Loading
What changed between revision 2 and revision 3, compared over the article's markdown source with its frontmatter — so a change to status, evidence or reversibility shows up as the edit it is.
Older · revision 2
Import
Re-import of content/rapamycin.md — the file changed after the initial import. Not an edit.
12.0 kB
Revision 2
Revision 3
lines 8–18 → 8–177 unchanged lines not shown
categories: ["longevity"]categories: ["longevity"]tags: ["mtor", "aging", "drug repurposing", "autophagy", "immunosenescence", "clinical trials"]tags: ["mtor", "aging", "drug repurposing", "autophagy", "immunosenescence", "clinical trials"]summary: "A macrolide immunosuppressant that inhibits the mTOR growth pathway and extends lifespan across several laboratory species, with no confirmed effect on human aging."summary: "A macrolide immunosuppressant that inhibits the mTOR growth pathway and extends lifespan across several laboratory species, with no confirmed effect on human aging."updated: "2026-10-29"updated: "2026-11-01"humanEvidence: "No human trial has tested lifespan or healthspan; low-dose rapalogs improved influenza vaccine response in older adults, a phase 3 respiratory-illness trial failed, and every lifespan result is from mice and other laboratory species."humanEvidence: "No human trial has tested lifespan or aging; low-dose mTOR inhibitors improved flu vaccine response, a phase 3 trial of one failed, and a 48-week rapamycin trial missed its primary endpoint."access: "Approved as sirolimus for transplant rejection and available as a generic; longevity use is off-label prescribing by a minority of physicians, at doses and schedules no regulator has evaluated."access: "Approved as sirolimus for transplant rejection and available as a generic; longevity use is off-label prescribing by a minority of physicians, at doses and schedules no regulator has evaluated."reversibility: "reversible"reversibility: "reversible"issues: ["PEARL trial results are described without a citation", "The 2019 RTB101 phase 3 failure is a load-bearing claim and carries no source"]------ ```infobox```infoboxlines 35–41 → 34–4216 unchanged lines not shown
or conservation. It is one of the few compounds shown to extend lifespan in yeast, nematodes, fliesor conservation. It is one of the few compounds shown to extend lifespan in yeast, nematodes, fliesand mice, and it is the most reproducible positive result in the US National Institute on Aging'sand mice, and it is the most reproducible positive result in the US National Institute on Aging's[[interventions-testing-program|Interventions Testing Program]]. Whether it does anything for human[[interventions-testing-program|Interventions Testing Program]]. Whether it does anything for humanaging is unknown. The human trials run so far have tested immune and functional surrogates in smallaging is unknown. The lifespan evidence comes from mice. A randomized lifespan trial in pet dogs hasnot reported, and no primate survival data have been published in a peer-reviewed journal. The humantrials run so far have tested immune, body-composition and functional surrogates in smallpopulations, and the one large randomized trial of a related compound failed its primary endpoint.populations, and the one large randomized trial of a related compound failed its primary endpoint. ## How it works## How it workslines 72–138 → 73–22330 unchanged lines not shown
{ "year": "1972", "title": "Compound isolated", "text": "Researchers at Ayerst in Montreal isolate an antifungal macrolide from the sample and name it rapamycin after the island." }, { "year": "1972", "title": "Compound isolated", "text": "Researchers at Ayerst in Montreal isolate an antifungal macrolide from the sample and name it rapamycin after the island." }, { "year": "1991", "title": "TOR genes identified", "text": "Yeast mutants resistant to rapamycin reveal the TOR genes, opening the pathway to molecular study; the mammalian homologue follows in 1994." }, { "year": "1991", "title": "TOR genes identified", "text": "Yeast mutants resistant to rapamycin reveal the TOR genes, opening the pathway to molecular study; the mammalian homologue follows