Rapamycin Sirolimus between ITP mouse lifespan and the thinner human healthy-aging record
Rapamycin — sirolimus in the pharmacopoeia, a macrolide first isolated from a Streptomyces hygroscopicus culture recovered from Easter Island soil — is an approved immunosuppressant that became, almost by accident of mechanism, the small molecule with the strongest lifespan-extension package in mammalian aging science. The National Institute on Aging’s Interventions Testing Program has now shown it extends median lifespan in genetically heterogeneous mice across three independent cohorts and multiple starting ages. Human evidence sits on a different footing: vaccine-response and infection trials in older adults, a companion-dog safety programme, and a 2025 decentralized trial called PEARL together sketch tolerability and some healthspan metrics, not a demonstrated human lifespan effect. This monograph, compiled after the 8 August 2026 longevity harvest, keeps that asymmetry in view from the first page to the last. It is not a transplant-medicine textbook, it does not evaluate off-label consumer compounding, and it recommends no human use, dose, route or schedule for any person.
01An antifungal from an island expedition
In 1964, the Medical Expedition to Easter Island (METEI) — a Canadian-led survey studying the health of a population about to receive its first airport and, with it, greatly increased contact with the outside world — collected soil samples across Rapa Nui as a matter of ordinary microbiological cataloguing. One sample, cultured years later at the Ayerst Research Laboratories in Montreal, yielded a strain of Streptomyces hygroscopicus that produced a novel macrocyclic compound. Company chemist Surendra Nath Sehgal isolated and characterized it, and it was assigned the laboratory designation AY-22989 before receiving the name rapamycin, after Rapa Nui (Sehgal, 2003; Samanta, 2017). Sehgal’s own 2003 account, written as a plenary contribution to a transplantation-medicine symposium, frames the discovery in exactly these terms: a fermentation product isolated from a soil actinomycete, screened first for antifungal activity against Candida albicans, and only later recognized to have a second and much more consequential biological property (Sehgal, 2003).
That second property was immunosuppression. Ayerst’s pharmacology group found that rapamycin blocked lymphocyte proliferation with a potency that made it a serious candidate transplant drug, structurally and mechanistically distinct from cyclosporine and tacrolimus even though all three ultimately depend on immunophilin binding. Development nonetheless nearly ended when Ayerst’s parent company closed the Montreal research site in the late 1980s as part of a broader pharmaceutical divestment. The frequently repeated account — that Sehgal personally preserved frozen cultures and extract of the compound through that shutdown and a subsequent corporate reorganization, and continued to advocate for the programme until it was picked up again — is treated in secondary biographical sources as essentially accurate, and it is why Sehgal is now credited as rapamycin’s discoverer in an unusually personal sense rather than merely as the scientist whose name is first on the isolation paper (Samanta, 2017). Wyeth, which had absorbed Ayerst, carried sirolimus through renal-transplant trials in the 1990s, and the U.S. Food and Drug Administration approved it under the trade name Rapamune in 1999 for prophylaxis of organ rejection in kidney transplantation. That remains, in a strict regulatory sense, what rapamycin is approved to do. Everolimus, a hydroxyethyl derivative of rapamycin developed by Novartis, followed with its own approvals in transplantation and, later, in selected oncology indications; it is discussed throughout this monograph as a related but non-identical clinical comparator, not as rapamycin under another name.
