Rapamycin
updated
What is Rapamycin?
Rapamycin is the original name and sirolimus is the drug name for the same active substance. Rapamune is oral systemic sirolimus, Hyftor is a topical gel, Fyarro is intravenous albumin-bound sirolimus, and compounded weekly products have separate exposure and quality limits. Everolimus and temsirolimus are different rapalogs.
Sirolimus has approved, product-specific medical uses. The D grade here applies to using it for healthy-human longevity. Dietary rapamycin extended lifespan in mice, while the cited small human aging trials did not improve their primary physical-function or visceral-fat endpoints and did not test lifespan.
sirolimus, a macrolide mTOR inhibitor
- Rapamycin and sirolimus are names for the same active substance
- Rapamune, Hyftor, and Fyarro have different formulations, routes, and indications
- The strongest lifespan result is from mice, not people
- RAPA-EX-01 and PEARL missed their primary human endpoints
- Current systemic labeling carries immunosuppression and interaction risks
Are rapamycin and sirolimus the same thing?
Rapamycin is the original name and sirolimus is the drug name for the same active substance. Rapamune is oral systemic sirolimus, Hyftor is a topical gel, Fyarro is intravenous albumin-bound sirolimus, and compounded weekly products have separate exposure and quality limits. Everolimus and temsirolimus are different rapalogs.
| Name | Route or form | Indication or role |
|---|---|---|
| Rapamune | Oral solution or tablets | Renal-transplant rejection prophylaxis and LAM |
| Hyftor | 0.2% topical gel | Facial angiofibroma associated with tuberous sclerosis |
| Fyarro | Intravenous albumin-bound particles | Malignant PEComa |
| Compounded sirolimus | Product-specific oral preparation | Used in PEARL; measured exposure was lower than expected |
| Everolimus or temsirolimus | Distinct rapalogs | Do not merge their trials with sirolimus |
DailyMed · oral systemic sirolimus, revised October 2024
FDA drug label
DailyMed. RAPAMUNE sirolimus oral solution and tablet, label revised October 2024.
Rapamune is oral systemic sirolimus. The label covers renal-transplant rejection prophylaxis in patients age 13 and older under defined regimens and treatment of lymphangioleiomyomatosis. Its boxed warning addresses serious infection, lymphoma or other malignancy, and increased risk in liver or lung transplant settings.
- Sirolimus binds FKBP-12 and the complex inhibits mTOR.
- Warnings include impaired wound healing or fluid accumulation, hyperlipidemia, renal decline or proteinuria, pneumonitis, latent infection, embryo-fetal toxicity, and male infertility.
- Strong CYP3A4 or P-gp inhibitors and inducers should be avoided; grapefruit and live vaccines are also addressed.
- Participants / model
- Patients with specified renal-transplant regimens or lymphangioleiomyomatosis
- Treatment
- Oral sirolimus solution or tablets under labeled therapeutic-drug monitoring
- Study design
- Current regulated product information
DailyMed · topical sirolimus gel, revised May 2025
FDA drug label
DailyMed. HYFTOR sirolimus topical gel, label revised May 2025.
Hyftor is 0.2% topical sirolimus gel approved for facial angiofibroma associated with tuberous sclerosis in adults and children age six and older. It is for topical use and is not an oral, ophthalmic, or intravaginal formulation.
- Study design
- Current regulated product information
Hyftor's topical absorption and indication do not apply to oral Rapamune.
Read the original sourceDailyMed · intravenous albumin-bound sirolimus
FDA drug label
DailyMed. FYARRO sirolimus protein-bound particles for injectable suspension, label revised December 2024.
Fyarro is an intravenous albumin-bound sirolimus product approved for adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor. Its formulation, route, schedule, and oncology safety context differ from oral or compounded sirolimus.
- Participants / model
- Adults with locally advanced unresectable or metastatic malignant PEComa
- Treatment
- Intravenous albumin-bound sirolimus in labeled oncology cycles
- Study design
- Current regulated product information
What does the D grade mean if sirolimus is FDA approved?
The grade concerns healthy-human longevity. It does not dispute the product-specific approvals for Rapamune, Hyftor, or Fyarro. None of the current labels has a healthy-aging, lifespan-extension, broad-healthspan, or cognitive-enhancement indication.
DailyMed · oral systemic sirolimus, revised October 2024
FDA drug label
DailyMed. RAPAMUNE sirolimus oral solution and tablet, label revised October 2024.
Rapamune is oral systemic sirolimus. The label covers renal-transplant rejection prophylaxis in patients age 13 and older under defined regimens and treatment of lymphangioleiomyomatosis. Its boxed warning addresses serious infection, lymphoma or other malignancy, and increased risk in liver or lung transplant settings.
