# Rapamycin (sirolimus): full monograph (Sirolimus Rx)
> Source page: https://sirolimusrx.com/monograph

Status: FDA-approved drug
Disclosure: Rapamycin (sirolimus) is an FDA-approved prescription immunosuppressant (Rapamune) for organ-transplant rejection prophylaxis. Taking it for longevity is off-label and unproven.
Updated: 2026-08-14

## Key facts
- Status: FDA-approved drug
- Tmax note: Blood levels in real-world longevity users peaked about 2 days after a weekly dose (observational data)
- Bioavailability: About 14% (oral solution); tablets about 27% higher than solution; the two are not bioequivalent (clinically equivalent at 2 mg)
- Distribution: Blood-to-plasma ratio 36 +/- 18 (sequestered in red cells); Vss/F 12 +/- 8 L/kg; about 92% protein bound
- Metabolism: Substrate of CYP3A4 and P-glycoprotein; extensive intestinal and hepatic metabolism
- Steady state note: Derived: with a 62-hour half-life, steady state arrives in roughly 11 to 13 days (4 to 5 half-lives)
- Route: Oral (solution or tablets), once daily per label
- Drug class: mTOR inhibitor immunosuppressant (source: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=384cb547-55a4-47fc-a0a6-054c18a51b84)
- Longevity status: Off-label; zero completed lifespan-outcome trials (source: https://pmc.ncbi.nlm.nih.gov/articles/PMC12074816/)
- Half-life: About 62 +/- 16 hours (source: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=384cb547-55a4-47fc-a0a6-054c18a51b84)
- Boxed warning: Immunosuppression: infection, lymphoma/malignancy risk (source: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=384cb547-55a4-47fc-a0a6-054c18a51b84)
- Monitoring: Whole-blood troughs; label recommends TDM for all patients (source: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=384cb547-55a4-47fc-a0a6-054c18a51b84)
- Key interaction: CYP3A4/P-gp substrate; grapefruit prohibited by label (source: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=384cb547-55a4-47fc-a0a6-054c18a51b84)
- Approved doses: 2 mg/day (renal, LAM start); 5 mg/day high-risk (source: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=384cb547-55a4-47fc-a0a6-054c18a51b84)
- Best animal result: ITP mice: +14% (F) / +9% (M) at 90th percentile, late-life start (source: https://pmc.ncbi.nlm.nih.gov/articles/PMC2786175/)
- Human evidence caveat: Famous elderly immune RCTs used everolimus, not sirolimus (source: https://pubmed.ncbi.nlm.nih.gov/25540326/)

## What is rapamycin (sirolimus)?
Rapamycin, sold as sirolimus (brand name Rapamune), is an FDA-approved oral immunosuppressant: approved in 1999 for kidney-transplant rejection prophylaxis, and since 2015 for the rare lung disease lymphangioleiomyomatosis (LAM)  [3,1]. It is also, separately, the drug with the strongest animal longevity data in pharmacology: the NIA's Interventions Testing Program extended mouse lifespan with it in both sexes, at three independent sites, even when started late in life  [12].
Those two facts power an off-label prescribing economy in longevity medicine, and this page keeps them in separate columns. The mouse data get full credit at mouse grade. The human record gets read as it actually is: transplant and LAM trials that prove the drug works for its approved uses, immune-aging trials that mostly tested a different rapalog (everolimus), and one completed longevity-population trial (PEARL) that missed its primary endpoint  [21,28]. No human trial has tested whether rapamycin extends human life  [28,23].

## Key facts
Sourced fact chips render from the facts array: class, FDA status, longevity status, half-life, boxed warning, monitoring, key interaction, approved doses, best animal result, and the compound-labeling caveat on the famous human trials.

## Is rapamycin FDA approved, and for what?
Yes, with a precise boundary. Rapamune oral solution was approved September 15, 1999 under NDA 021083; tablets under NDA 021110; generic sirolimus tablets and solution followed  [3,4]. The label indication is prophylaxis of organ rejection in renal transplant patients aged 13 or older, plus treatment of LAM, added by an efficacy supplement approved May 28, 2015  [1,3].
Longevity is not on that list. Taking sirolimus to slow aging is off-label prescribing of a real drug, not a supplement purchase, and every legitimate route to it runs through a prescriber and a licensed pharmacy  [1]. Other sirolimus products exist for other uses: HYFTOR, a topical gel for facial angiofibroma in tuberous sclerosis; FYARRO, an IV protein-bound sirolimus for a rare sarcoma; and SCOMARA, a topical cream  [4,5].

## What is sirolimus actually prescribed for?
In its approved lane, sirolimus earns its keep with hard numbers. In the two pivotal renal-transplant trials it roughly halved biopsy-confirmed acute rejection: 16.9 to 12.0 percent versus 29.8 percent against azathioprine, and 24.7 to 19.2 percent versus 41.5 percent against placebo  [24,25]. In the MILES trial, it stopped the lung-function decline of LAM while patients stayed on it: FEV1 slope +1 mL per month on drug versus -12 mL per month on placebo, with the decline resuming after discontinuation  [27].
The off-label longevity lane borrows the same molecule at lower, usually weekly doses, on the theory that mTOR inhibition will do for humans what it does for mice. That theory is coherent, actively researched, and unproven in any human outcome trial  [28,31].

