Rapamycin, known by its drug name sirolimus, is an immunosuppressant first isolated from a soil bacterium. In the US it is approved, as Rapamune, to prevent rejection of kidney transplants and to treat lymphangioleiomyomatosis (LAM), a rare lung disease. Newer products are approved for a rare tumor (Fyarro) and as a skin gel (Hyftor). It works by blocking mTOR, a kinase (signaling enzyme) that controls cell growth.
Rapamycin also has a large following in longevity circles, because it extended lifespan in mice. The most important fact for that audience: no approved use relates to aging, and no human trial has shown that it extends lifespan. Human studies of low or intermittent doses have been small and short, and have tracked markers such as vaccine response, body composition and lab values. The oral drug carries a boxed warning for immunosuppression, including infection and lymphoma.
This page summarizes what the FDA labels, the clinical trials and the animal studies report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Macrocyclic lactone; mTOR inhibitor immunosuppressant |
| Brands / approval | Rapamune oral solution (US approval 1999) and tablets; Fyarro IV (2021); Hyftor topical gel (2022); oral generics |
| Approved uses | Kidney transplant rejection prophylaxis (age ≥13); LAM; advanced malignant PEComa (Fyarro); facial angiofibroma in tuberous sclerosis (Hyftor) |
| Oral forms | Tablets 0.5, 1 and 2 mg; oral solution 1 mg/mL |
| Labeled oral dosing | Dose is adjusted to blood trough levels; for LAM, 2 mg/day to start, targeting a trough of 5–15 ng/mL |
| Half-life (label) | About 62 ± 16 h in stable kidney transplant patients |
| Oral bioavailability | About 14% (oral solution) |
| Boxed warning | Immunosuppression (infection, lymphoma and other cancers); not recommended in liver or lung transplants |
| Longevity use | Off-label only; not approved for aging, and human data are limited to small, short trials of surrogate markers |
| WADA status | Not named on the 2026 Prohibited List |
What it is
Rapamycin was described in 1975 as an antifungal antibiotic made by Streptomyces hygroscopicus, a bacterium found in a soil sample from Easter Island (Vézina et al., J Antibiot 1975). It was later developed for its effects on the immune system.
The Rapamune label describes sirolimus as a macrocyclic lactone with the formula C₅₁H₇₉NO₁₃ and a molecular weight of 914.2 (Rapamune label). Drugs@FDA lists the first approval of Rapamune oral solution in September 1999 and the LAM indication in May 2015 (Drugs@FDA).
Everolimus, temsirolimus and other “rapalogs” are separate drugs derived from rapamycin. Some of the human aging trials below used everolimus, not sirolimus, and they are labeled as such.
How it works
According to the label, sirolimus binds a protein inside cells called FKBP-12. The sirolimus–FKBP-12 complex then binds and blocks mTOR (mechanistic target of rapamycin), a key regulatory kinase (Rapamune label). The label lists these effects:
- it blocks T-cell activation and proliferation driven by IL-2, IL-4 and IL-15, halting the cell cycle between the G1 and S phases;
- it inhibits antibody production;
- unlike tacrolimus and cyclosporine, it does not inhibit calcineurin;
- in LAM, lung cells carry inactivating mutations in a tuberous sclerosis complex (TSC) gene, which leaves mTOR switched on; sirolimus blocks this overactive pathway.
mTOR works inside two protein complexes, mTORC1 and mTORC2. Rapamycin mainly inhibits mTORC1. In mice, long-term rapamycin also disrupted mTORC2, which the authors linked to impaired glucose tolerance and insulin action. Mice with genetically reduced mTORC1 activity lived longer without that insulin resistance (Lamming et al., Science 2012). This is the basis for the idea that intermittent dosing might keep benefits while limiting metabolic side effects. That idea comes from mouse work and has not been confirmed in humans.
mTORC1 is also the pathway that drives muscle protein synthesis after training and protein intake, which is directly relevant to lifters (see “Muscle protein synthesis” below).
