietary restriction and by TOR inhibition. The paper is equally careful about what autophagy cannot do on its own, because autophagy still runs in animals lacking DAF-16/FOXO and yet those animals are not long-lived. Boundary: worms; necessity was shown, sufficiency was not. |
| 2006 | A | Hypothalamic mTOR signaling regulates food intake COT2006 In rats, hypothalamic mTOR signalling (phosphorylated S6K1 and S6) changed with energy status in specific hypothalamic regions and was found in NPY and POMC neurons of the arcuate nucleus. Injecting leucine into the brain ventricles raised hypothalamic mTOR signalling and lowered food intake and body weight. Leptin also raised hypothalamic mTOR activity, and blocking mTOR with rapamycin in the brain blunted leptin's effect on reducing food intake. The authors proposed that hypothalamic mTOR acts as a fuel sensor linked to how much an animal eats. Boundary: rats, direct brain (intracerebroventricular) dosing, short-term food intake; drawn from the abstract only, so doses and effect sizes are not given here. |
| 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 | Molecular and metabolic dysregulation of lung cancer in developing anti-tumor activity by gambogic acid mediated mTOR signaling: in vitro and computational study. BO2026 Computational (network pharmacology and docking) plus in vitro study: gambogic acid is cytotoxic and pro-apoptotic in A549 lung cancer cells and docks most strongly to AKT and the mTOR effector S6K1 (RPS6KB1). Direct mTOR kinase inhibition was not measured; 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 did not protect a mouse spermatogonial cell line from cisplatin damage in vitro, unlike reports in female fertility models. |
| 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. |
| 2026 | M | Transcriptional modulation of the PI3K/AKT/mTOR signaling pathway mediated by HPV16 E5, E6, and E7 oncogene expression in breast cancer. DEOLIVEIRA2026 In breast tumour tissue (48 of 92 patients with usable RNA), HPV16 oncogene expression was associated with higher PI3K and lower mTOR transcript levels. The design is correlational and measures mRNA only, so it does not show that the virus activates the mTOR pathway. |
| 2026 | R | mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes BOB2026 Frames mTOR as a dynamic, context-dependent signaling hub integrating nutrient sensing, proteostasis, autophagy and stress adaptation across the hallmarks of aging; surveys geroprotective interventions (autophagy activation, dietary restriction, exercise, senotherapeutics) that partly converge on mTOR signaling. Causal evidence for mTOR in lifespan regulation is strong in model organisms; human data remain associative but biologically consistent. |
| 2026 | M | Phosphorylation of OTUB1 promotes autophagy initiation under starvation SUN2026B Under starvation, ERK phosphorylates the deubiquitinase OTUB1 at S118, which stabilizes it by letting it out-compete TRIM29 for binding to ANXA2. Stabilized OTUB1 upregulates DEPTOR, a natural mTOR inhibitor, which suppresses mTOR and triggers autophagy. In mice, restoring this fasting-triggered ERK-OTUB1-DEPTOR-mTOR axis countered the mTOR-activating effect of a Western diet and eased MASLD (fatty liver disease) progression, giving a mechanistic account of how fasting benefits the liver. |
| 2026 | M | Genome-wide CRISPRi screen in human iNeurons identifies novel negative mTOR regulator genes associated with focal cortical dysplasia TID2026 First unbiased genome-wide functional screen for negative regulators of mTOR signalling carried out in human neurons rather than in cancer lines or non-neural cells. Six genes (LRRC4, EIF3A, TSN, HIP1, PIK3R3, URI1) raise phospho-S6 when knocked down; only PIK3R3 and HIP1 raise phosphorylation across the whole AKT/mTOR/S6 axis, and each of those two has an independently reported candidate pathogenic variant in resected FCD brain tissue, which gives the screen external validity. Boundary: pS6 is a readout of mTORC1 output, not of mTORC1 itself, and four of the six hits did not show pathway-wide hyperphosphorylation, so their placement relative to mTORC1 is unresolved. The screen is in vitro in iPSC-derived neurons; no animal or human causal test of these genes in FCD is included. Relevant to the Atlas as an expansion of the upstream regulator set, and because the GDNF-withdrawal result shows the hits uncouple mTOR output from growth-factor input. |
| 2026 | M | An SLC7A5-dependent nutrient-sensing circuit overcomes cisplatin tolerance via mTOR-autophagy signaling. RAO2026 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. |
| 2026 | M | Brucella suis vaccine strain 2 promotes intracellular proliferation by inducing M2 macrophage polarization and autophagy through PI3K/Akt/mTOR signalling. LI2026B 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. |