in 1994." }, { "year": "1999", "title": "Approved as sirolimus", "text": "The drug is approved in the United States to prevent rejection in kidney transplantation, establishing decades of human safety data at immunosuppressive doses." }, { "year": "1999", "title": "Approved as sirolimus", "text": "The drug is approved in the United States to prevent rejection in kidney transplantation, establishing decades of human safety data at immunosuppressive doses." }, { "year": "2009", "title": "Lifespan extension in mice", "text": "The Interventions Testing Program reports that rapamycin started at 600 days of age extends median lifespan in genetically heterogeneous mice of both sexes." }, { "year": "2009", "title": "Lifespan extension in mice", "text": "The Interventions Testing Program reports that rapamycin started at 600 days of age extends median and maximal lifespan in genetically heterogeneous mice of both sexes." }, { "year": "2014", "title": "Immune benefit in older adults", "text": "A rapalog given at low dose for six weeks improves antibody response to influenza vaccination in adults over 65." }, { "year": "2014", "title": "Immune benefit in older adults", "text": "The rapalog everolimus, given at low dose for six weeks, raises antibody response to influenza vaccination in older volunteers by about 20%." }, { "year": "2019", "title": "Phase 3 failure", "text": "resTORbio's RTB101 does not reduce clinically symptomatic respiratory illness in older adults, ending the most advanced attempt to license an mTOR inhibitor for an aging-related indication." }, { "year": "2017", "title": "First dog trial", "text": "A ten-week placebo-controlled pilot in 24 middle-aged companion dogs reports no clinical side effects and improved echocardiographic measures." }, { "year": "2024", "title": "First dedicated longevity RCT reported", "text": "The PEARL trial of intermittent rapamycin in healthy adults reports tolerability and scattered secondary signals, without a clinical benefit." } { "year": "2019", "title": "Phase 3 failure", "text": "resTORbio's RTB101, a TORC1 inhibitor distinct from rapamycin, does not reduce clinically symptomatic respiratory illness in adults 65 and older, and the company stops developing it for that indication." }, { "year": "2024", "title": "Dog trial refunded", "text": "After the Dog Aging Project's main federal grant is not renewed, a separate NIH grant from December 2024 funds the TRIAD rapamycin trial through November 2029." }, { "year": "2025", "title": "PEARL results published", "text": "The 48-week PEARL trial of weekly compounded rapamycin in healthy adults misses its primary endpoint, visceral fat, with improvements in a few secondary measures in subgroups." }]]`````` ## Evidence in animals## Evidence in animals The mouse result is unusually robust. In the ITP, rapamycin extended median and maximal lifespan### Miceeven when treatment began at an age equivalent to human late middle age,[^harrison2009] and theeffect has been replicated across ITP cohorts and sites, a standard the field rarely meets. Higherdoses produce larger effects, and females generally respond more strongly, a sex difference that hasnever been fully explained.[^miller2014] Lifespan is not the same as [[healthspan]]. Treated mice show delayed decline in several tissues,The mouse result is unusually robust. In the ITP's 2009 study, genetically heterogeneous mice fedincluding reduced accumulation of [[cellular-senescence|senescent cells]] and better maintenance ofencapsulated rapamycin from 600 days of age, which the authors equate roughly to a 60-year-oldimmune and cognitive function, but other age-related pathologies proceed unchanged. Rapamycin doesperson, lived longer at all three test sites. Age at 90% mortality, the study's measure of maximalnot produce the uniform rejuvenation across the [[hallmarks-of-aging]] that popular accounts imply.lifespan, rose by 14% in females and 9% in males, and mean lifespan by 13% and 9%.