Pharmacokinetics
Data from the Rapamune label (FDA, 2022):
| Parameter | Value |
|---|---|
| Time to peak (oral solution) | About 1 h in healthy subjects; about 2 h in kidney transplant patients |
| Oral bioavailability | About 14% (solution); tablets about 27% higher than solution |
| Effect of a high-fat meal | Exposure (AUC) up 23–35%; label says take consistently with or without food |
| Distribution | Mostly inside red blood cells (blood-to-plasma ratio 36 ± 18); about 92% protein bound in plasma |
| Metabolism | CYP3A4 and P-glycoprotein (P-gp) substrate; metabolized in gut wall and liver |
| Excretion | 91% in feces, 2.2% in urine |
| Terminal half-life | About 62 ± 16 h after multiple doses in stable kidney transplant patients |
The intravenous Fyarro label reports a mean half-life of 59 hours (Fyarro label). Because of the long half-life, the Rapamune label warns that dose changes based on non-steady-state levels can lead to over- or underdosing. Because blood levels vary widely between people, the label recommends therapeutic drug monitoring of whole-blood trough levels for all patients.
Interactions that change blood levels
Strong CYP3A4/P-gp inhibitors and inducers change sirolimus exposure many-fold (Rapamune label):
| Co-medication | Effect on sirolimus |
|---|---|
| Ketoconazole (strong inhibitor) | AUC up 10.9-fold, peak up 4.3-fold; combination not recommended |
| Erythromycin | AUC up 4.2-fold, peak up 4.4-fold; combination not recommended |
| Rifampin (strong inducer) | Large fall in AUC and peak; combination not recommended |
| Grapefruit juice | Inhibits CYP3A4 metabolism; must not be taken with sirolimus |
| Cannabidiol | Label advises monitoring and possible dose reduction |
Approved medical use
Kidney transplant (Rapamune)
Rapamune is approved to prevent organ rejection in kidney transplant patients aged 13 and older (Rapamune label). Labeled regimens:
| Patient group | Labeled regimen |
|---|---|
| Low- to moderate-immunologic risk | 6 mg loading dose on day 1, then 2 mg/day, with cyclosporine and corticosteroids; cyclosporine withdrawn 2–4 months after transplant |
| After cyclosporine withdrawal | Dose adjusted to a trough of 16–24 ng/mL in year 1, then 12–20 ng/mL (chromatographic assay) |
| High-immunologic risk | Loading dose up to 15 mg on day 1, then 5 mg/day, with cyclosporine and corticosteroids for the first 12 months |
In the label’s placebo-controlled Study 2, biopsy-proven acute rejection at 6 months occurred in 24.7% (2 mg/day) and 19.2% (5 mg/day) vs 41.5% on placebo, all on top of cyclosporine and corticosteroids. The 5 mg dose showed no clear efficacy advantage over 2 mg.
Lymphangioleiomyomatosis (Rapamune)
LAM is a progressive cystic lung disease that mostly affects women. The approval rests on the MILES trial, a randomized, double-blind trial in 89 patients with moderate lung impairment (McCormack et al., NEJM 2011):
| Outcome over 12 months | Placebo (n = 43) | Sirolimus (n = 46) |
|---|---|---|
| FEV1 slope (lung function) | −12 ± 2 mL/month | +1 ± 2 mL/month |
| Between-group difference in FEV1 change | — | 153 mL, about 11% of baseline FEV1 |
Doses were adjusted to a trough of 5–15 ng/mL. After sirolimus was stopped, lung function decline resumed at the same rate as in the placebo group. Six-minute walk distance did not differ between groups.
Other sirolimus products
- Fyarro (sirolimus albumin-bound particles) is approved for adults with locally advanced unresectable or metastatic malignant PEComa (perivascular epithelioid cell tumor). The labeled dose is 100 mg/m² IV on days 1 and 8 of each 21-day cycle (Fyarro label).
- Hyftor (sirolimus topical gel 0.2%) is approved for facial angiofibroma linked to tuberous sclerosis in patients aged 6 and older, applied twice daily (Hyftor label).
Neither aging nor any longevity indication is approved for any sirolimus product.