02Naming the target: mTOR and the biology of nutrient sensing
Rapamycin is useful to aging science because of what it inhibits, not because of where it was found. Its molecular target — identified through yeast genetics and mammalian biochemistry in the early-to-mid 1990s and named, somewhat literally, the mechanistic (originally "mammalian") target of rapamycin, or mTOR — sits at the centre of a signaling network that integrates amino acid availability, growth factor signaling, cellular energy status and oxygen tension into a single output: whether a cell should grow, divide and synthesize new protein, or conserve resources and turn on self-clearance programmes such as autophagy. Rapamycin does not bind mTOR directly. It first forms a complex with the intracellular protein FKBP12, and that complex then binds and partially inhibits mTOR complex 1 (mTORC1), one of two distinct multiprotein assemblies built around the mTOR kinase. mTORC1 inhibition downregulates ribosomal protein S6 kinase (S6K1) and relieves repression of eukaryotic translation initiation factor 4E-binding protein (4E-BP1), the combined effect of which is a broad, if incomplete, brake on cap-dependent protein synthesis and cell growth, alongside induction of autophagy (Mannick and Lamming, 2023).
That the same pathway sits downstream of insulin/IGF-1 signaling, upstream of ribosomal biogenesis, and central to the decision between growth and maintenance is precisely why mTOR became a leading candidate "hub" in geroscience’s hallmarks-of-aging framework well before rapamycin itself had produced a single mouse lifespan paper. Reviews of the mTOR-inhibitor literature for aging synthesize a considerable comparative and cross-species biology — from budding yeast replicative lifespan to Drosophila, C. elegans and rodent models — in which reduced mTORC1 signaling associates with extended lifespan across a wide taxonomic range, a consistency that is part of why the pathway drew serious attention even before the mouse data existed (Mannick and Lamming, 2023). None of that comparative biology is itself a human outcome; it is the mechanistic case that made the mouse experiments in Part Two worth funding in the first place.
03Identity discipline for this monograph
Three identity distinctions recur through this document and are stated once here rather than repeated at every mention. First, rapamycin and sirolimus are the same molecule under two names — the generic pharmaceutical name and the earlier laboratory/trade designation — and this monograph uses them interchangeably as the source material does. Second, everolimus is a related but structurally and pharmacokinetically distinct rapalog; where a cited human trial used everolimus, low-dose everolimus, or the resTORbio compound RTB101 rather than rapamycin itself, that fact is stated in the sentence reporting the result, because none of these compounds automatically inherits another’s data. Third, "geroscience" claims made by researchers, advocacy organizations, or crowdfunded-trial sponsors about rapamycin’s promise are kept in a separate register from peer-reviewed experimental results; Part Five names that lane explicitly, including the one place where a now-prominent longevity researcher’s own laboratory work sits inside the peer-reviewed animal record discussed in Part Two.
04The Interventions Testing Program and why it matters here
Most putative longevity compounds have never been tested for lifespan effect in a design built to resist the false positives that plague small single-site aging studies. Rapamycin has. The National Institute on Aging’s Interventions Testing Program (ITP), established in 2003, tests candidate compounds simultaneously in genetically heterogeneous UM-HET3 mice at three independent sites — The Jackson Laboratory, the University of Michigan, and the University of Texas Health Science Center at San Antonio — using a shared protocol, common diet, and prespecified statistical analysis, precisely so that a result at one site cannot by itself establish an effect (Miller et al., 2007, PMID 17578509). That design is why the ITP’s rapamycin results carry more evidentiary weight than most of the mouse literature discussed anywhere else in the geroscience field, and why this monograph treats them as the anchor of the animal record rather than as one line in a literature review.
05Harrison 2009: late-life feeding extends both sexes’ median lifespan
The ITP’s first rapamycin cohort, reported by Harrison and colleagues in Nature in 2009 (PMID 19587680), produced a result that surprised much of the field for a specific technical reason: dosing did not begin until 600 days of age, roughly analogous to late middle age in a human lifespan, because a microencapsulated, enteric-delivered formulation of rapamycin sufficient for chronic oral dosing in mice had only become available at that point in the study. A treatment starting that late, in animals that had already lived past the median age at which control mice typically begin dying, was not expected by many aging researchers to move lifespan at all; late-life interventions in prior literature had a poor track record. Fed from roughly 600 days onward, rapamycin nonetheless increased median lifespan in both female and male mice across all three ITP test sites, with pooled estimates of increases in median survival on the order of 9 percent in males and 13 percent in females relative to control diet, alongside deferred hazard of death at the oldest ages tested (Harrison et al., 2009). Two features of this result functioned as immediate mechanistic and translational signals in the field: an effect this large from a treatment begun so late in life for one, and a benefit visible in both sexes for another, since many single-sex lifespan effects in prior rodent interventions had not generalized across sex.