[^harrison2009]The most informative test underway outside the laboratory is in companion dogs, where the Dog AgingWhen later cohorts started at 9 months, the effect grew with dose. At 42 ppm, three times theProject's randomized trial tests cardiac and cognitive outcomes over years. An earlier ten-week pilotoriginal dose, median lifespan rose by 23% in males and 26% in females, and females gained more thanreported improved echocardiographic measures, and the programme's funding was disrupted in 2024. A separatemales at every dose, which the authors suggested may reflect higher blood levels of the drug incommercial effort, [[loyal]], is pursuing canine lifespan drugs with other mechanisms through thefemales.[^miller2014] A 2020 study starting at 20 months found that a schedule of one month on andveterinary regulator. In common marmosets, daily dosing has been reported as well tolerated, with noone month off also extended survival in both sexes, though less than continuous dosing in females,established lifespan effect.while a single three-month course helped males only.[^strong2020] The programme's methods and otherresults are covered under [[interventions-testing-program]]. Lifespan is not the same as [[healthspan]], and neither is the same as slower aging. In the 2009study, treated mice died of the same pattern of diseases as controls.[^harrison2009] Late-lifetreatment has improved some functions; three months of rapamycin in 24-month-old female micereversed or attenuated age-related changes in heart function.[^flynn2013] But a broad phenotypingstudy in male mice found that rapamycin extended lifespan while improving few of the aging traitsmeasured, and several of the traits it did change shifted in young mice too, which the authors readas drug effects unrelated to aging itself.[^neff2013] Rapamycin does not produce the uniformrejuvenation across the [[hallmarks-of-aging]] that popular accounts imply. ### Dogs The first randomized dog study, a [[dog-aging-project|Dog Aging Project]] pilot published in 2017,gave 24 healthy middle-aged dogs a non-immunosuppressive dose of rapamycin or placebo for ten weeks.Treated dogs showed no clinical side effects compared with placebo, echocardiography suggestedimprovement in age-related measures of heart function, and mean red-cell volume fell.[^urfer2017] Thepilot did not measure lifespan. The decisive test is TRIAD, the Test of Rapamycin In Aging Dogs, a double-masked, placebo-controlledmulticentre trial whose investigators describe it as the first rigorous test of a drug againstbiological aging, with lifespan and healthspan endpoints, outside the laboratory in anyspecies.[^coleman2025] Its grant plans 580 companion dogs given 0.15 mg/kg of rapamycin or placeboonce a week for one year and followed for two more. The first aim is lifespan and the incidence ofage-related disease, and a second covers physical, neurological and cardiac function; 150dogs were enrolled when the grant was written.[^nih2024] The trial's completion was in doubt afterthe National Institute on Aging declined to renew the Dog Aging Project's main grant, as reported inJanuary 2024,[^stat2024] and a separate NIH award starting in December 2024 now funds it through November2029.[^nih2024] As of November 2026 TRIAD had not reported efficacy results, so there is not yet anydog evidence that rapamycin extends lifespan. A separate commercial effort, [[loyal]], is pursuingcanine lifespan drugs with other mechanisms through the veterinary regulator. ### Non-human primates Primate work has centred on the common marmoset, a small monkey short-lived enough for a survivalstudy. In the first report, encapsulated rapamycin given orally at roughly 1 mg/kg a day producedtrough blood levels averaging 5.2 ng/mL, which the authors placed within the therapeutic range forhumans. Over 14 months they saw no clinical anaemia, lung fibrosis or mouth ulcers, and theydescribed the drug as well tolerated.[^tardif2015] Later reports from the same San Antonio groupfound only minor metabolic effects, with no significant change in glucose tolerance or bloodlipids,[^ross2015] and only minor changes in blood counts after nine months of daily treatment inmiddle-aged animals.[^sills2019] The tissue results are mixed. A 2026 study associated chronic treatment with partial preservation ofsalivary-gland structure and fewer senescent cells in the gland.