Longevity
Lifespan extension; the key outcome tracked across mTOR-targeting interventions.
Living longer. How long an organism lives - the single outcome most often measured across every mTOR-targeting intervention in this Atlas.
Robust in yeast, worms, flies and mice (ITP, multiple sites); no human lifespan data exist. Effect is sex- and strain-dependent and separable from healthspan.
TL;DR. Longevity appears in 60 curated studies in Oliver's mTOR Atlas: 6 in people (2 syntheses of human data, 4 human studies); 39 in animal models; 2 at the molecular level (cells, biochemistry, structure); 11 reviews; 2 registered trials without results yet. It has 7 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| 4E-BP1 activates Longevity mechanism: functional-consequence · this link in full · on the map table | Keeping 4E-BP switched on extends lifespan in fruit flies on a restricted diet, by protecting their mitochondria. Holds under: Fly only, and only under dietary restriction - the effect was not seen on a full diet. not tested in people · emerging, few independent studies | A | ZID2009 |
| mTORC1 inhibits Longevity mechanism: functional-consequence · this link in full · on the map table | Turning mTORC1 down extends lifespan in yeast, worms, flies and mice – one of the best-replicated anti-ageing effects in laboratory animals. In mice, how big the effect is depends on sex, strain, diet and when treatment starts, and it has not been shown in people. Holds under: No human hard-endpoint evidence. This is the Atlas's flagged 'human endpoint desert'. Strongly modified by sex, strain, diet and the age at which inhibition starts. Effect direction is reproducible; effect size is not transferable between models. not tested in people · settled in the literature | A | HAR2009, LAM2012, ROB2012, VEL2003, HAN2008, POW2006, WAN2026 |
| Rapamycin activates Longevity mechanism: functional-consequence · this link in full · on the map table | Rapamycin makes mice live longer, even when given late in life – the single biggest result behind the whole "this pathway and ageing" idea. Holds under: Mouse only. No human lifespan or healthspan endpoint exists; EVERLAST has no results yet. BIT2016 shows a non-continuous schedule can still extend post-treatment life expectancy, but the result is dose- and route-specific: in the 8 mg/kg/day intraperitoneal arm males gained +60% post-treatment life expectancy (p=0.02) while females showed no survival benefit (p=0.261) and a shift toward aggressive haematopoietic cancers (16/16 vs 6/12, p=0.002); in the same paper's 126 ppm dietary encapsulated-rapamycin arm survival rose significantly in BOTH sexes, with a Cox model finding no evidence that sex modified the treatment effect (p=0.904). Cite the arm, not just the paper. ARR2016: an intermittent regimen (2 mg/kg every 5 days) started as late as 20 months of age extended lifespan in female C57BL/6J mice; the abstract reports the effect in females only. not tested in people · settled in the literature | A | HAR2009, BIT2016, KHA2014, CHE2009, ARR2016, ANI2011 |
| S6K1 inhibits Longevity mechanism: functional-consequence · this link in full · on the map table | Removing S6K1 makes FEMALE mice live longer (about a fifth longer) and resist obesity. In male mice the same change did not significantly extend life – that difference is part of the result, not a footnote. Still strong evidence that one branch, not the whole pathway, drives much of the ageing effect. Holds under: Female mice only in SEL2009 - the lifespan extension was not significant in males. not tested in people · emerging, few independent studies | A | SEL2009 |
| Fasting / caloric restriction activates Longevity mechanism: functional-consequence · this link in full · on the map table | Eating less improved health and survival in monkeys. But in mice that could eat as much as they wanted, cutting calories by watering down the food did not make them live longer; eating less protein compared with carbohydrate did. So whether it is the calories or the protein that counts is still open. Holds under: No human lifespan data exists. Effect direction is reproducible across several species; effect size and even the responsible variable (calories versus composition) are not settled. not tested in people · emerging, few independent studies | A | MAT2017 conflicting: SOL2014 |
| FOXO1/3 activates Longevity mechanism: functional-consequence · this link in full · on the map table | Part of how this pathway affects lifespan runs through stress-resistance genes switched on by FOXO – so far shown mainly in simple animals like worms, not yet in mammals. Holds under: An invertebrate result, and the two arms must not be merged. ROB2012's title reads 'TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO', but its own abstract splits them: the DAF-16/FoxO requirement belongs to genetic TORC1 inhibition, while the rapamycin effect is SKN-1-dependent and DAF-16-INDEPENDENT. Not shown in mammals in this corpus. not tested in people · emerging, few independent studies | A | ROB2012 |