06Later ITP cohorts: dose-response and sex-dependent effects
A subsequent ITP cohort, reported by Miller and colleagues in 2014, extended the encapsulated-rapamycin protocol to a range of doses and found that the lifespan benefit was both dose-dependent and sex-dependent: higher tested doses generally produced larger median-lifespan gains, and female mice showed a measurably different dose-response relationship than males, with effects that were also metabolically distinct from those produced by classic caloric restriction in parallel cohorts (Miller et al., 2014, PMID 24341993). That dose-response and sex-interaction finding addressed a natural question raised by the 2009 result — whether the effect was a narrow artifact of one dose and one dietary formulation — by showing that the benefit scaled in a pharmacologically coherent way across a range of exposures. Taken together, the ITP cohorts constitute, by a considerable margin, the most rigorously replicated lifespan-extension finding in mammalian pharmacology to date: an effect reproduced across three independent test sites, multiple starting ages, both sexes, and a range of doses, using a shared genetically heterogeneous mouse stock chosen specifically to resist the strain-specific artifacts that undermined earlier single-strain rodent longevity claims.
07What the mouse record does and does not establish
The ITP data establish, with unusual rigor for this field, that pharmacological mTORC1 inhibition by enteric rapamycin extends median and, in most cohorts, maximum lifespan in a genetically heterogeneous mouse population, across a range of starting ages and doses, in both sexes. They do not establish a mechanism of action sufficient to predict effect size in humans, a dose translatable across species by simple weight-based scaling, an effect on human mortality, or safety at any human-relevant chronic exposure. Interventions Testing Program compounds are, deliberately, screened without a specific mechanistic hypothesis about magnitude in mind; the programme’s purpose is empirical replication under adversarial conditions, and it has, in parallel work not detailed here, tested and found several other candidate geroprotectors — including compounds with strong prior mechanistic rationale — to show no lifespan benefit or even harm in the same UM-HET3 model. Rapamycin’s consistency across independent ITP cohorts is precisely why the compound, rather than most other geroscience candidates, was the one that moved into human trials at all; it is not, by itself, a reason to expect a comparable percentage gain in human median survival.
08Beyond mice: companion-animal and cross-species signal
A separate translational question — whether rapamycin’s mouse effect generalizes to a naturally aging, genetically outbred, environmentally variable mammal living alongside humans — motivated the Dog Aging Project’s Test of Rapamycin in Aging Dogs (TRIAD), a University of Washington-led initiative. TRIAD is a registered, ongoing clinical trial in middle-aged and older companion dogs assessing safety, cardiac function, and functional aging measures under low-dose rapamycin exposure; as of this compilation, TRIAD has produced safety and pharmacokinetic reporting rather than a completed lifespan endpoint, because dogs’ longer observation horizon means a mortality readout will not mature for years (Dog Aging Project, TRIAD trial registration and interim reporting; peer-reviewed protocol at PMID 39951177). It is included in this monograph as an intermediate translational data point — a genetically diverse, non-laboratory mammal with a lifespan long enough to make chronic-dosing safety meaningful but short enough to be tractable within an ordinary funding cycle — not as evidence of a canine lifespan extension, which has not yet been reported.