- Sirolimus binds FKBP-12 and the complex inhibits mTOR.
- Warnings include impaired wound healing or fluid accumulation, hyperlipidemia, renal decline or proteinuria, pneumonitis, latent infection, embryo-fetal toxicity, and male infertility.
- Strong CYP3A4 or P-gp inhibitors and inducers should be avoided; grapefruit and live vaccines are also addressed.
- Participants / model
- Patients with specified renal-transplant regimens or lymphangioleiomyomatosis
- Treatment
- Oral sirolimus solution or tablets under labeled therapeutic-drug monitoring
- Study design
- Current regulated product information
DailyMed · topical sirolimus gel, revised May 2025
FDA drug label
DailyMed. HYFTOR sirolimus topical gel, label revised May 2025.
Hyftor is 0.2% topical sirolimus gel approved for facial angiofibroma associated with tuberous sclerosis in adults and children age six and older. It is for topical use and is not an oral, ophthalmic, or intravaginal formulation.
- Study design
- Current regulated product information
Hyftor's topical absorption and indication do not apply to oral Rapamune.
Read the original sourceDailyMed · intravenous albumin-bound sirolimus
FDA drug label
DailyMed. FYARRO sirolimus protein-bound particles for injectable suspension, label revised December 2024.
Fyarro is an intravenous albumin-bound sirolimus product approved for adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor. Its formulation, route, schedule, and oncology safety context differ from oral or compounded sirolimus.
- Participants / model
- Adults with locally advanced unresectable or metastatic malignant PEComa
- Treatment
- Intravenous albumin-bound sirolimus in labeled oncology cycles
- Study design
- Current regulated product information
What does sirolimus do?
Sirolimus binds FKBP-12, and that complex inhibits mTOR. In the systemic label this suppresses cytokine-driven T-cell activation and proliferation. Established target pharmacology explains immunosuppressive effects; it does not make a human longevity outcome inevitable.
- Binding: sirolimus forms a complex with FKBP-12.
- mTOR inhibition: the complex inhibits mTOR signaling and T-cell activation.
- Clinical outcome: mTOR inhibition and mouse survival do not establish longer human lifespan.
DailyMed · oral systemic sirolimus, revised October 2024
FDA drug label
DailyMed. RAPAMUNE sirolimus oral solution and tablet, label revised October 2024.
Rapamune is oral systemic sirolimus. The label covers renal-transplant rejection prophylaxis in patients age 13 and older under defined regimens and treatment of lymphangioleiomyomatosis. Its boxed warning addresses serious infection, lymphoma or other malignancy, and increased risk in liver or lung transplant settings.
- Sirolimus binds FKBP-12 and the complex inhibits mTOR.
- Warnings include impaired wound healing or fluid accumulation, hyperlipidemia, renal decline or proteinuria, pneumonitis, latent infection, embryo-fetal toxicity, and male infertility.
- Strong CYP3A4 or P-gp inhibitors and inducers should be avoided; grapefruit and live vaccines are also addressed.
- Participants / model
- Patients with specified renal-transplant regimens or lymphangioleiomyomatosis
- Treatment
- Oral sirolimus solution or tablets under labeled therapeutic-drug monitoring
- Study design
- Current regulated product information
What did the mouse lifespan program actually show?
In genetically heterogeneous UM-HET3 mice, rapamycin mixed into chow from nine months of age increased survival in a dose-responsive experiment. At 42 ppm, median lifespan rose 23% in males and 26% in females, and maximum-lifespan measures also increased. These are strong mouse results under a specific dietary protocol, not a human dose or effect estimate.
UM-HET3 mice · median lifespan +23% male, +26% female at 42 ppm
Randomized preclinical lifespan study
Miller RA et al. Aging Cell. 2014. PMID 24341993.
Genetically heterogeneous UM-HET3 mice received encapsulated rapamycin in chow at 4.7, 14, or 42 parts per million starting at nine months of age and continuing until death. At 42 ppm, median lifespan increased 23% in males and 26% in females; maximum-lifespan measures also increased.
- Participants / model
- Genetically heterogeneous UM-HET3 mice
- Treatment
- Encapsulated rapamycin at 4.7, 14, or 42 ppm in chow
- Follow-up
- From nine months of age until death
- Study design
- Multi-site NIA Interventions Testing Program mouse lifespan experiment
- Funding
- US National Institute on Aging Interventions Testing Program
Food concentration and mouse lifespan effects do not define a human dose or prove a human longevity effect.
Read the original sourceDid RAPA-EX-01 improve physical function?