| Growth hormone / IGF-1 axis inhibits Longevity mechanism: functional-consequence · this link in full · on the map table | Less growth-hormone signalling, longer life in mice. Holds under: Mouse only. A lifelong GH-receptor-antagonist transgenic (LIST2026; an earlier study of the same line did not detect extension) and a tamoxifen-inducible whole-body Ghr knockout started at 12 months (DUR2026). mTOR signalling was not measured in either, so the route through PI3K-Akt-mTOR is inferred, not shown here. plausible in people, not shown directly · settled in the literature | A | LIST2026, DUR2026 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| S | Synthesis of human data | 2 |
| H | Human study | 4 |
| A | Animal model | 39 |
| M | Molecular — cells, biochemistry, structure | 2 |
| RT | Registered trial, no results yet | 2 |
| R | Review — secondary literature, not a new result | 11 |
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 | 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 GIL2026 In an uncontrolled phase-II pilot (no placebo), low-dose rapamycin was associated with reduced fatigue in ME/CFS. In plasma from responders, purine intermediates shifted, consistent with lower IMP dehydrogenase activity in PBMCs. Lab assays suggest that altered purines can impair mitochondrial metabolism and promote microglial inflammation; these links were not measured in patients. |
| 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. |
| 2018 | H | A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. KRA2018 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. |
| 2014 | H | 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 BAN2014 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. |
| 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 | Growth Hormone Receptor Antagonism Extends Lifespan LIST2026 Transgenic expression of a growth hormone receptor antagonist — the G119K mutant chemistry behind the FDA-approved drug Pegvisomant — significantly extended both median and maximal lifespan in male (p = 0.044; p = 0.0037) and female mice, with maximal lifespan extended by 186 and 265 days respectively. Two-year-old antagonist mice were less frail and had greater grip strength despite increased adiposity. This is the first demonstration that antagonising GH action (as opposed to congenital GH deficiency, as in Ames/Snell dwarfs) extends mammalian lifespan — the GH/IGF-1 axis sits upstream of PI3K-Akt-mTOR, which is why it belongs in this corpus. |
| 2026 | A | An ANGPTL8-AKT2-mTOR Axis Drives Adipose Senescence and Aging-Related Functional Decline HE2026 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. |
| 2026 | A | Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila WAN2026 Identifies Lsp2, a Drosophila fat-body storage protein, as an amino-acid-induced feedback activator of mTORC1 that specifically boosts translation of TOP-motif mRNAs (mostly ribosomal proteins) via 4E-BP — a rapamycin-resistant arm of mTORC1 output. Genetic loss of Lsp2 reduces TOP mRNA translation and robustly extends lifespan without cost to reproduction, revealing a rapamycin-independent route from mTORC1 activity to organismal longevity. |
| 2026 | A | Midlife Growth Hormone Receptor Ablation Extends Healthy Lifespan and Induces Sex-Specific Hepatic Transcriptional Changes at Single-Cell Resolution DUR2026 Deleting the growth hormone receptor in mice at 12 months of age, in middle age and long after development is complete, still significantly extended lifespan in both sexes without major effects on body growth. Males showed improved insulin sensitivity and were protected against age-related decline in neuromuscular performance and bone microarchitecture despite increased adiposity. Liver snRNA-seq revealed sex-dimorphic remodelling, including a shift toward feminised gene expression in male hepatocytes consistent with loss of pulsatile GH-STAT5 signalling. Important because most GH/IGF-1 longevity models are congenital: this shows a midlife start is still sufficient, which matters for translating growth-signalling (and by extension mTOR-adjacent) interventions to adults. |
| 2026 | A | A cross-species drug-discovery platform to accelerate the identification of lifespan-extending interventions PEREZ2026 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. |
| 2026 | A | Disruption of the insulin/IGF-1 signaling pathway in Caenorhabditis elegans dramatically increases male longevity and enhances reproductive health late in life ALS2026 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. |
| 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. |