What the research shows
Lifespan in mice (ITP)
The strongest evidence behind the longevity interest comes from the NIA Interventions Testing Program (ITP). These studies used genetically mixed (UM-HET3) mice at three independent sites. All of the results below are in mice.
| Study (mice) | Rapamycin start | Main finding |
|---|---|---|
| Harrison et al., Nature 2009 | 600 days of age, in food | Mean lifespan +9% in males and +13% in females (pooled); age at 90% mortality +9% (males) and +14% (females) |
| Harrison et al., second cohort | 270 days of age | Lower mortality risk in both sexes at an interim analysis |
| Miller et al., Aging Cell 2014 | 9 months, at 4.7, 14 or 42 ppm in food | At 42 ppm, median lifespan +23% (males) and +26% (females); females benefited more at every dose |
Three points matter when reading these results:
- Late start still worked in mice. Harrison et al. began treatment at 600 days, which was the reason for interest in older people. Disease patterns in treated mice did not differ from controls, and the authors could not say whether rapamycin slowed aging or mainly delayed cancer deaths.
- Exposure was high at the top dose. In Miller et al., blood levels at the 42 ppm dose were 80 ng/mL in females and 23 ng/mL in males. That compares with a labeled trough target of 5–15 ng/mL for LAM in people.
- Mouse metabolism changed. Rapamycin-treated males showed a paradoxical rise in glucose after an insulin injection at 14 and 42 ppm (Miller et al.), and long-term rapamycin impaired glucose tolerance in mice (Lamming et al., Science 2012).
Mouse lifespan results do not show that rapamycin extends human life. No published human trial has shown an effect on lifespan or mortality.
Immune function in older adults (everolimus and other mTOR inhibitors)
The best-known human “aging” trials used everolimus (RAD001) or a newer mTOR inhibitor, not sirolimus:
| Trial | Design and drug | Finding |
|---|---|---|
| Mannick et al., Sci Transl Med 2014 | Randomized, placebo-controlled; everolimus in older volunteers before flu vaccination | Response to the influenza vaccine improved by about 20% at doses that were relatively well tolerated; fewer T cells expressing PD-1 |
| Mannick et al., Sci Transl Med 2018 | Phase 2a, 264 older adults, 6 weeks; low-dose BEZ235 plus everolimus | Lower rate of self-reported infections over the following year (P = 0.001); better flu vaccine response |
| Mannick et al., Lancet Healthy Longev 2021 | Phase 2b (652 adults) and phase 3 (1,024 adults aged ≥65); RTB101 (BEZ235) for 16 weeks | Phase 2b: lab-confirmed respiratory infections 19% vs 28% (OR 0.60, 90% CI 0.39–0.92) for RTB101 10 mg daily, in the second prespecified analysis pooling both parts. Phase 3: no reduction in symptomatic respiratory illness (26% vs 25%; OR 1.07, 90% CI 0.80–1.42) |
In the phase 2b trial, the arm combining RTB101 with everolimus 0.1 mg daily did not significantly reduce infections compared with placebo. The larger phase 3 trial was negative on its primary outcome. So the early immune signal has not held up as a clinical benefit.
Sirolimus trials in healthy older adults
Direct sirolimus trials in aging are small:
| Trial | Design | Dose | Findings |
|---|---|---|---|
| Kraig et al., Exp Gerontol 2018 | Randomized, placebo-controlled pilot; 25 analyzed (11 rapamycin, 14 placebo), aged 70–95 | 1 mg/day for at least 8 weeks | No change in cognition, grip strength, walking speed or glucose tolerance; small but significant falls in hemoglobin, hematocrit and red cell count |
| PEARL; Moel et al., Aging 2025 | Randomized, double-blind, placebo-controlled, 48 weeks; 114 completers aged 50–85 | Compounded rapamycin 5 or 10 mg once weekly | Primary outcome (visceral fat by DXA) unchanged (p = 0.942); lean tissue mass and self-reported pain improved in women on 10 mg; adverse events similar across groups, with somewhat more GI symptoms on rapamycin |
| Moody et al., Geroscience 2026 | Open-label pilot, no control group; 6 men aged 70–76 | 1 mg/day for 8 weeks | Improvements in some cardiac MRI flow measures and skin endothelial function |
Details that limit PEARL:
- Of 114 participants analyzed, 40 took 5 mg, 35 took 10 mg and 39 took placebo. The positive findings came from secondary outcomes and subgroups.