RAPA-EX-01 missed its prespecified chair-stand endpoint. The adjusted 13-week difference was -2.13 repetitions, 95% CI -4.61 to 0.34, p=.089. Complete-case and per-protocol analyses favored placebo, and the trial was too small and short to establish long-term safety.
| Analysis | Compared groups | Result |
|---|---|---|
| Intention to treat | 20 randomized per arm | -2.13 repetitions, p=.089 |
| Complete case | 16 sirolimus vs 19 placebo | -2.46 repetitions, p=.045 |
| Per protocol | 15 sirolimus vs 16 placebo | -3.44 repetitions, p=.007 |
Both groups received the same home exercise program, so this trial tested weekly sirolimus added to that program.
40 older adults · primary chair-stand result nonsignificant
Randomized controlled trial
Stanfield B et al. Journal of Cachexia, Sarcopenia and Muscle. 2026. PMID 41985884.
Forty sedentary adults age 65 to 85 were randomized 1:1 to sirolimus 6 mg weekly or placebo for 13 weeks; both groups performed standardized home exercise. The primary intention-to-treat chair-stand difference was -2.13 repetitions, 95% CI -4.61 to 0.34, p=.089. Complete-case and per-protocol analyses favored placebo.
- Seventeen of 20 participants in each arm reported at least one adverse event.
- Investigators recorded 99 events with sirolimus and 63 with placebo.
- One serious pneumonia was judged possibly related to sirolimus.
- Participants / model
- 40 sedentary adults age 65 to 85, mean age 72.2; 47.5% women
- Treatment
- Oral sirolimus 6 mg once weekly or placebo, each with home chair-stand and exercise-cycle sessions three times weekly
- Follow-up
- 13 weeks
- Study design
- Randomized, double-blind, placebo-controlled trial; ACTRN12624000790549
Sensitivity analyses do not replace the prespecified intention-to-treat primary result.
Read the original sourceDid PEARL improve visceral fat or broad healthspan?
PEARL did not improve its primary visceral-adiposity endpoint; the reported p value was .942. The publication analyzed 114 completers and reported 11 discontinuations, while the registry lists 129 enrolled, leaving four people unreconciled in the main text. Lower-than-expected measured concentration from the compounded product and exploratory subgroup findings make both positive and negative interpretation narrower.
| Source or group | Count | What it means |
|---|---|---|
| Registry actual enrollment | 129 | Full enrolled denominator |
| Paper completers | 114 | 40 at 5 mg, 35 at 10 mg, 39 placebo |
| Paper discontinuations | 11 | 2 at 5 mg, 3 at 10 mg, 6 placebo |
| Not reconciled in main text | 4 | Outcome status not supplied there |
114 completers · primary visceral-fat endpoint null
Randomized controlled trial
Moel M et al. Aging. 2025. PMID 40188830; PMCID PMC12074816.
PEARL compared compounded sirolimus 5 mg or 10 mg once weekly with placebo for 48 weeks. The paper analyzed 114 completers: 40, 35, and 39 respectively. Its primary visceral-adiposity endpoint was null, p=.942. The paper reports lower-than-expected blood concentration from its compounded product and exploratory subgroup signals rather than a primary benefit.
- The paper reports 11 discontinuations: two at 5 mg, three at 10 mg, and six with placebo.
- Registry enrollment was 129, while the paper main text accounts for 114 completers plus 11 discontinuations, leaving four participants unreconciled there.
- Reported lean-tissue, pain, emotional-wellbeing, and general-health signals were subgroup or secondary findings and need multiplicity caution.
- Participants / model
- Adults age 50 to 85; 114 completers analyzed
- Treatment
- Compounded oral sirolimus 5 mg or 10 mg once weekly versus placebo
- Follow-up
- 48 weeks
- Study design
- Decentralized double-blind randomized placebo-controlled trial; completer analysis in the publication
A null visceral-fat endpoint is not a lifespan result. Low measured product exposure and incomplete participant accounting complicate interpretation.
Read the original sourceNCT04488601 · actual enrollment 129, completed
Clinical trial registry
ClinicalTrials.gov. NCT04488601, PEARL.
The registry lists 129 enrolled. The publication main text accounts for 114 completers and 11 discontinuations, leaving four participants unreconciled.
- Participants / model
- 129 enrolled adults age 50 to 85
- Treatment
- Weekly sirolimus 5 mg, weekly sirolimus 10 mg, or placebo
- Follow-up
- 48 weeks
- Study design
- Registered randomized parallel-assignment study
Has sirolimus been shown to extend human lifespan?