## What is the actual longevity evidence?
The animal side deserves its reputation. The NIA Interventions Testing Program, the most rigorous drug-testing framework in aging biology, fed rapamycin to genetically heterogeneous mice starting at 600 days old (late life) and extended lifespan in both sexes at all three independent sites: +14 percent for females and +9 percent for males at the 90th-percentile age  [12]. Started at 9 months, median survival rose 10 percent in males and 18 percent in females  [13]. At a threefold higher dose, +23 and +26 percent  [14]. A 3-month transient course in middle-aged mice raised remaining life expectancy up to 60 percent  [15]. The same program found resveratrol, simvastatin, fish oil, and metformin alone did nothing  [13,16]. TOR inhibition also extends lifespan in yeast, worms, and flies  [10]. In 24 companion dogs, a 10-week course produced no clinical side effects and echocardiographic improvements  [19]. This is the best preclinical longevity dossier any drug owns, and this table grades every row of it at its species  [31].
The human side is a different table. Zero completed randomized trials, of sirolimus or any rapalog, have tested lifespan, mortality, or disease incidence as a primary endpoint in a healthy aging population  [28,23]. The mouse rows in our study table say mouse. The human rows say what was actually measured: vaccine response, infection rates, DXA scans, safety labs. Where the marketing says 'rapamycin is proven to reverse aging,' the graded table is the reply.

## What human evidence exists, compound by compound?
Read the compound_studied column before the headline. The famous elderly immune trials, the ones quoted as proof that 'rapamycin' improves human aging, tested other rapalogs: the 2014 trial that improved flu-vaccine response by about 20 percent used everolimus (RAD001)  [21]; the 2018 trial that cut reported infections used dactolisib plus everolimus  [22]; and when RTB101 (dactolisib) advanced to a 1,024-person phase 3, it failed its primary endpoint outright, 26 percent symptomatic respiratory illness on drug versus 25 percent on placebo  [23]. Everolimus is a real, approved drug (Afinitor for oncology, Zortress for transplant) with a 30-hour half-life; it is not sirolimus  [6,7].
Sirolimus itself has been tested in aging populations exactly twice in completed randomized trials. Kraig 2018: 25 adults aged 70 to 95, 1 mg daily for 8 weeks, a safety pilot that changed no efficacy measure and flagged mild red-cell decrements  [20]. PEARL 2025: 129 enrolled adults, compounded 5 or 10 mg weekly for 48 weeks, run by the longevity telehealth company AgelessRx; its primary endpoint (visceral fat by DXA) did not move (p=0.942), while secondary analyses showed lean-mass and pain improvements in women on 10 mg and self-reported well-being gains at 5 mg  [28,32]. The strongest human data for sirolimus remain its approved-use trials: transplant rejection, LAM lung function, and a skin-cancer-prevention trial in transplant patients that cut new squamous-cell carcinoma (RR 0.56) at the cost of quadrupled serious adverse events  [24,27,26].

## Is weekly low-dose rapamycin actually different?
The claim behind longevity dosing is specific: once-weekly low doses inhibit mTORC1 (the longevity target) while sparing mTORC2 (the complex whose disruption drives glucose problems). The mechanistic core is real mouse science: chronic rapamycin impaired glucose tolerance via mTORC2 loss, and intermittent schedules reduced the metabolic and immune side effects in mice  [11,18].
In humans, the schedule has safety data, not outcome data. PEARL ran 5 and 10 mg compounded weekly for 48 weeks with adverse events similar to placebo  [28]. A survey of 333 off-label users, mostly on weekly regimens, reported initial safety signals through self-report  [29]. Real-world blood-level work found compounded product delivers about one third the exposure of commercial per milligram, which means many weekly users absorb less drug than their milligram number implies  [30]. What no source shows: that weekly dosing extends human healthspan or lifespan. The dosing folklore is ahead of its evidence, and the studied-doses table below keeps the two visibly separate  [28].

## How does rapamycin work?
Sirolimus binds the intracellular protein FKBP-12; the complex inhibits mTOR, a kinase that integrates nutrient and growth signals, which suppresses T-lymphocyte proliferation (the immunosuppressant effect) and shifts cells toward autophagy and reduced protein synthesis (the aging-biology interest)  [1,9]. The TOR genes were discovered in yeast in 1991 through rapamycin-resistance screens; the molecule itself was isolated in 1975 from Streptomyces hygroscopicus in an Easter Island soil sample and named for the island, Rapa Nui  [9,8].
The two-complex detail matters more than most mechanism trivia: mTORC1 inhibition tracks with the longevity effects in animals, while disruption of mTORC2 under chronic dosing tracks with insulin resistance and glucose intolerance  [11]. In flies, the lifespan effect runs through TORC1, autophagy, and translation  [10]. Every dosing debate in the longevity community is ultimately an argument about how to hit complex 1 without complex 2, and no human outcome trial has yet tested whether any schedule achieves that  [18,28].

