Rapamycin
Sirolimus; mTORC1 inhibitor (and, with chronic dosing, mTORC2 too); immunosuppressant; extends lifespan in mice.
The drug that made this pathway famous.
Sirolimus. Not an active-site inhibitor: the FKBP12–rapamycin complex binds the FRB domain and partially occludes substrate access, which is why 4E-BP1 phosphorylation is only incompletely blocked.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| S | Synthesis of human data | 1 |
| H | Human study | 7 |
| A | Animal model | 15 |
| M | Molecular — cells, biochemistry, structure | 12 |
| PP | Preprint, not peer-reviewed | 1 |
| R | Review — secondary literature, not a new result | 3 |
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. |
| 2019 | H | Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial CHU2019 A small human trial testing whether rapamycin can slow aging in a tissue you can actually see and biopsy - skin. Topical rapamycin significantly lowered the senescence marker p16 and raised collagen VII, with visible improvement in skin appearance. Early but tangible human evidence for rapamycin as an anti-aging agent. |
| 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. |
| 2011 | H | Efficacy and safety of sirolimus in lymphangioleiomyomatosis (MILES) MCC2011 A landmark placebo-controlled RCT (n=89) - the first to show that rapamycin (sirolimus) benefits a human lung disease. In LAM, lung function normally declines relentlessly; sirolimus STOPPED that decline while patients took it (and it resumed after stopping). Randomised human evidence that mTOR inhibition can suspend progression of this disease; the benefit did not persist after withdrawal. |
| 2009 | H | Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis DRU2009 Rapamycin given before resistance exercise completely blocked the normal post-exercise increase in human muscle protein synthesis. |
| 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 | 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 | Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERRα-dependent manner BCH2026 Chloroquine co-treatment attenuates rapamycin-induced hepatic steatosis (a known mTORC1-inhibitor side effect) in mice, and this rescue depends on the nuclear receptor ERRα; RNA-seq shows chloroquine reverses rapamycin-driven upregulation of lipid-metabolism genes, with ERRα identified as a top transcriptional regulator of the effect. |
| 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 | 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. |
| 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 | Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity LAM2012 In mice, chronic rapamycin also disrupts mTORC2, causing insulin resistance; lifespan extension can be uncoupled from this side effect. |
| 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. |
| 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. |
| 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. |
| 2010 | A | Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease SPI2010 Connected the longevity drug to a specific age-related disease. Long-term rapamycin prevented memory deficits and lowered toxic amyloid-beta in an Alzheimer's mouse model - and the benefit tracked with INCREASED autophagy in neurons. Suggested that the same autophagy boost that may slow aging could also help clear disease-causing proteins. |
| 2010 | A | Molecular interplay between mTOR, amyloid-beta, and Tau: effects on cognitive impairments CAC2010 Revealed a vicious cycle: amyloid-beta RAISES mTOR activity, and high mTOR in turn blocks the autophagy needed to clear amyloid and tau - so the disease feeds itself. Rapamycin broke the loop in 3xTg-AD mice, rescuing memory and lowering BOTH amyloid and tau, with autophagy shown to be required for the effect. |
| 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. |
| 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 | M | Rapamycin co-exposure fails to reduce cisplatin-induced damage in GC6-spg spermatogonial cell line. JIB2026 Rapamycin fails to protect spermatogonial stem cells from cisplatin-induced damage in vitro, indicating sex-specific or context-specific limits to rapamycin's cytoprotective role and suggesting male fertility preservation requires alternative strategies. |
| 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. |
| 2015 | M | mTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation LAB2015 Explained HOW rapamycin calms 'inflammaging'. Senescent cells spew inflammatory signals (the SASP) that damage surrounding tissue and even feed tumors. mTOR powers this by translating IL1A, the cytokine at the top of the cascade. Rapamycin selectively shuts it down - and blocked senescent cells from fueling prostate tumor growth in mice. |
| 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. |
| 2009 | M | An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1 THO2009 Dropped a bombshell: rapamycin does NOT fully block mTORC1. Using Torin1 (which jams the active site directly), the authors showed rapamycin leaves important mTORC1 jobs running - notably 4E-BP1 phosphorylation and autophagy suppression. This reframed a decade of rapamycin experiments and launched the search for complete inhibitors. |
| 2009 | M | Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2 FEL2009 The parallel discovery to Thoreen 2009 (same year), from the Shokat lab. Their TORKinibs (PP242, PP30) block mTOR's active site, hitting both complexes and shutting down cap-dependent translation that rapamycin misses. Together these two papers established a whole new drug class beyond rapamycin. |
| 2009 | M | Rapamycin decelerates cellular senescence DEM2009 Blagosklonny's key experiment behind his 'hyperfunction' theory of aging. When a cell's division is blocked but mTOR keeps driving growth, the cell tips into permanent senescence. Rapamycin uncouples the two - keeping arrested cells reversible instead of senescent. Direct evidence that mTOR actively drives the senescent state, not just passively accompanies it. |
| 2007 | M | mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex CUN2007 Showed mTOR isn't just about building proteins - it also runs the cell's POWER plants. mTORC1 drives mitochondrial gene expression and oxygen consumption through a YY1-PGC-1alpha transcriptional program; block mTOR with rapamycin and mitochondrial output falls. Explains part of why mTOR inhibition reshapes metabolism. |
| 2006 | M | Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB SAR2006 The molecular explanation for rapamycin's dark side. Short-term rapamycin only hits mTORC1, but LONG-term treatment also strips down mTORC2 in many cells, cutting Akt signaling. This is the mechanistic root of the insulin-resistance side effect later shown in mice (see Lamming 2012) - crucial for anyone dosing rapamycin for longevity. |
| 1996 | M | Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP CHO1996 The crystal structure that showed HOW rapamycin works at the atomic level: one rapamycin molecule glues two proteins together - FKBP12 and mTOR's FRB domain - by plugging into two hydrophobic pockets at once. A textbook example of a small molecule acting as 'molecular glue' to force protein dimerization. |
| 1994 | M | RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs SAB1994 Discovery of the protein RAFT1 (today's mTOR) as the direct target of the FKBP12-rapamycin complex; founding paper of the entire mTOR field. |
| 1991 | M | Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast HEI1991 Discovery of the TOR1 and TOR2 genes in yeast as the targets whose disruption causes rapamycin's cell-cycle-arresting toxicity - the original genetic identification of the TOR pathway. |
| 1975 | M | Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle VEZ1975 The original isolation of rapamycin from a soil bacterium found on Easter Island, discovered first as an antifungal compound decades before its mTOR-inhibiting mechanism was known. |
| 2024 | PP | Targeting mTOR restores tau-induced metabolic, mitochondrial, and cognitive deficits in a tauopathy mouse model TAN2024 In mice engineered to overexpress a phosphomimetic tau variant, one week of rapamycin reversed tau-driven mitochondrial dysfunction and rescued cognitive performance in the Morris water maze - extends the mTOR-autophagy-neurodegeneration link (already seen with Huntington's) to a direct tau-phosphorylation mechanism relevant to Alzheimer's. |