The cited PubMed and ClinicalTrials.gov records contain no completed trial with a healthy-aging lifespan or mortality efficacy endpoint. Existing human studies use biomarkers, immune responses, skin measures, periodontal outcomes, or other surrogates.
40 older adults · primary chair-stand result nonsignificant
Randomized controlled trial
Stanfield B et al. Journal of Cachexia, Sarcopenia and Muscle. 2026. PMID 41985884.
Forty sedentary adults age 65 to 85 were randomized 1:1 to sirolimus 6 mg weekly or placebo for 13 weeks; both groups performed standardized home exercise. The primary intention-to-treat chair-stand difference was -2.13 repetitions, 95% CI -4.61 to 0.34, p=.089. Complete-case and per-protocol analyses favored placebo.
- Seventeen of 20 participants in each arm reported at least one adverse event.
- Investigators recorded 99 events with sirolimus and 63 with placebo.
- One serious pneumonia was judged possibly related to sirolimus.
- Participants / model
- 40 sedentary adults age 65 to 85, mean age 72.2; 47.5% women
- Treatment
- Oral sirolimus 6 mg once weekly or placebo, each with home chair-stand and exercise-cycle sessions three times weekly
- Follow-up
- 13 weeks
- Study design
- Randomized, double-blind, placebo-controlled trial; ACTRN12624000790549
Sensitivity analyses do not replace the prespecified intention-to-treat primary result.
Read the original source114 completers · primary visceral-fat endpoint null
Randomized controlled trial
Moel M et al. Aging. 2025. PMID 40188830; PMCID PMC12074816.
PEARL compared compounded sirolimus 5 mg or 10 mg once weekly with placebo for 48 weeks. The paper analyzed 114 completers: 40, 35, and 39 respectively. Its primary visceral-adiposity endpoint was null, p=.942. The paper reports lower-than-expected blood concentration from its compounded product and exploratory subgroup signals rather than a primary benefit.
- The paper reports 11 discontinuations: two at 5 mg, three at 10 mg, and six with placebo.
- Registry enrollment was 129, while the paper main text accounts for 114 completers plus 11 discontinuations, leaving four participants unreconciled there.
- Reported lean-tissue, pain, emotional-wellbeing, and general-health signals were subgroup or secondary findings and need multiplicity caution.
- Participants / model
- Adults age 50 to 85; 114 completers analyzed
- Treatment
- Compounded oral sirolimus 5 mg or 10 mg once weekly versus placebo
- Follow-up
- 48 weeks
- Study design
- Decentralized double-blind randomized placebo-controlled trial; completer analysis in the publication
A null visceral-fat endpoint is not a lifespan result. Low measured product exposure and incomplete participant accounting complicate interpretation.
Read the original sourceHuman longevity outcomes
Human clinical evidence
PubMed and ClinicalTrials.gov.
The cited PubMed and ClinicalTrials.gov records include RAPA-EX-01, PEARL, the 2018 pilot, and RESTOR. These human trials measured surrogate or functional outcomes rather than lifespan; the cited databases include no completed human trial with lifespan or mortality as the healthy-aging efficacy endpoint.
Read the original sourceDoes the recruiting RESTOR study answer the longevity question yet?
NCT06658093 is recruiting and has no posted results. Its endpoints include pharmacokinetic, pharmacodynamic, and soluble ICAM measures across rapamycin and everolimus schedules, not human lifespan.
NCT06658093 · recruiting, no results
Clinical trial registry
ClinicalTrials.gov. NCT06658093, RESTOR.
RESTOR is recruiting, with an actual start on 4 March 2026, estimated enrollment of 194, and estimated primary completion in July 2028. It compares rapamycin and everolimus schedules using pharmacokinetic, pharmacodynamic, and soluble ICAM outcomes. It has no posted results and no lifespan endpoint.
- Participants / model
- Planned 194 participants across study cohorts
- Treatment
- Registered rapamycin and everolimus schedule comparisons
- Study design
- Recruiting early phase 1 study
Everolimus is a distinct rapalog. Its arm must not be reported as direct sirolimus evidence.
Read the original sourceWhat safety risks matter for longevity experiments?
Systemic sirolimus is an immunosuppressive drug with boxed warnings for serious infection and lymphoma or other malignancy, plus dangerous use in liver or lung transplant settings. The label also covers impaired wound healing, edema, hyperlipidemia, renal effects or proteinuria, pneumonitis, latent infection, reproductive toxicity, male infertility, live-vaccine restrictions, and CYP3A4 or P-gp interactions.
Weekly aging trials have different exposure from labeled transplant treatment. Their small samples do not erase mechanism-based risks or estimate rare, cumulative, or long-latency harms.