## What is the boxed warning?
The label's highest-level warning is about immunosuppression itself: increased susceptibility to infection and the possible development of lymphoma and other malignancies, with the instruction that only physicians experienced in immunosuppressive therapy and renal-transplant management should use the drug  [1]. In the pivotal trials, lymphoma or lymphoproliferative disease occurred in 0.7 to 3.2 percent of sirolimus patients versus 0.6 to 0.8 percent of controls  [1].
The same box rules the drug out entirely in two transplant settings: liver transplantation, where sirolimus combinations were associated with excess mortality, graft loss, and hepatic artery thrombosis, and lung transplantation, where bronchial anastomotic dehiscence cases were mostly fatal  [1]. Longevity users dose lower and less often, and PEARL reported adverse events similar to placebo at 5 to 10 mg compounded weekly for 48 weeks; what nobody has shown is where between 2 mg daily and 10 mg compounded weekly the boxed-warning biology stops applying  [28,1].

## What are the side effects?
From the label, at transplant doses: the most common adverse reactions include peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, increased creatinine, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, and arthralgia  [1]. The warning sections add hyperlipidemia requiring treatment, impaired wound healing and fluid accumulation, interstitial lung disease and non-infectious pneumonitis, proteinuria, hyperglycemia and new-onset diabetes, skin-cancer risk with a sun-protection instruction, hypersensitivity including angioedema, and azoospermia or oligospermia  [1]. In the LAM study population (2 mg daily, no cyclosporine), the most frequent reactions were stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory infection, headache, dizziness, myalgia, and hypercholesterolemia  [1].
At longevity doses, the honest answer is thinner and milder, and it is measured, not proven absent. Kraig 2018 (1 mg daily, 8 weeks, ages 70 to 95) saw facial rash, stomatitis, and GI complaints in a handful of subjects, plus statistically significant but clinically insignificant red-cell decrements, and no glucose deterioration on formal testing  [20]. PEARL (5 or 10 mg compounded weekly, 48 weeks) reported adverse and serious adverse events similar to placebo, with blood biomarkers staying in normal ranges  [28]. Mouth ulcers, the signature mTOR-inhibitor complaint, appear in the LAM label list as stomatitis and in the off-label user survey  [1,29]. The mouse literature adds a mechanism-level caution: chronic dosing impairs glucose tolerance via mTORC2, the exact effect intermittent dosing is meant to avoid  [11,18].

## What interacts with sirolimus?
Sirolimus is a substrate of both CYP3A4 and P-glycoprotein, which makes its blood level hostage to other chemistry. The label says to avoid strong CYP3A4/P-gp inhibitors (ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) and strong inducers (rifampin, rifabutin)  [1]. Grapefruit juice gets its own section: it inhibits CYP3A4-mediated metabolism of sirolimus and must not be taken with it or used to dilute the solution  [1].
Three more label rules worth knowing even as an educated reader: sirolimus is taken 4 hours after cyclosporine when the two are combined; live vaccines (measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, TY21a typhoid) should be avoided during treatment; and cannabidiol requires close monitoring for rising sirolimus levels  [1]. A weekly longevity dose does not opt out of this chemistry: a 62-hour half-life means the drug is present all week, every week  [1].

## What monitoring does sirolimus require?
The label recommends therapeutic drug monitoring for all patients: whole-blood trough concentrations, checked at least 3 to 4 days after loading, after dose changes, in hepatic impairment, and around interacting drugs  [1]. In LAM the target trough is 5 to 15 ng/mL  [1]. Because sirolimus sequesters in red cells (blood-to-plasma ratio 36), trough measurement uses whole blood, and assay methods differ, so the same sample can read differently by immunoassay versus chromatography  [1].
Beyond drug levels, the label's warning sections imply the lab panel: lipids (hyperlipidemia requiring treatment), glucose (hyperglycemia and new-onset diabetes), urinary protein (proteinuria monitoring is recommended), and blood counts  [1]. The half-life arithmetic sets the tempo: at 62 hours, steady state arrives in roughly 11 to 13 days, which is why level checks days after a change are meaningful and same-day checks are not  [1]. Off-label prescribers who order no labs at all are running a protocol no studied population ran: even PEARL monitored blood biomarkers throughout  [28].

## What about pregnancy and fertility?
The label states sirolimus can cause fetal harm based on animal studies and its mechanism, was embryo/fetotoxic in rats at sub-therapeutic doses, and pregnant women should be advised of the risk; effective contraception is expected before, during, and after therapy per the label's specific-populations text  [1]. On the male side, azoospermia or oligospermia may occur, listed in the label as a male-infertility warning  [1]. For a drug taken by healthy adults on a wellness theory, reversible sperm suppression and fetal-harm potential are not fine print.