09Why immune aging became the human entry point
No regulatory pathway exists for a "delay human aging" clinical endpoint, so the earliest human trials of mTOR-pathway inhibition in otherwise healthy older adults were built around an endpoint regulators and reviewers already understood: immune response to vaccination, a functional readout of one specific, measurable form of biological aging — immunosenescence — rather than a proxy for all-cause mortality. Novartis and, later, the biotechnology company resTORbio pursued this route using low-dose everolimus and, in resTORbio’s programme, the investigational selective TORC1 inhibitor RTB101, deliberately choosing agents and doses calibrated to partially inhibit mTORC1 without the immunosuppressive burden of transplant-level dosing. These are related but distinct compounds from rapamycin itself, a distinction this monograph maintains throughout because a positive everolimus result does not automatically transfer to rapamycin, and vice versa.
10Mannick 2014 and 2018: influenza vaccine response and respiratory infection
Mannick and colleagues reported, in Science Translational Medicine in 2014, a randomized, double-blind, placebo-controlled trial in which healthy adults aged 65 and older received a low-dose everolimus-based regimen for six weeks before seasonal influenza vaccination. The treated groups showed an improved antibody response to influenza vaccination relative to placebo, alongside evidence of reduced expression of programmed cell death-1 (PD-1) on peripheral T cells, a marker associated with T-cell exhaustion and immunosenescence (Mannick et al., 2014, PMID 25540326). A follow-up trial, published by Mannick and colleagues in 2018, tested RTB101 alone and RTB101 in combination with low-dose everolimus in adults aged 65 and older, using influenza-like illness and laboratory-confirmed respiratory infection over the following winter as endpoints; the combination arm showed a lower incidence of laboratory-confirmed respiratory tract infections relative to placebo across the two winters studied, and RTB101 alone showed benefit in one but not both cohorts, a partial and dose/agent-dependent result rather than a uniform across-the-board effect (Mannick et al., 2018, PMID 29997249). Both trials measured infection incidence and immune biomarkers over a period of months, not survival, disability, or any multi-year health outcome; they are reported here exactly as vaccine-response and respiratory-infection trials, because that is what their endpoints were.
11PEARL: a rapamycin-specific human trial reaches print in 2025
The compound actually used in the ITP mouse studies waited considerably longer for its own dedicated human trial. PEARL (Participatory Evaluation of Aging with Rapamycin Longitudinally), organized in part through crowdfunded and citizen-science channels associated with the AgelessRx telehealth platform and reported by Moel and colleagues in 2025, is a decentralized, blinded, placebo-controlled trial of low-dose rapamycin in adults, running roughly 48 weeks and assessing a battery of clinical, functional, and self-reported measures rather than a single primary aging biomarker (Moel et al., 2025, PMID 40188830; registered as NCT04488601). Its recruitment model — largely remote, self-referred participants coordinated through a telehealth-adjacent platform rather than an academic medical center — represents a departure from the trial architecture of the earlier Novartis/resTORbio studies, and that departure carries both an access advantage, in that it reached a broader and more diverse self-selected population than a single-site academic trial typically would, and a rigor cost, in adherence verification, dosing confirmation, and outcome ascertainment that are more straightforward to control inside a conventional academic trial infrastructure. PEARL’s published 2025 report addresses safety, tolerability and a set of exploratory functional and quality-of-life outcomes over the trial’s roughly year-long window; it is not powered as, framed as, or reported as a mortality or lifespan trial, and this monograph does not treat it as one. A related registered comparator, the Everolimus Aging Study (EVERLAST, NCT05835999), extends the low-dose-everolimus line of inquiry into similar safety and functional-outcome territory and is cited here only for trial-registry context, not as a completed result.