| 2022 | A | Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice STR2022 NIA Interventions Testing Program C2017 cohort. In MALE mice, rapamycin plus acarbose started at 9 months produced a longer lifespan than either of the two prior ITP cohorts treated with rapamycin alone, suggesting the combination is more potent than its components used separately. In FEMALES the combination was neither better nor worse than rapamycin alone, which the authors relate to the limited survival benefit acarbose alone had shown in earlier female cohorts. Captopril gave a small but significant lifespan increase in females (4-5%). CAVEAT (important for how this is cited): the rapamycin-only comparison is HISTORICAL, against prior cohorts, not a concurrent rapamycin-only arm in the same experiment, so 'more potent than either component' is the authors' suggestion rather than a within-experiment randomised comparison. |
| 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. |
| 2017 | A | Caloric restriction improves health and survival of rhesus monkeys MAT2017 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. |
| 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. |
| 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 | Cardioprotection and lifespan extension by the natural polyamine spermidine EIS2016 The mammalian follow-up to EIS2009 and the reason the spermidine branch matters for human health claims: oral spermidine extends mouse lifespan, reduces cardiac hypertrophy and preserves diastolic function, and the protection disappears in mice whose cardiomyocytes lack Atg5, which makes autophagy necessary rather than merely correlated. Boundary: the human part is a dietary questionnaire correlated with blood pressure and cardiovascular incidence, so it is observational and does not carry the causal claim the mouse data carry. |
| 2016 | A | Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice ARR2016 Female C57BL/6J mice that started rapamycin at 20 months of age, 2 mg/kg once every 5 days, lived longer than control females. This is the schedule that the same group had earlier shown to have a smaller effect on glucose tolerance and T cells than daily dosing (ARR2015), so the authors argue that rapamycin's effect on lifespan can be separated from many of its side effects. Boundary: this record rests on the abstract only. The size of the lifespan gain, any male data and any side-effect measurements in these old mice are not extracted yet. The separation claim comes from combining two mouse studies (ARR2015 used young males), not from a single experiment. |
| 2014 | A | The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice SOL2014 Lifespan and cardiometabolic health were determined not by caloric intake but by the protein:carbohydrate ratio; a low protein ratio was associated with lower hepatic mTOR activation. |
| 2014 | A | Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. HAR2014 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. |
| 2014 | A | BMAL1-dependent regulation of the mTOR signaling pathway delays aging KHA2014 Loss of the clock protein BMAL1 raised mTORC1 activity in mice and in cultured cells, and rapamycin extended the lifespan of Bmal1-/- mice by 50%. Places the circadian clock upstream of mTORC1 as a brake, and links that brake to ageing. |
| 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 | Overexpression of Atg5 in mice activates autophagy and extends lifespan PYO2013 Mice engineered with extra copies of the autophagy gene Atg5 lived 17% longer and were leaner and more insulin-sensitive. |
| 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 | 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 | Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice STR2012 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. |
| 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. |
| 2011 | A | Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice ANI2011 Female 129/Sv inbred mice received rapamycin intermittently, 2 weeks in every month, from 2 months of age for the rest of their lives. Treated mice gained less weight with age, showed a slower estimated rate of ageing, lived longer, with the gain most visible among the last survivors, and developed spontaneous tumours later. 22.9% of rapamycin-treated mice were still alive when the last control mouse died. The paper provided evidence that an intermittent rapamycin schedule can extend lifespan in a normal inbred mouse strain, adding to earlier results in genetically heterogeneous mice. Boundary: Female mice of a single inbred strain (129/Sv) only; drafted from the abstract only, so dose, group sizes and median-lifespan statistics are not given here. |
| 2010 | A | Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster BJE2010 Feeding rapamycin extended fly lifespan through autophagy and reduced translation, and worked even in flies already on a lifespan-maximizing diet. |
| 2009 | A | Ribosomal protein S6 kinase 1 signaling regulates mammalian life span SEL2009 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. |
| 2009 | A | 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila ZID2009 Connected the dots between diet, mTOR, and lifespan. 4E-BP, an mTOR target, is upregulated on dietary restriction and here 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. |