DailyMed · oral systemic sirolimus, revised October 2024
FDA drug label
DailyMed. RAPAMUNE sirolimus oral solution and tablet, label revised October 2024.
Rapamune is oral systemic sirolimus. The label covers renal-transplant rejection prophylaxis in patients age 13 and older under defined regimens and treatment of lymphangioleiomyomatosis. Its boxed warning addresses serious infection, lymphoma or other malignancy, and increased risk in liver or lung transplant settings.
- Sirolimus binds FKBP-12 and the complex inhibits mTOR.
- Warnings include impaired wound healing or fluid accumulation, hyperlipidemia, renal decline or proteinuria, pneumonitis, latent infection, embryo-fetal toxicity, and male infertility.
- Strong CYP3A4 or P-gp inhibitors and inducers should be avoided; grapefruit and live vaccines are also addressed.
- Participants / model
- Patients with specified renal-transplant regimens or lymphangioleiomyomatosis
- Treatment
- Oral sirolimus solution or tablets under labeled therapeutic-drug monitoring
- Study design
- Current regulated product information
40 older adults · primary chair-stand result nonsignificant
Randomized controlled trial
Stanfield B et al. Journal of Cachexia, Sarcopenia and Muscle. 2026. PMID 41985884.
Forty sedentary adults age 65 to 85 were randomized 1:1 to sirolimus 6 mg weekly or placebo for 13 weeks; both groups performed standardized home exercise. The primary intention-to-treat chair-stand difference was -2.13 repetitions, 95% CI -4.61 to 0.34, p=.089. Complete-case and per-protocol analyses favored placebo.
- Seventeen of 20 participants in each arm reported at least one adverse event.
- Investigators recorded 99 events with sirolimus and 63 with placebo.
- One serious pneumonia was judged possibly related to sirolimus.
- Participants / model
- 40 sedentary adults age 65 to 85, mean age 72.2; 47.5% women
- Treatment
- Oral sirolimus 6 mg once weekly or placebo, each with home chair-stand and exercise-cycle sessions three times weekly
- Follow-up
- 13 weeks
- Study design
- Randomized, double-blind, placebo-controlled trial; ACTRN12624000790549
Sensitivity analyses do not replace the prespecified intention-to-treat primary result.
Read the original source114 completers · primary visceral-fat endpoint null
Randomized controlled trial
Moel M et al. Aging. 2025. PMID 40188830; PMCID PMC12074816.
PEARL compared compounded sirolimus 5 mg or 10 mg once weekly with placebo for 48 weeks. The paper analyzed 114 completers: 40, 35, and 39 respectively. Its primary visceral-adiposity endpoint was null, p=.942. The paper reports lower-than-expected blood concentration from its compounded product and exploratory subgroup signals rather than a primary benefit.
- The paper reports 11 discontinuations: two at 5 mg, three at 10 mg, and six with placebo.
- Registry enrollment was 129, while the paper main text accounts for 114 completers plus 11 discontinuations, leaving four participants unreconciled there.
- Reported lean-tissue, pain, emotional-wellbeing, and general-health signals were subgroup or secondary findings and need multiplicity caution.
- Participants / model
- Adults age 50 to 85; 114 completers analyzed
- Treatment
- Compounded oral sirolimus 5 mg or 10 mg once weekly versus placebo
- Follow-up
- 48 weeks
- Study design
- Decentralized double-blind randomized placebo-controlled trial; completer analysis in the publication
A null visceral-fat endpoint is not a lifespan result. Low measured product exposure and incomplete participant accounting complicate interpretation.
Read the original sourceWhat does the evidence cover?
Current FDA labels establish three distinct product uses. The NIA experiment measured mouse lifespan; RAPA-EX-01 and PEARL measured short-term human outcomes; RESTOR is recruiting; the cited PubMed and ClinicalTrials.gov records include no completed human lifespan trial.
DailyMed · oral systemic sirolimus, revised October 2024
FDA drug label
DailyMed. RAPAMUNE sirolimus oral solution and tablet, label revised October 2024.
Rapamune is oral systemic sirolimus. The label covers renal-transplant rejection prophylaxis in patients age 13 and older under defined regimens and treatment of lymphangioleiomyomatosis. Its boxed warning addresses serious infection, lymphoma or other malignancy, and increased risk in liver or lung transplant settings.
- Sirolimus binds FKBP-12 and the complex inhibits mTOR.
- Warnings include impaired wound healing or fluid accumulation, hyperlipidemia, renal decline or proteinuria, pneumonitis, latent infection, embryo-fetal toxicity, and male infertility.