| 2026 | M | Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations NOR2026 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. |
| 2026 | R | Rapamycin across biology and medicine: From molecular mechanisms to clinical and translational frontiers NOL2026 Comprehensive review tracing rapamycin from its discovery as an antifungal macrolide to its identification as the founding mTOR inhibitor. Covers mTOR's role integrating nutrient/growth-factor/stress signals, established and emerging clinical applications of rapamycin/rapalogs, limitations and adverse effects of mTOR inhibition, and translational prospects for using mTOR inhibition to prevent or delay chronic disease and extend healthspan. |
| 2026 | M | LINP1 suppresses radiation-induced cellular senescence in keratinocytes by modulating the mTOR-p53 axis LIANG2026 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. |
| 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. |
| 2025 | M | Transient APC/C inactivation by mTOR boosts glycolysis during cell cycle entry PAU2025 After mitogen stimulation, mTOR quickly phosphorylates the APC/C adaptor CDH1, partly releasing it and briefly inactivating APC/C; the glycolytic enzyme PFKFB3 accumulates and glycolysis rises, until a delayed phosphatase restores APC/C. This incoherent feed-forward loop produces a pulse of glycolysis that cell cycle entry requires. |
| 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). |
| 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. |
| 2019 | R | mTOR as a central hub of nutrient signalling and cell growth KIM2019 Review: mTOR as a central hub of nutrient signalling and cell growth. |
| 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. |
| 2017 | M | Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes ABU2017 Turns the lysosome from a place where mTORC1 is switched on into something mTORC1 also controls: inhibiting mTOR strongly reduces the efflux of most essential amino acids out of the lysosome, so the organelle becomes a store rather than a source. Measured directly by rapidly isolating lysosomes and profiling their contents, which is why the claim is about concentrations inside the organelle and not inferred from signalling readouts. Boundary: one human cell line, acute pharmacological inhibition. |
| 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. |
| 2016 | M | Tor forms a dimer through an N-terminal helical solenoid with a complex topology BAR2016 Cryo-EM shows TOR dimerizes through an N-terminal helical solenoid, informing mTORC1 architecture. |
| 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. |
| 2013 | R | Where is mTOR and what is it doing there? BETZ2013 Review of where mTOR localizes and its compartmentalized functions. |
| 2012 | R | Regulation and function of mTOR signalling in T cell fate decisions CHI2012 Review of mTOR signalling in T-cell fate decisions. |
| 2011 | R | Regulation of immune responses by mTOR POW2011 Review of mTOR as an integrator of immune-cell metabolism and differentiation. |
| 2011 | M | Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size SAC2011 Rac1 binds and regulates both mTORC1 and mTORC2, controlling their localization and cell growth. |
| 2011 | M | Spatial coupling of mTOR and autophagy augments secretory phenotypes NAR2011 Protein synthesis and autophagic degradation are usually described as opposites that mTOR switches between, and this paper shows a compartment where the cell deliberately runs both at once. In senescent cells, autolysosomes and mTOR gather at one side of the Golgi (the TASCC), mTOR gets there in an amino-acid- and Rag-dependent way, and destroying that arrangement cuts interleukin-6/8 secretion. Boundary: cells, not organisms; it explains how the senescent secretory programme is fuelled, not whether blocking it helps an animal. |
| 2010 | M | Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer SAT2010 Screened point mutations from cancer genome databases and found two, S2215Y (large intestine adenocarcinoma) and R2505P (renal cell carcinoma), that kept mTOR signalling on even under nutrient starvation. mTORC1 purified from starved cells carrying the mutants still phosphorylated 4E-BP1 in vitro. Mutant cells had more S-phase cells (42.0% vs 28.2% for S2215Y) and resisted the shrinkage caused by amino-acid withdrawal. The mutants stayed sensitive to rapamycin. Boundary: overexpressed mutants in cultured cells; the mutations were found in tumour databases, their driver role in patients was not tested. |