## Pharmacokinetics
The numbers that explain the dosing rules: terminal half-life about 62 +/- 16 hours in stable renal transplant patients, so once-daily dosing stacks and even once-weekly dosing never fully clears  [1]. Oral solution bioavailability is about 14 percent, tablets about 27 percent higher, and the two are not bioequivalent (clinically equivalent only at 2 mg)  [1]. The drug rides in red cells (blood-to-plasma ratio 36 +/- 18), is about 92 percent protein bound, and is cleared through CYP3A4 and P-gp, the door every major interaction walks through  [1]. In real-world longevity users, blood levels peaked about 2 days after a weekly dose, and compounded product delivered roughly a third of commercial exposure per milligram  [30].

## What doses have actually been studied?
Approved dosing is precise: renal transplant at low-to-moderate risk gets a 6 mg loading dose then 2 mg daily; high-risk gets up to 15 mg loading then 5 mg daily; LAM starts at 2 mg daily and titrates to a 5 to 15 ng/mL trough  [1]. Studied longevity-adjacent dosing is thinner: 1 mg daily for 8 weeks (Kraig pilot) and compounded 5 or 10 mg weekly for 48 weeks (PEARL)  [20,28]. Real-world users take commercial 2 to 8 mg or compounded 5 to 15 mg weekly  [30].
The mouse doses do not convert. The ITP dosed in parts per million of chow (4.7 to 42 ppm) with exposure verified by mouse blood levels; no validated method turns those into a human milligram number, and this site does not invent one  [14]. The comparison table below puts every studied dose next to the folklore so the gap is visible instead of implied  [1,28].

## How is sirolimus stored?
Oral solution: refrigerated at 2 C to 8 C (36 F to 46 F), protected from light, used within one month of opening; brief room-temperature storage is allowed per the label. Tablets store at controlled room temperature  [1,2]. A slight haze can develop in refrigerated solution; the label describes handling for it. Compounded capsules follow the compounding pharmacy's labeling, one more way a compounded product is not the studied article  [30].

## What we do not know yet
Rendered from limits_text; the honest boundary of this page.

## Frequently asked questions
Rendered from the faq array; answers are html-canonical with cite superscripts, and each carries a 320-character direct answer for the machine layer.

## References
Numbered references render from citations[] in n order; the same array ships as the machine-readable citation manifest.

## Related compounds and comparisons
Comparisons render from comparisons[]: sirolimus vs everolimus (the compound the famous trials actually used), and studied doses vs folklore doses. Related fleet reading: metformin discourse is addressed in the FAQ with the ITP's own metformin rows.