- Strong CYP3A4 or P-gp inhibitors and inducers should be avoided; grapefruit and live vaccines are also addressed.
- Participants / model
- Patients with specified renal-transplant regimens or lymphangioleiomyomatosis
- Treatment
- Oral sirolimus solution or tablets under labeled therapeutic-drug monitoring
- Study design
- Current regulated product information
DailyMed · topical sirolimus gel, revised May 2025
FDA drug label
DailyMed. HYFTOR sirolimus topical gel, label revised May 2025.
Hyftor is 0.2% topical sirolimus gel approved for facial angiofibroma associated with tuberous sclerosis in adults and children age six and older. It is for topical use and is not an oral, ophthalmic, or intravaginal formulation.
- Study design
- Current regulated product information
Hyftor's topical absorption and indication do not apply to oral Rapamune.
Read the original sourceDailyMed · intravenous albumin-bound sirolimus
FDA drug label
DailyMed. FYARRO sirolimus protein-bound particles for injectable suspension, label revised December 2024.
Fyarro is an intravenous albumin-bound sirolimus product approved for adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor. Its formulation, route, schedule, and oncology safety context differ from oral or compounded sirolimus.
- Participants / model
- Adults with locally advanced unresectable or metastatic malignant PEComa
- Treatment
- Intravenous albumin-bound sirolimus in labeled oncology cycles
- Study design
- Current regulated product information
UM-HET3 mice · median lifespan +23% male, +26% female at 42 ppm
Randomized preclinical lifespan study
Miller RA et al. Aging Cell. 2014. PMID 24341993.
Genetically heterogeneous UM-HET3 mice received encapsulated rapamycin in chow at 4.7, 14, or 42 parts per million starting at nine months of age and continuing until death. At 42 ppm, median lifespan increased 23% in males and 26% in females; maximum-lifespan measures also increased.
- Participants / model
- Genetically heterogeneous UM-HET3 mice
- Treatment
- Encapsulated rapamycin at 4.7, 14, or 42 ppm in chow
- Follow-up
- From nine months of age until death
- Study design
- Multi-site NIA Interventions Testing Program mouse lifespan experiment
- Funding
- US National Institute on Aging Interventions Testing Program
Food concentration and mouse lifespan effects do not define a human dose or prove a human longevity effect.
Read the original source40 older adults · primary chair-stand result nonsignificant
Randomized controlled trial
Stanfield B et al. Journal of Cachexia, Sarcopenia and Muscle. 2026. PMID 41985884.
Forty sedentary adults age 65 to 85 were randomized 1:1 to sirolimus 6 mg weekly or placebo for 13 weeks; both groups performed standardized home exercise. The primary intention-to-treat chair-stand difference was -2.13 repetitions, 95% CI -4.61 to 0.34, p=.089. Complete-case and per-protocol analyses favored placebo.
- Seventeen of 20 participants in each arm reported at least one adverse event.
- Investigators recorded 99 events with sirolimus and 63 with placebo.
- One serious pneumonia was judged possibly related to sirolimus.
- Participants / model
- 40 sedentary adults age 65 to 85, mean age 72.2; 47.5% women
- Treatment
- Oral sirolimus 6 mg once weekly or placebo, each with home chair-stand and exercise-cycle sessions three times weekly
- Follow-up
- 13 weeks
- Study design
- Randomized, double-blind, placebo-controlled trial; ACTRN12624000790549
Sensitivity analyses do not replace the prespecified intention-to-treat primary result.
Read the original source114 completers · primary visceral-fat endpoint null
Randomized controlled trial
Moel M et al. Aging. 2025. PMID 40188830; PMCID PMC12074816.
PEARL compared compounded sirolimus 5 mg or 10 mg once weekly with placebo for 48 weeks. The paper analyzed 114 completers: 40, 35, and 39 respectively. Its primary visceral-adiposity endpoint was null, p=.942. The paper reports lower-than-expected blood concentration from its compounded product and exploratory subgroup signals rather than a primary benefit.
- The paper reports 11 discontinuations: two at 5 mg, three at 10 mg, and six with placebo.
- Registry enrollment was 129, while the paper main text accounts for 114 completers plus 11 discontinuations, leaving four participants unreconciled there.
- Reported lean-tissue, pain, emotional-wellbeing, and general-health signals were subgroup or secondary findings and need multiplicity caution.
- Participants / model
- Adults age 50 to 85; 114 completers analyzed
- Treatment
- Compounded oral sirolimus 5 mg or 10 mg once weekly versus placebo
- Follow-up
- 48 weeks
- Study design
- Decentralized double-blind randomized placebo-controlled trial; completer analysis in the publication
A null visceral-fat endpoint is not a lifespan result. Low measured product exposure and incomplete participant accounting complicate interpretation.
