Longevity
Lifespan extension; the key outcome tracked across mTOR-targeting interventions.
Living longer.
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.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| S | Synthesis of human data | 1 |
| H | Human study | 4 |
| A | Animal model | 22 |
| RT | Registered trial, no results yet | 1 |
| R | Review — secondary literature, not a new result | 9 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2024 | S | Targeting ageing with rapamycin and its derivatives in humans: a systematic review LEE2024 The first systematic review of rapamycin/rapalogs in humans for aging. Screened 18,400 articles, included 19 studies. Found improvements in immune, cardiovascular, and skin (integumentary) parameters; NO significant effect on endocrine, muscular, or neurological systems. No serious adverse events in healthy people, but more infections and raised cholesterol/triglycerides in people with age-related disease. This is the highest-tier human-evidence summary in the whole Atlas - it aggregates many individual human studies rather than reporting one. |
| 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 Low-dose rapamycin in ME/CFS patients reduced fatigue symptoms, modulated purine biosynthesis via IMP dehydrogenase inhibition, reduced microglial inflammatory responses, and improved mitochondrial energy metabolism in a phase-II observational pilot study. |
| 2025 | H | Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results MOE2025 First completed long-term RCT of rapamycin for healthy human aging (NCT04488601, 48 weeks, n=114). Primary endpoint (visceral fat by DXA) showed NO significant change (p=0.942) - a null result exactly as pre-registered. Secondary endpoints were more promising: women on the 10mg/week dose had significant improvements in lean muscle mass and self-reported pain. A textbook example of why the pre-registered primary endpoint, not the most exciting secondary finding, is what should drive the headline conclusion. |
| 2018 | H | A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort 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. |
| 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. |
| 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 improved heart function measures in healthy pet dogs with no clinical side effects. |
| 2016 | A | Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice BIT2016 Just 3 months of rapamycin late in life increased subsequent life expectancy by up to 60% - evidence that transient, not lifelong, dosing can capture the benefit. |
| 2014 | A | 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; low protein ratio suppressed hepatic mTOR. |
| 2014 | A | Acarbose, 17-alpha-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. |
| 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) mice for 3 months improved aged heart function, reversing age-related cardiac changes via anti-hypertrophic and anti-inflammatory effects. Started late, still worked. |
| 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 mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice HAL2012 Asked whether the lifespan-extending dose of rapamycin harms or helps the aging BRAIN. Reassuringly, it enhanced learning and memory in young mice, prevented age-related cognitive decline in old ones, and even reduced anxiety and depression-like behavior - linked to boosted brain monoamines. Cognitive benefit, not cost. |
| 2012 | A | Rapamycin slows aging in mice WIL2012 Answered a crucial objection: does rapamycin really slow AGING, or just prevent the cancers that kill mice? By showing slower age-related change across many tissues (heart, liver, tendon, activity), it argued for genuine slowing of aging. Honestly reported harms too - more cataracts and testicular degeneration - making it a balanced landmark, not hype. |
| 2011 | A | Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice MIL2011 In the same experimental design that showed rapamycin extended median lifespan by 10-18%, neither resveratrol nor simvastatin had any significant effect on survival - a direct head-to-head negative control run at the same time, in the same mice. |
| 2010 | A | 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. Dietary restriction lowers mTOR activity, which frees up 4E-BP - and here 4E-BP was shown to be REQUIRED for the lifespan boost, working by selectively boosting translation of mitochondrial genes. A rare case pinning a specific mTOR effector to the longevity benefit of eating less. |
| 2009 | A | Rapamycin fed late in life extends lifespan in genetically heterogeneous mice HAR2009 Rapamycin fed from 600 days of age extended median lifespan by 9-14% in both sexes. |
| 2005 | A | Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients KAE2005 A systematic screen of 564 yeast gene deletions found TOR and Sch9 pathway genes as the strongest lifespan-extending hits. |
| 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 longevity, not just correlated. |
| 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. |
| 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 The landmark synthesis showing that eating less (dietary restriction) and dialing down nutrient-sensing pathways - mTOR and growth hormone/IGF-1 - extend healthy lifespan by the SAME conserved mechanisms from yeast to monkeys to humans. This is the paper that frames why mTOR sits at the crossroads of diet and aging. |
| 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. |
| RT | Everolimus Aging Study (EVERLAST): Clinical Evaluation of mTORC1 Inhibition for Geroprotection NCT05835999 Currently active phase 2 trial (NCT05835999) directly testing this Atlas's open dosing hypothesis: whether daily low-dose (0.5mg) versus weekly (5mg) everolimus can improve aging biomarkers and insulin resistance in humans without the metabolic penalty seen with continuous higher-dose rapalog use. No results yet - status ACTIVE_NOT_RECRUITING. |