| 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. |
| 2009 | A | Induction of autophagy by spermidine promotes longevity EIS2009 The opening paper of the caloric-restriction-mimetic branch: a natural polyamine whose level falls with human age extends lifespan in yeast, flies, worms and human immune cells, and the effect depends on autophagy. In ageing yeast this works through inhibition of histone acetyltransferases, which raises autophagy gene expression. The paper did not measure mTOR, so whether this route bypasses mTOR is not tested here. Boundary: no mammalian lifespan data in this paper. |
| 2009 | A | mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells CHE2009 mTOR hyperactivation drives HSC aging; rapamycin restores hematopoietic stem-cell function. |
| 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. |
| 2007 | A | Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans HAN2007 The authors systematically tested whether lowering protein synthesis extends lifespan in the worm C. elegans. Reducing ribosomal proteins, the S6 kinase homologue rsks-1 or translation-initiation factors increased lifespan, and these perturbations, like TOR inhibition, increased resistance to heat stress. Different kinds of translation inhibition split into two groups: one that needed the FOXO transcription factor DAF-16 for the lifespan and stress effects and one that did not. The results linked TOR, but not sir-2.1, to the lifespan extension caused by dietary restriction in worms, and suggested that neither TOR inhibition nor dietary restriction works simply by reducing total protein synthesis. Boundary: Nematode only, with gene knockdown by RNAi or mutation; drafted from the abstract only, so effect sizes and which TOR experiments were new in this paper are not given here. |
| 2004 | A | Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway KAP2004 Genetically reducing TOR pathway activity extends fruit fly lifespan, overlapping with dietary restriction effects. |
| 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. |
| 2003 | A | Autophagy genes are essential for dauer development and life-span extension in C. elegans MEL2003 Worms lacking the autophagy gene bec-1 lost the lifespan-extending benefit of reduced insulin-like signaling - autophagy is mechanistically required for daf-2 (insulin-signalling) lifespan extension and for dauer formation in C. elegans. |
| 1996 | A | Dwarf mice and the ageing process BRO1996 Mice with growth hormone deficiency lived substantially longer than normal littermates - founding observation linking reduced growth-signaling to mammalian longevity. |
| 2026 | R | Biological limits of lifespan extension: evidence for a shift from pathway leverage to system-level buffering across species PIR2026 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. |
| 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 | 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 | 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. |
| 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 | 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. |
| 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. |
| 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. |
| 2012 | R | mTOR signaling in growth control and disease LAP2012 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. |
| 2010 | R | Extending healthy life span--from yeast to humans FON2010 Influential review proposing that dietary restriction and reduced nutrient-sensing signalling (mTOR, GH/IGF-1) may slow ageing through similar, evolutionarily conserved mechanisms. Lifespan extension is shown in yeast, invertebrates, rodents and rhesus monkeys; in humans the evidence is limited to protective biomarker changes and genetic associations. |
| 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). |
| 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. |
| RT | Everolimus Aging Study (EVERLAST): Clinical Evaluation of mTORC1 Inhibition for Geroprotection NCT05835999 Phase 2 trial (NCT05835999, EVERLAST) testing this Atlas's open dosing hypothesis directly: whether daily low-dose (0.5 mg/day) or weekly (5 mg/week) everolimus for 24 weeks can improve physiological and molecular hallmarks of aging in insulin-resistant or prediabetic adults aged 55-80, without the metabolic penalty seen with continuous higher-dose rapalog use. Double-blind and placebo-controlled with four arms (everolimus daily, everolimus weekly, and a matching placebo for each), n=106, plus a separate untreated 18-35 cohort for comparison. Primary endpoint is peripheral insulin sensitivity by dual-tracer OGTT; mTORC1 and mTORC2 signalling are secondary endpoints in muscle and blood cells. STATUS: the registry records the trial as COMPLETED, with primary completion 2026-06-30 and completion 2026-07-22. No results are posted yet, so there is nothing to read into the outcome either way. |
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