Read the original sourceNCT04488601 · actual enrollment 129, completed
Clinical trial registry
ClinicalTrials.gov. NCT04488601, PEARL.
The registry lists 129 enrolled. The publication main text accounts for 114 completers and 11 discontinuations, leaving four participants unreconciled.
- Participants / model
- 129 enrolled adults age 50 to 85
- Treatment
- Weekly sirolimus 5 mg, weekly sirolimus 10 mg, or placebo
- Follow-up
- 48 weeks
- Study design
- Registered randomized parallel-assignment study
NCT06658093 · recruiting, no results
Clinical trial registry
ClinicalTrials.gov. NCT06658093, RESTOR.
RESTOR is recruiting, with an actual start on 4 March 2026, estimated enrollment of 194, and estimated primary completion in July 2028. It compares rapamycin and everolimus schedules using pharmacokinetic, pharmacodynamic, and soluble ICAM outcomes. It has no posted results and no lifespan endpoint.
- Participants / model
- Planned 194 participants across study cohorts
- Treatment
- Registered rapamycin and everolimus schedule comparisons
- Study design
- Recruiting early phase 1 study
Everolimus is a distinct rapalog. Its arm must not be reported as direct sirolimus evidence.
Read the original sourceHuman longevity outcomes
Human clinical evidence
PubMed and ClinicalTrials.gov.
The cited PubMed and ClinicalTrials.gov records include RAPA-EX-01, PEARL, the 2018 pilot, and RESTOR. These human trials measured surrogate or functional outcomes rather than lifespan; the cited databases include no completed human trial with lifespan or mortality as the healthy-aging efficacy endpoint.
Read the original sourceStudies and sources
DailyMed · oral systemic sirolimus, revised October 2024
FDA drug label
DailyMed. RAPAMUNE sirolimus oral solution and tablet, label revised October 2024.
Rapamune is oral systemic sirolimus. The label covers renal-transplant rejection prophylaxis in patients age 13 and older under defined regimens and treatment of lymphangioleiomyomatosis. Its boxed warning addresses serious infection, lymphoma or other malignancy, and increased risk in liver or lung transplant settings.
- Sirolimus binds FKBP-12 and the complex inhibits mTOR.
- Warnings include impaired wound healing or fluid accumulation, hyperlipidemia, renal decline or proteinuria, pneumonitis, latent infection, embryo-fetal toxicity, and male infertility.
- Strong CYP3A4 or P-gp inhibitors and inducers should be avoided; grapefruit and live vaccines are also addressed.
- Participants / model
- Patients with specified renal-transplant regimens or lymphangioleiomyomatosis
- Treatment
- Oral sirolimus solution or tablets under labeled therapeutic-drug monitoring
- Study design
- Current regulated product information
DailyMed · topical sirolimus gel, revised May 2025
FDA drug label
DailyMed. HYFTOR sirolimus topical gel, label revised May 2025.
Hyftor is 0.2% topical sirolimus gel approved for facial angiofibroma associated with tuberous sclerosis in adults and children age six and older. It is for topical use and is not an oral, ophthalmic, or intravaginal formulation.
- Study design
- Current regulated product information
Hyftor's topical absorption and indication do not apply to oral Rapamune.
Read the original sourceDailyMed · intravenous albumin-bound sirolimus
FDA drug label
DailyMed. FYARRO sirolimus protein-bound particles for injectable suspension, label revised December 2024.
Fyarro is an intravenous albumin-bound sirolimus product approved for adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor. Its formulation, route, schedule, and oncology safety context differ from oral or compounded sirolimus.
- Participants / model
- Adults with locally advanced unresectable or metastatic malignant PEComa
- Treatment
- Intravenous albumin-bound sirolimus in labeled oncology cycles
- Study design
- Current regulated product information
UM-HET3 mice · median lifespan +23% male, +26% female at 42 ppm
Randomized preclinical lifespan study
Miller RA et al. Aging Cell. 2014. PMID 24341993.
Genetically heterogeneous UM-HET3 mice received encapsulated rapamycin in chow at 4.7, 14, or 42 parts per million starting at nine months of age and continuing until death. At 42 ppm, median lifespan increased 23% in males and 26% in females; maximum-lifespan measures also increased.
- Participants / model
- Genetically heterogeneous UM-HET3 mice
- Treatment
- Encapsulated rapamycin at 4.7, 14, or 42 ppm in chow
- Follow-up
- From nine months of age until death
- Study design
- Multi-site NIA Interventions Testing Program mouse lifespan experiment
- Funding
- US National Institute on Aging Interventions Testing Program
Food concentration and mouse lifespan effects do not define a human dose or prove a human longevity effect.