## Study results
| Study | Species/model | n | Duration | Outcome | Effect size |
| --- | --- | --- | --- | --- | --- |
| S01 (https://pmc.ncbi.nlm.nih.gov/articles/PMC2786175/) | mouse (NIA ITP: late-life start (600 days), 14 ppm dietary, 3 independent sites) | 1,901 mice (UM-HET3, pooled sites, both sexes) | From 600 days of age to death | Lifespan extended in both sexes at all 3 sites; age at 90% mortality +14% females, +9% males; disease patterns unchanged vs controls | +14% (F) / +9% (M) at 90th-percentile age |
| S02 (https://pmc.ncbi.nlm.nih.gov/articles/PMC3021372/) | mouse (NIA ITP: adult start (9 months), 14 ppm dietary, 3 sites; resveratrol and simvastatin arms null) | Multi-site ITP cohorts, both sexes | From 9 months of age to death | Median survival +10% males, +18% females; maximum lifespan also increased at each site | +10% (M) / +18% (F) median survival |
| S03 (https://pmc.ncbi.nlm.nih.gov/articles/PMC4032600/) | mouse (NIA ITP: three dietary doses; sex-stratified survival) | Multi-site ITP cohorts, both sexes | Chronic to death | Median lifespan +23% males, +26% females at the highest dose; females gained more at every dose; metabolic profile distinct from dietary restriction | +23% (M) / +26% (F) median lifespan at 42 ppm |
| S04 (https://pmc.ncbi.nlm.nih.gov/articles/PMC4996648/) | mouse (Randomized 3-month treatment in middle-aged mice (UW)) | Middle-aged C57BL/6 cohorts, both sexes | 3-month treatment, lifelong follow-up | Remaining life expectancy up to +60%; healthspan measures improved; one female dose did not extend lifespan and shifted cancers toward aggressive hematopoietic types | Up to +60% remaining life expectancy |
| S05 (https://pmc.ncbi.nlm.nih.gov/articles/PMC5013015/) | mouse (NIA ITP: metformin alone and metformin plus rapamycin) | Multi-site ITP cohorts | Chronic to death | Metformin alone: no significant lifespan extension. Metformin plus rapamycin: robust extension | Combination robustly extended lifespan; metformin alone null |
| S06 (https://pmc.ncbi.nlm.nih.gov/articles/PMC5892694/) | mouse (HET3 mice, rapamycin diet with and without metformin) | Male and female HET3 mice | Up to 9 months co-treatment | Rapamycin impaired glucose metabolism within 1 month in both sexes; metformin alleviated the defect in females | Female glucose tolerance normalized with co-treatment |
| S07 (https://pmc.ncbi.nlm.nih.gov/articles/PMC3324089/) | mouse (Mouse genetics + chronic dosing (Whitehead/Penn)) | Multiple engineered and treated cohorts | Chronic | Glucose intolerance and insulin resistance traced to mTORC2 disruption; longevity effect separable from glucose defects | Mechanistic dissociation (mTORC1 longevity vs mTORC2 metabolic harm) |
| S08 (https://pmc.ncbi.nlm.nih.gov/articles/PMC4717280/) | mouse (Mice on daily vs intermittent rapamycin; rapalog comparison) | C57BL/6J cohorts | Weeks | Intermittent schedule: minimal glucose-tolerance impact, reduced immune impact vs daily; everolimus/temsirolimus inhibited mTORC1 with less glucose impact | Side-effect reduction with intermittent dosing (no lifespan endpoint) |
| S09 (https://pmc.ncbi.nlm.nih.gov/articles/PMC2824086/) | fruit fly (Adult Drosophila fed rapamycin; TORC1 pathway genetics) | Fly cohorts | Adult lifespan | Lifespan extension via TORC1, autophagy and translation; also extended lifespan of dietary-restricted flies | Lifespan extension replicating TOR-mutant phenotype |
| S10 (https://pmc.ncbi.nlm.nih.gov/articles/PMC5411365/) | dog (Randomized placebo-controlled 10-week pilot (Dog Aging Project precursor)) | 24 middle-aged healthy dogs | 10 weeks | No clinical side effects vs placebo; echocardiographic improvement in diastolic and systolic age-related measures; MCV decreased | E/A ratio, fractional shortening, ejection fraction improved (pilot-scale) |
| S11 (https://pubmed.ncbi.nlm.nih.gov/1715094/) | yeast (Yeast genetics: rapamycin-resistance screens) | S. cerevisiae strains | n/a | TOR1 and TOR2 genes identified; FKBP-rapamycin complex shown to arrest the cell cycle in G1 | Target discovery |
| S12 (https://pmc.ncbi.nlm.nih.gov/articles/PMC5869166/) | human (Randomized, placebo-controlled pilot in adults 70-95) | 25 enrolled (11 rapamycin, 14 placebo analyzed) | 8 weeks | No changes in glucose tolerance, cognition, physical performance, or self-perceived health; statistically significant but not clinically significant red-cell decrements; mild AEs | Feasibility and short-term safety only; no efficacy endpoint |
| S13 (https://pubmed.ncbi.nlm.nih.gov/25540326/) | human (Randomized, placebo-controlled trial in elderly volunteers) | Elderly volunteers (multi-arm dose-ranging) | 6 weeks before influenza vaccination | Influenza vaccine response improved by about 20% at well-tolerated doses; PD-1-positive T cells reduced | About +20% vaccine response |
| S14 (https://pubmed.ncbi.nlm.nih.gov/29997249/) | human (Phase 2a randomized, placebo-controlled) | 264 elderly subjects | 6 weeks dosing; 1 year infection follow-up | Reported infection rate decreased (P=0.001) for a year; antiviral gene expression up; vaccine response improved | Significant infection-rate reduction (phase 2a) |
| S15 (https://pmc.ncbi.nlm.nih.gov/articles/PMC8102040/) | human (Phase 2b (652) and phase 3 (1,024) randomized, placebo-controlled) | 1,024 (phase 3); 652 (phase 2b) | 16 weeks (winter season) | Phase 2b: lab-confirmed RTIs 19% vs 28% (OR 0.601, p=0.02, second prespecified analysis). Phase 3: FAILED primary endpoint, symptomatic respiratory illness 26% vs 25% (OR 1.07, p=0.65) | Phase 3 null on primary |
| S16 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12074816/) | human (PEARL: 48-week decentralized, double-blind RCT (AgelessRx-run; authors are company employees)) | 129 enrolled (NCT04488601) | 48 weeks | PRIMARY MISSED: visceral adiposity by DXA unchanged (p=0.942). Secondary: women on 10 mg improved lean mass (p=0.013) and self-reported pain (p=0.015); 5 mg group improved self-reported well-being and general health. AEs similar to placebo | Null primary; sex- and dose-specific secondary signals |
| S17 (https://pmc.ncbi.nlm.nih.gov/articles/PMC10187519/) | human (Cross-sectional survey, self-selected users vs non-users) | 333 users + 172 non-users | Cross-sectional | Authors describe initial evidence of safe use in adults of normal health; self-report design; limited side-effect and no efficacy data | No efficacy endpoint; descriptive safety |
| S18 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12397450/) | human (Two real-world cohorts: blood levels 24 h post-dose plus observational database) | 44 commercial + 23 compounded; 316 observational users | Cross-sectional with repeat tests | Compounded bioavailability estimated at 31.03% of commercial per mg; levels peak about day 2; large inter-individual variability | Compounded is about one third as bioavailable per mg |
| S19 (https://pubmed.ncbi.nlm.nih.gov/10963197/) | human (US pivotal trial: randomized, double-blind vs azathioprine (Study 1)) | 719 | 6-month primary; 12-month follow-up | Efficacy failure 18.7% (2 mg) and 16.8% (5 mg) vs 32.3% azathioprine; biopsy-confirmed rejection 16.9% and 12.0% vs 29.8% | Roughly halved acute rejection |
| S20 (https://pubmed.ncbi.nlm.nih.gov/11213073/) | human (Worldwide phase 3: randomized, double-blind vs placebo (Study 2)) | 576 | 6-month primary; 12-month follow-up | Biopsy-confirmed acute rejection 24.7% (2 mg) and 19.2% (5 mg) vs 41.5% placebo; reductions of 40.5% and 53.7% | 40.5% to 53.7% relative reduction in rejection |
| S21 (https://pmc.ncbi.nlm.nih.gov/articles/PMC3118601/) | human (MILES: randomized, double-blind, placebo-controlled, 12-month treatment + 12-month observation) | 89 women with LAM | 12 months treatment | FEV1 slope +1 +/- 2 mL/month on sirolimus vs -12 +/- 2 mL/month on placebo (P<0.001); decline resumed after stopping | 153 mL absolute FEV1 difference (about 11% of baseline) |
| S22 (https://pubmed.ncbi.nlm.nih.gov/22830463/) | human (TUMORAPA: randomized conversion to sirolimus vs staying on calcineurin inhibitors) | 120 kidney-transplant patients with prior SCC | 2 years | New squamous-cell carcinoma 22% vs 39% (RR 0.56); but 60 vs 14 serious adverse events and 23% discontinuation | RR 0.56 (95% CI 0.32-0.98) for new SCC |
| S23 (https://pmc.ncbi.nlm.nih.gov/articles/PMC8190242/) | mouse (review) (Narrative review of a decade of mouse rapamycin data) | n/a | n/a | Strong evidence areas: lifespan, cardiac function, CNS, immune system, senescence, in mice; clinical translation named as the open step | n/a |