- Mid-trial, the investigators learned the compounded drug reached about one-third of the blood concentration of commercial sirolimus at 24 hours. They estimated 10 mg compounded was equivalent to about 3.33 mg of generic sirolimus.
- One participant on 5 mg developed anemia that needed a blood transfusion.
- The authors are employees and shareholders of AgelessRx, according to the paper’s conflict-of-interest statement.
A 2024 systematic review found 19 eligible human studies of rapamycin or rapalogs on aging-related outcomes (Lee et al., Lancet Healthy Longev 2024). It reported:
- improvements in some immune, cardiovascular and skin measures;
- no significant effects on endocrine, muscular or neurological measures;
- no serious adverse events attributed to the drugs in healthy people;
- more infections and higher total cholesterol, LDL cholesterol and triglycerides in people with age-related diseases.
The review called for studies of long-term exposure.
Muscle protein synthesis
In a human study, 15 untrained young men did heavy leg exercise. Seven of them took a single 12 mg dose of rapamycin (about 0.15 mg/kg) 2 hours beforehand. Rapamycin blocked the roughly 40% rise in muscle protein synthesis seen 1–2 hours after exercise in the control group, along with mTORC1 signaling markers (Drummond et al., J Physiol 2009).
That was one large acute dose, not a training study, so it does not show what weekly low doses do to muscle growth over months. PEARL’s lean-mass finding in women points the other way, but it was a secondary outcome. The 2024 review found no significant effect on muscular outcomes overall. There are no controlled trials of rapamycin in people who are resistance training or using anabolic steroids.
Side effects and risks
Boxed warning
The Rapamune label carries a boxed warning (Rapamune label):
- Immunosuppression: greater risk of infection and possible lymphoma and other cancers. Only physicians experienced in immunosuppressive therapy should use it for transplant patients.
- Liver transplant: excess mortality, graft loss and hepatic artery thrombosis in studies; use not recommended.
- Lung transplant: bronchial anastomotic dehiscence (breakdown of the airway join); use not recommended.
In the two pivotal kidney transplant trials, lymphoma or lymphoproliferative disease occurred in 0.7–3.2% of patients on Rapamune vs 0.6–0.8% on azathioprine or placebo. Skin cancer risk is raised, and the label advises limiting sun and UV exposure.
Metabolic effects
- Lipids: hypercholesterolemia in 43–46% and hypertriglyceridemia in 45–57% of transplant patients on Rapamune, vs 23% each on placebo. In trials, up to 90% needed lipid-lowering drugs. Rapamune with statins was linked to CPK rises (3%), muscle pain (6.7%) and rhabdomyolysis (under 1%).
- Glucose: diabetes mellitus was reported in 3% to under 20% of transplant patients, and hyperglycemia and diabetes appear in post-marketing reports. Fyarro’s label lists hyperglycemia as a warning (Fyarro label).
Other label warnings
- Wound healing and fluid: impaired or delayed wound healing, lymphocele, edema, and pleural and pericardial effusions.
- Mouth sores: stomatitis was among the most common reactions in LAM (20% or more), and is the first warning on the Fyarro label.
- Lungs: interstitial lung disease and non-infectious pneumonitis, some fatal.
- Kidneys: proteinuria and decline in kidney function, especially in long-term use with cyclosporine.
- Hypersensitivity and angioedema.
- Latent viral infections: BK virus nephropathy and progressive multifocal leukoencephalopathy (PML) have been reported.
Fertility and pregnancy
- Male fertility: azoospermia (no sperm) or oligospermia (low sperm count) may occur. Azoospermia reversed after stopping in most reported cases.
- Female fertility: ovarian cysts and menstrual disorders have been reported.
- Pregnancy: can cause fetal harm based on animal studies. The label recommends highly effective contraception during treatment and for 12 weeks after the last dose.