[^abdulazees2026] A preprint foundthat treatment from about mid-life did not change age-related osteoarthritis severity on imaging butincreased meniscus calcification, particularly in females.[^minton2025] Epigenetic clocks built formarmosets detected no significant effect of rapamycin on the epigenetic age of blood.[^horvath2021] The group began a lifespan study and reported in 2019 that, more than three years into treatment, itwas starting to assess longevity.[^salmon2019] In a 2024 radio interview the study's leader, AdamSalmon, said the treated animals were living longer and called it "the first non-human primate studyshowing a drug intervention-increased lifespan".[^petrie2025] As of November 2026 no survival datafrom the study had appeared in a peer-reviewed journal, so the claim cannot yet be assessed. Norhesus macaque lifespan result for rapamycin has been reported either. ## Human evidence## Human evidence No trial has tested whether rapamycin changes how long people live or how long they stay healthy.No trial has tested whether rapamycin changes how long people live or how long they stay healthy.The human evidence that exists falls into three groups.The human evidence that exists falls into four groups. The first is decades of transplant experience, which establishes the safety profile atThe first is decades of transplant experience, which establishes the safety profile atimmunosuppressive doses: stomatitis and mouth ulcers, raised blood lipids, impaired glucoseimmunosuppressive doses: stomatitis and mouth ulcers, raised blood lipids, impaired glucosehandling, delayed wound healing, oedema and increased infection risk. Geroscience does not proposehandling, delayed wound healing, oedema and increased infection risk. Geroscience does not proposeto use these doses.to use these doses. The second is immune-function work at low or intermittent doses. Rapalog treatment improvedThe second is immune-function work at low or intermittent doses, mostly with drugs related toinfluenza vaccine responses in older adults[^mannick2014] and, in a follow-up combination study, wasrapamycin. Six weeks of the rapalog everolimus raised influenza vaccine response in older volunteersassociated with fewer reported respiratory infections. Those results gave the field its most citedby about 20%.[^mannick2014] In a 2018 phase 2a trial in 264 older adults, a low-dose combination ofparadox: a drug classed as an immunosuppressant appeared to improve some aspects of immune functioneverolimus and the catalytic inhibitor BEZ235 was associated with fewer reported infections over thein the old, plausibly by reducing the accumulation of exhausted and senescent lymphocytes that alsofollowing year.[^mannick2018] Those results gave the field its most cited paradox: a drug classed asdrives [[inflammaging]]. The later phase 3 trial of RTB101 failed, the strongest single piece ofan immunosuppressant appeared to improve some aspects of immune function in the old, plausibly bynegative human evidence about the strategy.reducing the accumulation of exhausted and senescent lymphocytes that also drives [[inflammaging]]. The third is the PEARL trial, a decentralized, placebo-controlled study of weekly rapamycin inA later developer, resTORbio, renamed BEZ235 as RTB101 and took it into larger trials. In a phase 2bhealthy adults over 48 weeks. It reported no serious adverse events and a small number of favourabletrial of 652 participants, the first prespecified analysis, of RTB101 combined with everolimus,secondary measures, with most prespecified outcomes unchanged. It was neither designed nor poweredmissed significance, while a second analysis pooling both parts found fewer laboratory-confirmed respiratory infections with 10 mg dailyto detect a change in aging.(19% of patients) than with placebo (28%). The phase 3 PROTECTOR 1 trial in 1,024 adults aged 65 andolder then found no reduction in clinically symptomatic respiratory illness: 26% of patients onRTB101 had one, against 25% on placebo.[^mannick2021] The company announced the failure on 15November 2019 and stopped developing the drug for that indication.