## What we do not know yet
What we do not know yet, as of this writing. Whether rapamycin extends human lifespan or healthspan: no completed randomized trial of sirolimus or any rapalog has tested lifespan, mortality, or disease incidence as a primary endpoint in a healthy population, and this is the single most important absence on this page. Whether weekly low-dose schedules avoid the label's metabolic and immune effects over years: the mouse mechanism is encouraging, PEARL's 48 weeks matched placebo on adverse events, and nothing longer exists. What an optimal human dose would even be: the mouse doses do not convert, compounded product carries about a third of commercial bioavailability, and no dose-finding outcome trial has run. Whether the secondary signals in PEARL (lean mass and pain in women at 10 mg) replicate: they came from an industry-run trial that missed its primary endpoint, and the authors themselves frame efficacy as future work. Whether the everolimus immune results generalize to sirolimus: the phase 3 that tried to build on them failed, and sirolimus was never the tested molecule. This page will change when a sirolimus outcome trial publishes; until then, the honest headline stays: the best animal longevity data in pharmacology, and no human proof.

## Questions and answers
### Does rapamycin extend human lifespan?
Unknown. It extends mouse lifespan in the NIH's replicated ITP studies (up to +26% median in females), plus yeast, worms, flies, and it is the field's best animal result. But zero completed human trials have tested lifespan or disease outcomes, and the one longevity-population RCT (PEARL) missed its primary endpoint.

Nobody knows, and the two halves of the evidence deserve to be stated together. In mice, rapamycin owns the strongest pharmacological longevity record ever assembled: the NIA Interventions Testing Program extended lifespan in genetically heterogeneous mice at three independent sites, in both sexes, even starting at 600 days old, with 90th-percentile gains of 14 percent in females and 9 percent in males, and up to 23 to 26 percent median extension at higher doses. The same program found resveratrol and metformin alone did nothing.In humans, no completed randomized trial of sirolimus or any rapalog has tested lifespan, mortality, or disease incidence as a primary endpoint. The one completed longevity-population RCT, PEARL, tested compounded weekly sirolimus for 48 weeks and did not move its primary endpoint, and the largest rapalog outcome trial in older adults failed outright. Best animal data in pharmacology, zero human proof: both are true at once.

### Is rapamycin FDA approved?
Yes. Sirolimus (Rapamune) was approved in 1999 for kidney-transplant rejection prophylaxis and in 2015 for the lung disease LAM. Generics exist, and other sirolimus products (HYFTOR gel, FYARRO IV) cover other uses. Longevity use is off-label: legal to prescribe, never FDA-reviewed for that purpose.

Yes. Rapamune (sirolimus) oral solution was approved September 15, 1999 under NDA 021083, with tablets under NDA 021110 and multiple generics since. The label covers renal-transplant rejection prophylaxis in patients 13 and older, and, since a May 2015 supplement, treatment of lymphangioleiomyomatosis.Rapamycin (sirolimus) is an FDA-approved prescription immunosuppressant (Rapamune) for organ-transplant rejection prophylaxis. Taking it for longevity is off-label and unproven. The transplant trials behind the approval roughly halved acute rejection, and the MILES trial stabilized LAM lung function.