| 2010 | M | The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin RAO2010 Working with naive OT-I CD8 T cells stimulated by antigen plus B7.1, the authors showed that IL-12 both raised and prolonged mTOR phosphorylation and S6K1 Thr389 phosphorylation out to 48 hours, and that this required PI3K throughout and STAT4 for the late phase. Rapamycin, added at the start or only at 12 hours, blocked the sustained expression of T-bet and with it the heritable type I effector programme, while raising Eomesodermin and producing cells with a memory-precursor phenotype (CD62L high, KLRG1 low, Bcl-2 high). Restoring T-bet by a tamoxifen-inducible construct brought back IFN-gamma production and lowered Eomesodermin, which places T-bet downstream of mTOR in this system. After transfer, the rapamycin-treated cells persisted better, gave stronger antigen-recall responses, and more than 78 percent of recipients stayed tumour-free to day 120 against 50 percent fatality with IL-12-conditioned effector cells. Boundary: mouse CD8 T cells, one TCR-transgenic system with pharmacological mTOR inhibition in vitro before transfer; the transplantable E.G7 tumour is a model, not a treatment result in people, and the memory-precursor phenotype faded by day 40 after transfer. |
| 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. |
| 2008 | M | The TSC-mTOR signaling pathway regulates the innate inflammatory response WEI2008 The TSC-mTOR pathway controls the innate inflammatory response of monocytes/macrophages. |
| 2008 | M | The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C FAC2008 Cells lacking the mTORC2 components mTOR, SIN1 or rictor lost phosphorylation of Akt and of conventional protein kinase C at the turn motif, a site near the end of the kinase domain. This phosphorylation did not depend on growth factors, and the authors reported the same function in yeast. Turn-motif phosphorylation helped newly made Akt and PKC fold correctly and stay stable; without it, Akt was held by the chaperone Hsp90 and protected from ubiquitin-mediated breakdown. mTORC2 controlled the Akt turn-motif and hydrophobic-motif (Ser473) sites independently in vivo and phosphorylated both directly in vitro. Boundary: Cell culture, yeast and in vitro kinase assays, with mouse tissue for the in vivo site analysis. Shows a protein-maturation role of mTORC2, not an organismal phenotype. Drafted from the abstract only. |
| 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. |
| 2006 | M | Extension of chronological life span in yeast by decreased TOR pathway signaling POW2006 Decreased TOR pathway signalling extends chronological lifespan in yeast. |
| 2005 | M | Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients KAE2005 A systematic screen of 564 yeast gene deletions found 10 deletions that extend replicative lifespan; genes of the nutrient-responsive TOR and Sch9 pathways were the most frequent hits (6 of 10). |
| 2005 | M | Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase NOB2005 The companion paper to BYF2005, from a different laboratory: the amino acid input to mTORC1 is separate from the insulin input and runs through class 3 PI3K (hVps34), not through class 1 PI3K. Historically important because it states that the amino acid branch is the older one and that insulin signalling was grafted onto it. Boundary: cell lines, pharmacological and knockdown evidence; the later Rag/Ragulator account describes a different route to the same target, and the two accounts are not reconciled in the work this Atlas holds. |
| 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. |
| 2003 | M | The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif NOJ2003 Raptor binds mTOR substrates via their TOS motifs, acting as the substrate-presenting scaffold of mTORC1. |
| 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. |
| 2002 | M | Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E FIN2002 mTOR controls mammalian cell size through its downstream translational targets S6K1 and 4E-BP1/eIF4E. |
| 2002 | M | A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus TAN2002 The authors showed that mTOR, 4E-BP1, 4E-BP2 and eIF4E are present in rat hippocampus and sit in dendrites, close to synapses, where their staining overlapped with the postsynaptic protein PSD-95. Blocking mTOR with rapamycin in hippocampal slices reduced late-phase long-term potentiation (LTP) after high-frequency stimulation, while early-phase LTP was unaffected. Rapamycin also blocked the synaptic potentiation induced by the growth factor BDNF. This was one of the early papers to tie a rapamycin-sensitive pathway to the protein-synthesis-dependent phase of synaptic plasticity and to suggest it controls local translation at synapses. Boundary: rodent brain slices and cultured neurons; mTOR targets were localised but their phosphorylation during LTP was not reported in the abstract; no behaviour or memory test. |
| 2001 | M | Mammalian TOR: a homeostatic ATP sensor DEN2001 The authors tested whether mTOR signalling responds to the cell's energy level, not only to amino acids. They reported that lowering intracellular ATP reduced signalling through the mTOR pathway, and that this happened independently of amino acid levels. Based on the kinase properties of mTOR, they proposed that mTOR itself senses ATP. Later work showed that much of the energy signal reaches mTORC1 through AMPK and TSC2, so the direct ATP-sensor model is one part of a larger picture. Boundary: cultured cells and in vitro kinase measurements; the ATP-sensor interpretation is the authors' model and has been revised by later AMPK work. |