[^restorbio2019] RTB101 is notrapamycin, so the failure does not test rapamycin itself. The third is the PEARL trial, run by the telemedicine company AgelessRx. Adults aged 50 to 85received placebo or 5 mg or 10 mg of compounded rapamycin weekly for 48 weeks. Among the 114 whocompleted it, the primary outcome, visceral fat, did not change significantly, and adverse and serious adverseevents were similar across groups. Lean tissue mass and self-reported pain improved in women on 10mg, and self-reported emotional well-being and general health in the 5 mg group; no other effectswere significant. Midway through, the investigators learned that the compounded drug might be poorly absorbed; it waslater found to reach about a third of the blood concentration of the commercial formulation, the 10 mg group contained only eightwomen, and the authors were employees and shareholders of AgelessRx.[^moel2025] The fourth is a small trial of functional outcomes. In a 2026 exploratory trial, 40 sedentary adultsaged 65 to 85 took 6 mg of sirolimus or placebo weekly for 13 weeks alongside home exercise. The drugdid not improve the exercise gains, sensitivity analyses favoured placebo, and although 17 participants ineach arm reported an adverse event, the sirolimus group had more events in total (99 against 63),including one possibly drug-related serious adverse event, a pneumonia.[^stanfield2026] > [!caution] Off-label use runs ahead of evidence> [!caution] Off-label use runs ahead of evidence> A minority of physicians prescribe rapamycin off-label for longevity, and a self-selected> A minority of physicians prescribe rapamycin off-label for longevity, and a self-selected> community of users takes it. Surveys of that population report a tolerable side-effect profile at> community of users takes it. In a 2023 survey of 333 adults with a history of off-label use, about> intermittent doses, but self-reported outcomes from people who chose the drug cannot establish> nine in ten current users took it once a week, and mouth ulceration was the only condition reported> benefit, and no dose, schedule or monitoring standard has been validated for healthy adults.> significantly more often than by 172 non-users. The authors themselves note that self-reported data> from a possibly self-selected group are less reliable than a randomized trial.[^kaeberlein2023] No> dose, schedule or monitoring standard has been validated for healthy adults. > [!debate] What the record does not show> Popular claims that drugs such as rapamycin can hold people at a fixed biological age go well> beyond the evidence. In mice, the best-studied mammal, rapamycin lengthens life, but treated mice still die> of the same pattern of diseases as untreated ones,[^harrison2009] and in one broad study it> improved few of the aging traits measured.[^neff2013] The one dog> lifespan trial has not reported, no primate survival result has been peer-reviewed, the marmoset> clock analysis detected no significant change in epigenetic age, and no human trial has measured aging or lifespan> as an outcome. ## Limitations## Limitations The question of dose and schedule is unresolved. Animal lifespan data come from continuous exposureThe question of dose and schedule is unresolved. Most animal lifespan data come from continuousat concentrations that would be immunosuppressive in humans, while the human longevity communitydietary exposure, and the ITP's intermittent test alternated whole months on and off theuses weekly pulses chosen largely by inference from mTORC2 pharmacology. Nobody knows whether thedrug.[^strong2020] Most surveyed off-label users take a single weekly dose,[^kaeberlein2023] apulsed schedule keeps the effect that the continuous schedule produced in mice.schedule chosen largely by inference from mTORC2 pharmacology. Nobody knows whether the weekly pulsekeeps the effect that continuous dosing produced in mice. The endpoint question is harder still. No regulator accepts a measure ofThe endpoint question is harder still. No regulator accepts a measure of[[aging-biomarkers|biological aging]] as a surrogate, so a trial would have to be powered on disease[[aging-biomarkers|biological aging]] as a surrogate, so a trial would have to be powered on diseaselines 162–167 → 247–25423 unchanged lines not shown