### What did the PEARL trial actually find?
PEARL (48 weeks, 129 enrolled, compounded 5 or 10 mg weekly) missed its primary endpoint: visceral fat by DXA did not change (p=0.942). Secondary wins: women on 10 mg gained lean mass (p=0.013) and reported less pain; the 5 mg group reported better well-being. Adverse events matched placebo. Run by AgelessRx.

PEARL is the largest completed randomized trial of sirolimus in a healthy aging population, and its headline is a null. Over 48 weeks, 129 enrolled adults received placebo or compounded rapamycin at 5 or 10 mg once weekly; the primary outcome, visceral adiposity by DXA, did not change significantly (p=0.942).The real findings sit in the secondaries: women on 10 mg improved lean tissue mass (p=0.013) and self-reported pain (p=0.015), and the 5 mg group improved self-reported emotional well-being and general health. Adverse and serious adverse events were similar across groups. Two context notes belong next to every quote of it: the trial was run and authored by AgelessRx, a longevity telehealth company, and it used compounded rapamycin, which separate work estimates at about a third of commercial bioavailability per milligram.

### Is weekly low-dose rapamycin safer than daily dosing?
Mechanistically plausible, humanly unproven. Mouse data show intermittent dosing spares glucose metabolism and immunity (mTORC2 sparing). In humans: PEARL's 48-week weekly dosing matched placebo on adverse events, and a 333-user survey reports tolerability. No trial has compared schedules or tested outcomes.

The rationale is real science: chronic rapamycin disrupts mTORC2, driving insulin resistance in mice, and intermittent mouse schedules blunted the glucose and immune side effects.The human evidence for the weekly schedule is safety-shaped, not outcome-shaped: PEARL ran compounded 5 to 10 mg weekly for 48 weeks with adverse events similar to placebo, and a survey of 333 off-label users reads as initial tolerability evidence, by self-report. No trial has randomized weekly versus daily dosing in healthy adults, and none has tested any outcome that matters for longevity. A 62-hour half-life also means weekly dosing is not drug-free time; the molecule is present all week.

### What side effects show up at longevity doses?
Measured so far: mouth sores/stomatitis, GI complaints, facial rash, and small red-cell decrements (Kraig, 1 mg daily); PEARL's 48-week weekly dosing matched placebo on adverse events. Transplant-dose effects (lipids, glucose, wound healing, pneumonitis) are label warnings that low-dose data cannot rule out.

Two completed randomized trials measured this. At 1 mg daily for 8 weeks in adults 70 to 95, side effects were limited to facial rash, stomatitis, and gastrointestinal complaints in a few subjects, plus statistically significant but clinically insignificant drops in red-cell measures; glucose testing did not worsen. At 5 or 10 mg compounded weekly for 48 weeks, PEARL reported adverse and serious adverse events similar to placebo, with biomarkers in normal ranges.The label's ledger at treatment doses is heavier: hyperlipidemia requiring treatment, hyperglycemia and new-onset diabetes, impaired wound healing, proteinuria, interstitial lung disease, stomatitis, and the boxed immunosuppression warning. Short low-dose trials cannot rule those out; they can only report not seeing them yet.

### Why can't you have grapefruit with sirolimus?
The label prohibits it: grapefruit juice inhibits CYP3A4, the enzyme that clears sirolimus, so levels can climb unpredictably. It must not be taken with sirolimus or used to dilute the solution. The same chemistry is why ketoconazole, clarithromycin, rifampin and others are avoid-listed.

Because grapefruit chemically sabotages the drug's clearance. Sirolimus is a substrate of CYP3A4 and P-glycoprotein; grapefruit juice inhibits CYP3A4-mediated metabolism, so the label states it must not be taken with sirolimus or used for diluting the oral solution.The same pathway explains the label's avoid lists: strong CYP3A4/P-gp inhibitors (ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) push levels up, and strong inducers (rifampin, rifabutin) pull them down. With a 62-hour half-life, a weekly-dose user is exposed to these interactions every day of the week, not just dose day.

### What blood work does sirolimus require?
The label recommends therapeutic drug monitoring for all patients: whole-blood trough levels (LAM target 5-15 ng/mL), checked days after changes (62-hour half-life; steady state about 2 weeks). Warning sections add lipids, glucose, urine protein, and blood counts. Off-label use without labs matches no studied protocol.

The label recommends therapeutic drug monitoring for all patients: whole-blood trough concentrations, first checked 3 to 4 days after loading, re-checked after dose changes, hepatic impairment, or interacting drugs; the LAM target range is 5 to 15 ng/mL. Troughs use whole blood because the drug concentrates in red cells (blood-to-plasma ratio 36).Around the drug level sits the panel the warnings imply: lipids (hyperlipidemia requiring treatment), glucose (hyperglycemia, new-onset diabetes), urinary protein, and blood counts. The 62-hour half-life sets the tempo: steady state needs roughly 11 to 13 days, so same-week level checks after a change mislead. Even PEARL, the friendliest trial to longevity dosing, monitored blood biomarkers throughout.