| 2000 | M | Tor-mediated induction of autophagy via an Apg1 protein kinase complex KAM2000 The founding experiment of the whole TOR-to-autophagy axis. Starvation or rapamycin raises the kinase activity of Apg1 (the yeast counterpart of ULK1), and TOR keeps autophagy off by holding Apg13 hyperphosphorylated so that it cannot bind and activate Apg1. Boundary: yeast only, and the mammalian version of the same step (ULK1-ATG13-FIP200) was shown separately nine years later. |
| 2000 | M | Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin OLD2000 The authors identified and characterised dTOR, the fruit fly version of TOR. Genetic and biochemical experiments indicated that dTOR affects growth in a cell-autonomous way by changing the activity of the fly S6 kinase, dS6K, and so connects to the insulin signalling pathway. Unlike other insulin pathway components, partial loss of dTOR reduced growth mainly in endoreplicating tissues, which copy their DNA without dividing. The authors read this as evidence that dTOR sits on a parallel pathway that senses amino acids. Boundary: Drosophila genetics and biochemistry; the parallel amino acid pathway is an interpretation from fly phenotypes, not a direct measurement of amino acid sensing. |
| 2000 | M | Regulation of cellular growth by the Drosophila target of rapamycin dTOR ZHA2000 The authors showed that fly TOR (dTOR) is needed inside each cell for normal growth and proliferation during larval development. dTOR was also needed for the extra cell growth caused by activating PI3K signalling. As in mammalian cells, dTOR kinase activity was needed for growth factor-dependent phosphorylation of S6 kinase in vitro, and overexpressing S6 kinase rescued dTOR mutant flies to viability. dTOR loss also produced signs of amino acid starvation, such as smaller nucleoli and lipid droplet clumping in the fat body, plus a cell-type-specific cell cycle arrest that cyclin E could bypass. The authors proposed that dTOR links growth factor signalling to nutrient availability during development. Boundary: Drosophila larvae and in vitro kinase assays; rescue relied on overexpression of S6 kinase, and results are not shown in mammals here. |
| 1999 | M | Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism GIN1999 4E-BP1 is phosphorylated by an ordered, priming two-step mechanism that controls its release of eIF4E. |
| 1998 | M | Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism HAR1998 Amino acid sufficiency signals through mTOR to p70 S6K and 4E-BP1 via a common effector, first linking nutrients to mTOR. |
| 1997 | M | Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin BRU1997 mTOR directly phosphorylates 4E-BP1 (PHAS-I), releasing eIF4E and establishing mTOR's role in translational control. |
| 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; one of three 1994 reports (with Brown et al. and Chiu et al.) that identified mammalian TOR, three years after TOR was found in yeast. |
| 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. |
| 2025 | RT | Test of Rapamycin in Aging Dogs (TRIAD): study design and rationale for a prospective, parallel-group, double-masked, randomized, placebo-controlled, multicenter trial of rapamycin in healthy middle-aged dogs from the Dog Aging Project COL2025 Design and rationale paper (protocol), NOT results. TRIAD is a double-masked, randomized, placebo-controlled, multicenter trial testing whether rapamycin prolongs lifespan and improves healthspan measures in healthy middle-aged dogs from the Dog Aging Project. Its authors describe it as the first rigorous test of a drug against biological aging with lifespan and healthspan endpoints performed outside the laboratory in any species. Planned size is 580 dogs with 3 years of treatment (NIH-funded, per Texas A&M announcement; 170 dogs enrolled at that time). No efficacy or safety results exist yet, so this must not be cited as evidence of benefit. |
| 2025 | PP | The tumor suppressor CYLD acts as a deubiquitinase for mTOR to constrain its activity FER2025 An RNAi screen identified the tumor suppressor CYLD as a deubiquitinase that binds mTOR and removes non-degradative K63-linked ubiquitin chains from several of its residues, restraining both mTORC1 and mTORC2. Cells lacking CYLD show hyperactive mTORC1/2, higher protein synthesis, larger cell size and resistance to serum-starvation-induced cell death. In C. elegans, knocking down cyld-1 fully abolishes the extended lifespan of low-TORC1-activity mutants, and skin biopsies from CYLD cutaneous syndrome patients show mTORC1 hyperactivation. Preprint, not peer-reviewed. |
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