- [[autophagy]]- [[autophagy]]- [[caloric-restriction]]- [[caloric-restriction]]- [[dog-aging-project]]- [[interventions-testing-program]]- [[metformin]]- [[metformin]]- [[senolytics]]- [[senolytics]]- [[geroscience-hypothesis]]- [[geroscience-hypothesis]]lines 175–179 → 262–2877 unchanged lines not shown
[^lamming2012]: `paper` Lamming, D.W. et al. "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity." *Science*, 2012.[^lamming2012]: `paper` Lamming, D.W. et al. "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity." *Science*, 2012.[^harrison2009]: `paper` Harrison, D.E. et al. "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice." *Nature*, 2009. {The Interventions Testing Program ran this at three sites in genetically heterogeneous mice; dosing was continuous in food, not the intermittent schedule people take off-label.}[^harrison2009]: `paper` Harrison, D.E. et al. "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice." *Nature*, 2009. {The Interventions Testing Program ran this at three sites in genetically heterogeneous mice; dosing was continuous in food, not the intermittent schedule people take off-label.}[^miller2014]: `paper` Miller, R.A. et al. "Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction." *Aging Cell*, 2014.[^miller2014]: `paper` Miller, R.A. et al. "Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction." *Aging Cell*, 2014.[^strong2020]: `paper` Strong, R. et al. "Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects." *Aging Cell* 19:e13269, 2020. https://doi.org/10.1111/acel.13269 {The authors note that differences in pre-treatment weight gain, linked to food from two suppliers, complicate interpretation.}[^flynn2013]: `paper` Flynn, J.M. et al. "Late-life rapamycin treatment reverses age-related heart dysfunction." *Aging Cell* 12(5):851-862, 2013. https://doi.org/10.1111/acel.12109[^neff2013]: `paper` Neff, F. et al. "Rapamycin extends murine lifespan but has limited effects on aging." *Journal of Clinical Investigation* 123(8):3272-3291, 2013. https://doi.org/10.1172/JCI67674 {Male C57BL/6J mice of a single inbred strain, not the genetically heterogeneous mice the ITP uses.}[^urfer2017]: `paper` Urfer, S.R. et al. "A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs." *GeroScience* 39(2):117-127, 2017. https://doi.org/10.1007/s11357-017-9972-z {Ten weeks of dosing in 24 dogs; it measured heart function and blood values, not lifespan.}[^coleman2025]: `paper` Coleman, A.E., Creevy, K.E. et al. "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." *GeroScience* 47(3):2851-2877, 2025. https://doi.org/10.1007/s11357-024-01484-7 {A design paper; it reports no outcome data.}[^nih2024]: `report` National Institutes of Health. RePORTER project record R01AG090843, "Test of Rapamycin in Aging Dogs (TRIAD)", Texas A&M AgriLife Research, project period December 2024 to November 2029. {Enrolment, dosing and endpoint figures come from the grant abstract, not from published results.}[^stat2024]: `news` Balthazar, D. "As NIH grant runs out, Dog Aging Project founders look to raise up to $50 million." *STAT*, 24 January 2024. https://www.statnews.com/2024/01/24/dog-aging-project-founders-on-losing-nih-funding/[^tardif2015]: `paper` Tardif, S. et al. "Testing efficacy of administration of the antiaging drug rapamycin in a nonhuman primate, the common marmoset." *Journals of Gerontology: Series A* 70(5):577-587, 2015. https://doi.org/10.1093/gerona/glu101 {A dosing and tolerability study with a 3-week and a 14-month arm; it was not designed to measure lifespan.