Read the original source40 older adults · primary chair-stand result nonsignificant
Randomized controlled trial
Stanfield B et al. Journal of Cachexia, Sarcopenia and Muscle. 2026. PMID 41985884.
Forty sedentary adults age 65 to 85 were randomized 1:1 to sirolimus 6 mg weekly or placebo for 13 weeks; both groups performed standardized home exercise. The primary intention-to-treat chair-stand difference was -2.13 repetitions, 95% CI -4.61 to 0.34, p=.089. Complete-case and per-protocol analyses favored placebo.
- Seventeen of 20 participants in each arm reported at least one adverse event.
- Investigators recorded 99 events with sirolimus and 63 with placebo.
- One serious pneumonia was judged possibly related to sirolimus.
- Participants / model
- 40 sedentary adults age 65 to 85, mean age 72.2; 47.5% women
- Treatment
- Oral sirolimus 6 mg once weekly or placebo, each with home chair-stand and exercise-cycle sessions three times weekly
- Follow-up
- 13 weeks
- Study design
- Randomized, double-blind, placebo-controlled trial; ACTRN12624000790549
Sensitivity analyses do not replace the prespecified intention-to-treat primary result.
Read the original source114 completers · primary visceral-fat endpoint null
Randomized controlled trial
Moel M et al. Aging. 2025. PMID 40188830; PMCID PMC12074816.
PEARL compared compounded sirolimus 5 mg or 10 mg once weekly with placebo for 48 weeks. The paper analyzed 114 completers: 40, 35, and 39 respectively. Its primary visceral-adiposity endpoint was null, p=.942. The paper reports lower-than-expected blood concentration from its compounded product and exploratory subgroup signals rather than a primary benefit.
- The paper reports 11 discontinuations: two at 5 mg, three at 10 mg, and six with placebo.
- Registry enrollment was 129, while the paper main text accounts for 114 completers plus 11 discontinuations, leaving four participants unreconciled there.
- Reported lean-tissue, pain, emotional-wellbeing, and general-health signals were subgroup or secondary findings and need multiplicity caution.
- Participants / model
- Adults age 50 to 85; 114 completers analyzed
- Treatment
- Compounded oral sirolimus 5 mg or 10 mg once weekly versus placebo
- Follow-up
- 48 weeks
- Study design
- Decentralized double-blind randomized placebo-controlled trial; completer analysis in the publication
A null visceral-fat endpoint is not a lifespan result. Low measured product exposure and incomplete participant accounting complicate interpretation.
Read the original sourceNCT04488601 · actual enrollment 129, completed
Clinical trial registry
ClinicalTrials.gov. NCT04488601, PEARL.
The registry lists 129 enrolled. The publication main text accounts for 114 completers and 11 discontinuations, leaving four participants unreconciled.
- Participants / model
- 129 enrolled adults age 50 to 85
- Treatment
- Weekly sirolimus 5 mg, weekly sirolimus 10 mg, or placebo
- Follow-up
- 48 weeks
- Study design
- Registered randomized parallel-assignment study
NCT06658093 · recruiting, no results
Clinical trial registry
ClinicalTrials.gov. NCT06658093, RESTOR.
RESTOR is recruiting, with an actual start on 4 March 2026, estimated enrollment of 194, and estimated primary completion in July 2028. It compares rapamycin and everolimus schedules using pharmacokinetic, pharmacodynamic, and soluble ICAM outcomes. It has no posted results and no lifespan endpoint.
- Participants / model
- Planned 194 participants across study cohorts
- Treatment
- Registered rapamycin and everolimus schedule comparisons
- Study design
- Recruiting early phase 1 study
Everolimus is a distinct rapalog. Its arm must not be reported as direct sirolimus evidence.
Read the original sourceHuman longevity outcomes
Human clinical evidence
PubMed and ClinicalTrials.gov.
The cited PubMed and ClinicalTrials.gov records include RAPA-EX-01, PEARL, the 2018 pilot, and RESTOR. These human trials measured surrogate or functional outcomes rather than lifespan; the cited databases include no completed human trial with lifespan or mortality as the healthy-aging efficacy endpoint.
Read the original sourceWhy is Rapamycin in D tier?
The D grade applies to healthy-human longevity and broad healthspan. Rapamune, Hyftor, and Fyarro have separate product-specific approvals for renal-transplant rejection prophylaxis or lymphangioleiomyomatosis, facial angiofibroma, and malignant PEComa.