### Rapamycin vs metformin: what does the evidence actually say?
In the NIH's ITP mice, they are not peers: metformin alone (0.1% of diet) did not significantly extend lifespan; rapamycin extended it in every test. Metformin plus rapamycin extended lifespan and eased rapamycin's glucose effects in females. In humans, neither has a completed longevity-outcome trial.

The cleanest comparison comes from the same lab benches: the NIA Interventions Testing Program tested both. Metformin alone at 0.1 percent of diet did not significantly extend mouse lifespan; metformin plus rapamycin (14 ppm) robustly extended it. Rapamycin alone, by contrast, extended lifespan in every ITP test, both sexes, all sites.The combination story is also a side-effect story: metformin reduced rapamycin-induced glucose intolerance in female mice. In humans, the honest symmetry is that neither drug has a completed randomized trial with a longevity outcome; whatever your feed says, that trial has not been run for either molecule.

### Were the famous human 'rapamycin' trials actually rapamycin?
Mostly no. The 2014 vaccine-response trial used everolimus (RAD001); the 2018 infection trial used dactolisib plus everolimus; the failed 2021 phase 3 used RTB101 (dactolisib). All are mTOR inhibitors; none is sirolimus. Our study table carries a compound column so every row is labeled.

Check the compound before you quote the trial. The 2014 study that improved elderly flu-vaccine response by about 20 percent tested RAD001, which is everolimus. The 2018 trial that cut reported infections used low-dose dactolisib (BEZ235) plus everolimus. The 1,024-person phase 3 that then failed its primary endpoint used RTB101, dactolisib alone.Everolimus is its own approved drug (Afinitor in oncology, Zortress in transplant) with its own label and a roughly 30-hour half-life versus sirolimus's 62. Same pathway, different molecules, different evidence. Every human row in our study table names its compound so the label does the correcting, not the reader.

### Can the mouse doses be converted to a human dose?
No. The ITP dosed mice at 4.7 to 42 ppm of food, verified by mouse blood levels; no validated conversion turns diet ppm into a human mg dose, and this site refuses to invent one. Human anchors are the label's doses (2-5 mg/day, trough 5-15 ng/mL in LAM) and the doses trials actually gave (1 mg/day; 5-10 mg/week).

No, and dose folklore often starts exactly here. The ITP mouse studies dosed rapamycin as parts per million of chow, 4.7 to 42 ppm, with exposure verified by measured mouse blood levels. Converting a dietary ppm in a 40-gram animal with different absorption, metabolism, and dosing continuity into a human milligram number requires assumptions no fetched source validates, so this site states the absence instead of inventing the math.The honest human anchors already exist: the label's studied doses (6 mg load then 2 mg daily; up to 15 mg load then 5 mg daily in high-risk transplant; 2 mg daily titrated to 5 to 15 ng/mL troughs in LAM) and the doses longevity trials actually administered: 1 mg daily for 8 weeks, and compounded 5 or 10 mg weekly for 48 weeks.

### Does rapamycin cause cancer or protect against it?
Both signals exist, in different settings. The boxed warning: immunosuppression may lead to lymphoma (0.7-3.2% vs 0.6-0.8% in transplant trials). Yet in transplant patients with prior skin cancer, switching to sirolimus cut new squamous-cell carcinoma (RR 0.56). Mouse data even show a dose shifting cancer types.

The label and the trials point in both directions, in different contexts. The boxed warning is unambiguous: immunosuppression brings possible development of lymphoma and other malignancies, particularly of the skin, with lymphoma/lymphoproliferative disease at 0.7 to 3.2 percent in sirolimus arms versus 0.6 to 0.8 percent in controls, and a sun-protection instruction in the warnings.Yet mTOR inhibition also has an anti-tumor face: in the TUMORAPA trial, kidney-transplant patients with prior squamous-cell carcinoma who switched to sirolimus developed new SCC at 22 percent versus 39 percent (relative risk 0.56), at the cost of far more serious adverse events. Mouse work adds nuance: one female dose in the transient-treatment study shifted cancer prevalence toward aggressive hematopoietic types without extending lifespan. Context decides which face you meet; no healthy-population data settle it.

### Is compounded rapamycin the same as the approved product?
No. Real-world testing estimated compounded rapamycin at about 31% of commercial bioavailability per mg, so a 10 mg compounded weekly dose can deliver roughly what 3 mg commercial does. PEARL used compounded product. Tablets vs solution are not even bioequivalent to each other per the label.

No, and the difference is measured, not hypothetical. In real-world cohorts, compounded rapamycin showed an estimated 31.03 percent of the bioavailability of the commercial product per milligram, with blood levels peaking about two days after dosing and substantial person-to-person variability. PEARL, the main longevity RCT, used compounded 5 and 10 mg doses, which matters when translating its findings to commercial tablets.Even within the approved products, the label states tablets and solution are not bioequivalent (tablet bioavailability about 27 percent higher; clinically equivalent only at the 2 mg level). Milligram numbers only compare within one formulation.

## References
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