}[^ross2015]: `paper` Ross, C. et al. "Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus)." *Aging (Albany NY)* 7(11):964-973, 2015. https://doi.org/10.18632/aging.100843[^sills2019]: `paper` Sills, A.M. et al. "Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets." *American Journal of Primatology* 81(2):e22927, 2019. https://doi.org/10.1002/ajp.22927[^abdulazees2026]: `paper` Abdul-Azees, P.A. et al. "Rapamycin Attenuates Age-Related Changes in Marmoset Submandibular Gland: A Non-Human Primate Model of Human Oral Aging." *Aging and Disease*, 2026. https://doi.org/10.14336/AD.2026.0057[^minton2025]: `preprint` Minton, D.M. et al. "Inhibition of mTORC1 by rapamycin results in feedback activation of Akt(S473) and aggravates hallmarks of osteoarthritis in female mice and non-human primates." *bioRxiv*, version of March 2025. https://doi.org/10.1101/2024.05.14.594256[^horvath2021]: `paper` Horvath, S. et al. "DNA methylation age analysis of rapamycin in common marmosets." *GeroScience* 43(5):2413-2425, 2021. https://doi.org/10.1007/s11357-021-00438-7[^salmon2019]: `paper` Salmon, A.B. "Intervention with rapamycin to improve healthy aging and longevity in a non-human primate." *Innovation in Aging* 3(Suppl 1):S108, 2019. https://doi.org/10.1093/geroni/igz038.403 {A conference abstract from the Gerontological Society of America 2019 meeting, not a full paper.}[^petrie2025]: `news` Petrie, B. "Science & Medicine: Anti-aging drug shows promise in marmosets." Texas Public Radio, 30 March 2025. https://www.tpr.org/podcast/petrie-dish/2025-03-30/science-medicine-anti-aging-drug-shows-promise-in-marmosets {A radio interview first broadcast on 28 July 2024; it gives no survival figures or sample sizes.}[^mannick2014]: `paper` Mannick, J.B. et al. "mTOR inhibition improves immune function in the elderly." *Science Translational Medicine*, 2014. {The drug tested was the rapalog everolimus rather than rapamycin, and the endpoint was antibody titre after influenza vaccination rather than any infection outcome.}[^mannick2014]: `paper` Mannick, J.B. et al. "mTOR inhibition improves immune function in the elderly." *Science Translational Medicine*, 2014. {The drug tested was the rapalog everolimus rather than rapamycin, and the endpoint was antibody titre after influenza vaccination rather than any infection outcome.}[^mannick2018]: `paper` Mannick, J.B. et al. "TORC1 inhibition enhances immune function and reduces infections in the elderly." *Science Translational Medicine* 10(449):eaaq1564, 2018. https://doi.org/10.1126/scitranslmed.aaq1564 {A phase 2a trial; infections were self-reported by participants over the following year.}[^mannick2021]: `paper` Mannick, J.B. et al. "Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials." *Lancet Healthy Longevity* 2(5):e250-e262, 2021. https://doi.org/10.1016/S2666-7568(21)00062-3 {Peer-reviewed report of both trials; six of the eight authors were employees of resTORbio, which made RTB101.}[^restorbio2019]: `statement` resTORbio, Inc. "resTORbio Announces That the Phase 3 PROTECTOR 1 Trial of RTB101 in Clinically Symptomatic Respiratory Illness Did Not Meet the Primary Endpoint." Press release filed as Exhibit 99.1 to Form 8-K, US SEC, 15 November 2019. https://www.sec.gov/Archives/edgar/data/1720580/000119312519292868/d832662dex991.htm[^moel2025]: `paper` Moel, M. et al. "Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results." *Aging (Albany NY)* 17(4):908-936, 2025. https://doi.org/10.18632/aging.206235 {Registered as NCT04488601; the analysis covers only the 114 participants who completed the trial.}[^stanfield2026]: `paper` Stanfield, B. et al. "Exercise and Weekly Sirolimus (Rapamycin) in Older Adults: RAPA-EX-01 Randomised, Double-Blind, Placebo-Controlled Trial." *Journal of Cachexia, Sarcopenia and Muscle* 17(2):e70274, 2026. https://doi.org/10.1002/jcsm.70274 {An exploratory trial; the primary intention-to-treat difference was not statistically significant.}[^kaeberlein2023]: `paper` Kaeberlein, T.L. et al. "Evaluation of off-label rapamycin use to promote healthspan in 333 adults." *GeroScience* 45(5):2757-2768, 2023. https://doi.org/10.1007/s11357-023-00818-1 {An online survey of users and non-users, not a trial; several authors prescribe rapamycin or work for AgelessRx.} removed, struck through added, underlinedLine numbers count the serialised markdown of each revision, frontmatter included.
137 lines are the same in both revisions, and 83 of them are not shown. Neither revision here is necessarily the current article — read Rapamycin for the text this wiki stands behind today.