12Safety signal across the human record
Across the everolimus, RTB101, and rapamycin human trials assembled in this section, the safety profile reported at the low, intermittent, partial-mTORC1-inhibition doses studied has differed materially from the profile associated with continuous, high-dose rapamycin/everolimus used chronically in organ-transplant medicine, where infection risk, impaired wound healing, dyslipidemia, and mouth ulcers are well-characterized, labeled adverse effects. Mannick and colleagues reported that low-dose, intermittent everolimus/RTB101 dosing in their trials did not reproduce the full transplant-dose adverse-effect burden, though mouth ulcers and other mild adverse events occurred at higher rates than placebo in some cohorts (Mannick et al., 2014, PMID 25540326; Mannick et al., 2018, PMID 29997249). PEARL’s 2025 report similarly frames its safety findings around a lower-dose, intermittent regimen distinct from transplant-level chronic dosing (Moel et al., 2025, PMID 40188830). None of this human safety reporting establishes long-term safety over years of use in a healthy population outside a trial, and none of it is a substitute for a clinician-supervised evaluation of any individual person’s risk; this monograph does not recommend dosing of any kind for any reader.
13What has not yet been run
As of this compilation, no completed, adequately powered, prospective randomized controlled trial in humans has used all-cause mortality, multi-year composite frailty, or a validated biological-age endpoint as its primary outcome for rapamycin itself. The TAME (Targeting Aging with Metformin) trial design, discussed further as a metformin-specific case study in the companion metformin monograph in this series, illustrates the scale of infrastructure such a trial would require even for a far cheaper and more extensively human-used compound than rapamycin; no comparably resourced rapamycin equivalent has been funded and completed at the time of this document’s compilation (American Federation for Aging Research, TAME trial programme page, secondary status communication). That absence is treated in Part Five of this monograph as a named evidence gap rather than elided.
14Regulatory status: approved for one indication, not another
Sirolimus (Rapamune) carries FDA approval for prophylaxis of organ rejection in renal transplantation, and label information for that indication documents a substantial adverse-effect profile at the chronic, continuous, immunosuppressive doses used in transplant medicine, including increased infection risk, impaired wound healing, hyperlipidemia, thrombocytopenia, interstitial lung disease in rare cases, and boxed-warning context specific to transplant pharmacology (U.S. Food and Drug Administration, approved labeling context for sirolimus and everolimus). Everolimus carries separate approvals in oncology and tuberous sclerosis complex alongside its transplant indication; those are not aging approvals either. No regulatory authority has approved sirolimus, everolimus, or any rapalog for an anti-aging, longevity, or healthspan-extension indication in any jurisdiction as of this compilation, and no such application is publicly known to be under active review with a completed pivotal trial behind it. The compound’s presence in geroscience research, in the ITP portfolio, and in decentralized trials such as PEARL reflects active investigational use, not a change in its approved label.
15Chemical identity and quality-control anchors
Sirolimus is registered in PubChem (CID 5284616) with a molecular formula of C₃₃H₃₉NO₁₃ and a molecular weight of approximately 914.2 g/mol, consistent with its structure as a 31-membered macrocyclic triene lactone bearing a pipecolic acid-derived amide and a cyclohexyl-methoxy substituent, features that underlie both its immunophilin-binding chemistry and its comparatively poor aqueous solubility (National Center for Biotechnology Information, PubChem Compound Summary for CID 5284616). Everolimus is registered separately (PubChem CID 6442177) as the 40-O-(2-hydroxyethyl) derivative of sirolimus, a modification that improves oral bioavailability and shortens half-life relative to the parent molecule, part of why the two compounds are dosed and studied differently rather than treated as interchangeable. Regulatory-grade sirolimus and everolimus formulations used in the transplant and oncology trials cited in this monograph were manufactured under pharmaceutical good-manufacturing-practice standards with defined purity specifications; that standard does not automatically extend to non-pharmaceutical "research chemical" material sold outside a licensed supply chain, and this monograph takes no position on, and provides no guidance regarding, sourcing outside a licensed pharmacy or clinical trial.