Vaccines
Live vaccines, such as measles, mumps, rubella, yellow fever and varicella, should be avoided during treatment.
Off-label longevity use
The low-dose trials above reported tolerable safety over 8–48 weeks in selected, mostly healthy volunteers. Their size and length cannot rule out rarer or long-term risks, such as cancers or serious infections, that are documented at transplant doses. Sirolimus levels also vary many-fold with diet, formulation and common drugs (see the interaction table), and compounded products may not match commercial tablets.
Related compounds
Metformin is another approved drug that is often discussed for aging; see Metformin. Its evidence, risks and mechanism are separate from those of rapamycin.
Key takeaways
- An approved immunosuppressant, not an anti-aging drug. FDA-approved uses are kidney transplant, LAM, malignant PEComa and facial angiofibroma in tuberous sclerosis. No product is approved for aging.
- Boxed warning for immunosuppression. The label warns of infection, lymphoma and other cancers, and of high lipid levels in roughly half of transplant patients.
- Lifespan data are from mice. In the ITP, rapamycin raised median lifespan by up to 23–26% in genetically mixed mice, even when started late in life. No human trial has shown a lifespan benefit.
- Human aging trials are small and mixed. PEARL missed its primary outcome. The early immune benefit seen with everolimus did not reduce respiratory illness in a 1,024-person phase 3 trial of a related mTOR inhibitor.
- Relevant to muscle. A single 12 mg dose blocked the rise in muscle protein synthesis after resistance exercise in young men. Long-term effects of low intermittent doses on training gains are unknown.
- Levels are hard to predict. The half-life is about 62 hours, bioavailability is about 14%, and CYP3A4 drugs or grapefruit can change exposure several-fold.
Sources
- Pfizer (PF Prism C.V.). Rapamune (sirolimus) oral solution and tablets prescribing information, NDA 021083/S-069, S-070 and 021110/S-087, S-088. Revised August 2022. FDA.
- Food and Drug Administration. Drugs@FDA: Rapamune, NDA 021083. Drugs@FDA.
- Aadi Bioscience. Fyarro (sirolimus protein-bound particles for injectable suspension) (albumin-bound) prescribing information, NDA 213312/S-014. 2026. FDA.
- Nobelpharma. Hyftor (sirolimus topical gel) 0.2% prescribing information, NDA 213478. 2022. FDA.
- Vézina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo). 1975;28(10):721–726. PubMed.
- McCormack FX, Inoue Y, Moss J, et al. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011;364(17):1595–1606. PubMed.
- Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392–395. PubMed.
- Miller RA, Harrison DE, Astle CM, et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. 2014;13(3):468–477. PubMed.
- Lamming DW, Ye L, Katajisto P, et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012;335(6076):1638–1643. PubMed.
- Mannick JB, Del Giudice G, Lattanzi M, et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med. 2014;6(268):268ra179. PubMed.
- Mannick JB, Morris M, Hockey HP, et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med. 2018;10(449):eaaq1564. PubMed.
- Mannick JB, Teo G, Bernardo P, 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 Longev. 2021;2(5):e250–e262. PubMed.
- Kraig E, Linehan LA, Liang H, et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects. Exp Gerontol. 2018;105:53–69. PubMed.
- Moel M, Harinath G, Lee V, et al. Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results. Aging (Albany NY). 2025;17(4):908–936. PubMed.
- Moody AJ, Wu Y, Romo TQ, et al. Short-term mTOR inhibition by rapamycin improves cardiac and endothelial function in older men: a proof-of concept pilot study. Geroscience. 2026;48(3):4121–4137. PubMed.
- Lee DJW, Hodzic Kuerec A, Maier AB. Targeting ageing with rapamycin and its derivatives in humans: a systematic review. Lancet Healthy Longev. 2024;5(2):e152–e162. PubMed.
- Drummond MJ, Fry CS, Glynn EL, et al. Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis. J Physiol. 2009;587(Pt 7):1535–1546. PubMed.
- World Anti-Doping Agency. The 2026 Prohibited List. WADA 2026 Prohibited List.