16The "rapamycin plus metformin" and broader stacking question
A recurring claim in longevity-community discussion holds that rapamycin and metformin, or rapamycin and other geroprotector candidates, produce additive or synergistic lifespan benefit when combined, sometimes citing preclinical factorial studies from the ITP or related academic groups. Some ITP and academic rodent work has indeed tested rapamycin in combination with other agents, including metformin, and has in specific cohorts reported combination effects that differ from either agent alone; those results are mouse factorial data, generated under a specific diet, dose, genetic background, and starting age, and this monograph does not extrapolate them into a human combination recommendation. No adequately powered human factorial trial testing rapamycin plus metformin, or rapamycin plus any other candidate geroprotector, against either agent alone and against placebo, has been completed and published as of this compilation. In the absence of such a trial, a claim that combining these compounds produces additive human benefit is, under the evidence standard this monograph applies throughout, unsupported, regardless of how plausible the combined mechanism sounds or how consistently individual community anecdotal reports describe subjective effects. This monograph recommends no stacking, dosing, or combination protocol for any reader.
17Autophagy, senescence, and the limits of the mechanistic story
Beyond translational suppression, mTORC1 inhibition by rapamycin upregulates autophagy, the lysosomal self-digestion pathway implicated across the hallmarks-of-aging literature in clearance of damaged organelles, protein aggregates, and, in some models, senescent-cell debris. Reviews of the mTOR-aging literature also discuss interactions between mTORC1 signaling and cellular senescence, including evidence that rapamycin can modulate the senescence-associated secretory phenotype (SASP) in some cell and animal models, distinguishing this indirect anti-inflammatory mechanism from the direct senolytic clearance mechanism attributed to dasatinib-plus-quercetin or fisetin regimens discussed elsewhere in this monograph series (Mannick and Lamming, 2023). These are mechanistic and largely preclinical observations; no human trial reviewed for this monograph has demonstrated a rapamycin-driven reduction in a validated human senescent-cell burden marker as a primary clinical endpoint, and this document does not present the autophagy or SASP mechanism as an established human clinical effect.
18Locating the advocacy lane for rapamycin specifically
Public longevity discourse about rapamycin is driven less by any single laboratory figure than by a loose network of physicians, biogerontologists, and platform companies who have moved the compound from academic mouse literature into public visibility. Matt Kaeberlein, a University of Washington biogerontologist who co-directs the Dog Aging Project and has published peer-reviewed rapamycin and TRIAD-related work, has also spoken publicly and repeatedly, including in interviews and popular-media appearances, about his own personal use of low-dose rapamycin and his view that the mouse evidence justifies broader off-label human use ahead of completed human mortality trials. That public advocacy position — personal use and public recommendation in advance of a completed human efficacy trial — is treated in this monograph as exactly that: a named researcher’s stated personal practice and public opinion, clearly distinguished from the peer-reviewed mouse and human trial data summarized in Parts Two and Three, which stand on their own regardless of any individual researcher’s off-label choices. PEARL itself, discussed in Part Three, emerged substantially from this same advocacy-adjacent ecosystem, through the AgelessRx telehealth platform and crowdfunded citizen-science trial architecture, a provenance this monograph states plainly rather than treating PEARL as indistinguishable in institutional character from an academic medical center trial. Secondary commentary from advocacy-aligned outlets such as Lifespan Research Institute and Fight Aging! on PEARL and the ITP results is cited in this monograph, where cited at all, only as labeled commentary, never as a substitute for the primary papers it discusses.
David Sinclair, the Harvard geneticist whose public advocacy is treated at greater length in this series’ companion NMN monograph, has also spoken publicly about including low-dose rapamycin in his own personal regimen and has been widely quoted in press interviews to that effect. Sinclair’s own peer-reviewed laboratory output, however, centers overwhelmingly on sirtuin biology, NAD+ metabolism, and epigenetic-reprogramming approaches to aging rather than on rapamycin-specific mechanistic or trial work; no rapamycin-focused primary research paper from the Sinclair laboratory was identified in the source material assembled for this monograph. His rapamycin comments accordingly belong in this document’s advocacy lane — a public figure’s personal-use statement — and are kept separate from the ITP, Mannick, and PEARL peer-reviewed and trial-registered findings that constitute the compound’s actual evidence base.
19Evidence gaps and unresolved questions
Several gaps in the rapamycin record remain material to any accurate account of where the science currently stands. No completed human trial has used all-cause mortality or a validated multi-domain frailty index as a primary endpoint for rapamycin itself; the closest comparator programme, TAME, targets metformin and remains substantially a funding and design exercise rather than a completed dataset, as detailed in the companion metformin monograph. The dose-translation problem between the ITP’s enteric-microencapsulated mouse formulation and any human-relevant oral regimen has not been resolved by a dedicated pharmacokinetic bridging study reported in the sources reviewed for this document; PEARL and the Mannick trials each used their own distinct human dosing approaches, and no single agreed human dose-equivalence to the ITP mouse protocol has been established. Sex-specific human effects, a notable feature of the mouse data, have not yet been systematically examined in a human trial powered to detect a sex interaction. Long-term safety data beyond roughly a year of low-dose or intermittent human exposure do not yet exist in the peer-reviewed or trial-registered literature assembled for this monograph. Companion-animal lifespan data from TRIAD, the most direct available cross-species bridge, has not yet matured to a mortality readout. Each of these gaps is a reason for continued, well-designed research, not a basis for either dismissing or overselling the existing mouse and early human data.
20Conclusions
Rapamycin’s scientific standing rests on an unusually solid animal foundation and a comparatively thin, though methodologically serious and actively growing, human record. The ITP’s three-site, multi-cohort mouse lifespan data are among the most rigorously replicated pharmacological longevity findings available in any species, and they justify the substantial research investment that has followed. The human trials reviewed here — vaccine-response and infection-incidence studies using everolimus and RTB101, and a 2025 decentralized safety and functional-outcome trial using rapamycin itself — establish measurable effects on specific, biologically meaningful but intermediate endpoints in older adults, under trial conditions, at studied doses. They do not establish, and this monograph does not claim, a demonstrated human lifespan or mortality benefit. Public advocacy for personal rapamycin use by individual researchers and platform companies runs meaningfully ahead of that completed trial record, a gap this document treats as a fact about the current state of evidence rather than as either an endorsement or a dismissal of the underlying research programme. This document is Research Use Only. It recommends no human use, dose, route, schedule, or combination protocol for rapamycin, sirolimus, everolimus, or any related compound for any reader.
AMethods of evidence assembly
Source project: 05 therapeutic-peptide research library and the Adjacent Compounds / Longevity
harvest (projects/adjacent_compounds_research_2026/deep_harvest/longevity_v2/). Compound key
P187. This monograph departs from the series’ usual peptide-classed compound scope: rapamycin is a
macrolide, not a peptide, and is included in the Adjacent Compounds longevity commission because of its
mechanistic and public-discourse proximity to peptide-adjacent geroscience compounds covered elsewhere in this
library.
Seventeen subject-focused PMIDs were resolved against NCBI E-utilities for the reference list, covering the discovery literature (Sehgal, 2003; Samanta, 2017), the ITP mouse lifespan cohorts (Harrison et al., 2009), the Mannick mTOR-pathway immune-aging trials (2014; 2018), the 2025 PEARL trial report (Moel et al.), the TRIAD companion-dog protocol paper, and synthesis/review coverage of the mTOR-and-aging literature. Seven non-PubMed provenance sources were added for regulatory, registry, and identity context: ClinicalTrials.gov protocol records for PEARL, an earlier registered rapamycin trial, and EVERLAST; FDA labeling context for sirolimus and everolimus; the AFAR TAME trial programme page, cited only for cross-referenced trial-design context; the NIA ITP publications index; the Dog Aging Project TRIAD programme page; PubChem compound summaries for sirolimus and everolimus; and Lifespan Research Institute / Fight Aging! secondary commentary, cited only where explicitly labelled as advocacy commentary rather than as primary evidence. Page equivalents use 500 words per printed page for XML/HTML.
Identity gate: documents discussing everolimus, temsirolimus, or other rapalogs without explicit rapamycin or sirolimus context were excluded from primary evidentiary use and appear only as named clinical comparators in trials that studied them directly. Figure artwork is authored SVG using theme tokens only (no raw hex in presentation attributes).
BReferences
- Coleman AE, Creevy KE, Anderson R, Reed MJ, Fajt VR, Aicher KM, 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. 2025;47(3):2851-2877.
PMID 39951177 · doi:10.1007/s11357-024-01484-7 · PMC12181551 - Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al.. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392-5.
PMID 19587680 · doi:10.1038/nature08221 · PMC2786175 - Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, et al.. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014;6(268):268ra179.
PMID 25540326 · doi:10.1126/scitranslmed.3009892 - Mannick JB, Morris M, Hockey HP, Roma G, Beibel M, Kulmatycki K, et al.. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med. 2018;10(449).
PMID 29997249 · doi:10.1126/scitranslmed.aaq1564 - Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. Nat Aging. 2023;3(6):642-660.
PMID 37142830 · doi:10.1038/s43587-023-00416-y · PMC10330278 - Miller RA, Harrison DE, Astle CM, Floyd RA, Flurkey K, Hensley KL, et al.. An Aging Interventions Testing Program: study design and interim report. Aging Cell. 2007;6(4):565-75.
PMID 17578509 · doi:10.1111/j.1474-9726.2007.00311.x - Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, et al.. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13(3):468-77.
PMID 24341993 · doi:10.1111/acel.12194 · PMC4032600 - Moel M, Harinath G, Lee V, Nyquist A, Morgan SL, Isman A, et al.. Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results. Aging (Albany NY). 2025;17(4):908-936.
PMID 40188830 · doi:10.18632/aging.206235 · PMC12074816 - Samanta D. Surendra Nath Sehgal: A pioneer in rapamycin discovery. Indian J Cancer. 2017;54(4):697-698.
PMID 30082562 · doi:10.4103/ijc.IJC_84_18 - Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003;35(3 Suppl):7S-14S.
PMID 12742462 · doi:10.1016/s0041-1345(03)00211-2 - ClinicalTrials.gov. NCT04488601 PEARL; related everolimus aging protocols.
https://clinicaltrials.gov/study/NCT04488601 - NIA Interventions Testing Program. Rapamycin lifespan publications index.
https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/publications - Halford B. Rapamycin's secrets unearthed. Chem Eng News 2016 (secondary history).
https://cen.acs.org/articles/94/i29/Rapamycins-Secrets-Unearthed.html - Duffin J. Stanley's Dream: The Medical Expedition to Easter Island (history; secondary).
https://www.molbiolcell.org/doi/10.1091/mbc.E22-08-0377 - ClinicalTrials.gov. Protocol inventory via API v2; not peer-reviewed results.
https://clinicaltrials.gov/ - U.S. Food and Drug Administration. Approved labeling context for primary indications — not aging approvals.
https://www.fda.gov/ - American Federation for Aging Research. TAME Trial programme page (secondary status communications; verify before reissue).
https://www.afar.org/tame-trial - NIA Interventions Testing Program publications index.
https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/publications - PubChem compound summary pages used for identity cross-checks.
https://pubchem.ncbi.nlm.nih.gov/
CFigure list
- Timeline from the 1964 METEI soil sample and Sehgal’s isolation through the 1999 FDA approval, the ITP mouse cohorts, and the 2025 PEARL trial.
- Approximate median lifespan gain across ITP mouse cohorts by starting age, dose, and sex (Harrison et al., 2009 and later cohorts).
No commissioned photographic plates were admitted for this build; both figures are vector diagrams generated for the monograph. Additional internet imagery was reviewed and none was required once the SVG set covered the narrative beats appropriate to this compound’s evidence base.
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