Rapamycin / Sirolimus

Not a peptide. Rapamycin is a macrolide small molecule produced by the soil bacterium Streptomyces hygroscopicus. It is included because it is constantly discussed alongside peptides in longevity circles and people search for it here. The same evidence standards apply.

sirolimus (INN), Rapamune, Hyftor (topical gel), Fyarro (albumin-bound IV), AY-22989; related "rapalogs": everolimus, temsirolimus

Longevity & cellular

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Note on this profile. Sirolimus is an approved prescription medicine (transplant rejection, lymphangioleiomyomatosis, and a topical gel for tuberous sclerosis skin lesions). This page explains the published science. Its use for "longevity" or healthy ageing is off-label, unproven in humans, and carries the real risks of an immunosuppressant.

Summary

Class: Macrolide lactone (molecular weight ~914), a small molecule, not a peptide; mTOR inhibitor
Mechanism: Binds the protein FKBP12, and the pair then jams mTORC1 — the cell's main nutrient-sensing switch — so the cell shifts from growth and protein synthesis toward recycling (autophagy) and stress resistance
Routes studied: Oral tablets and solution (approved); topical gel (approved); IV albumin-bound (approved, cancer); animal studies by diet, injection
Dose range reported: Approved: kidney transplant 6 mg loading then 2 mg daily (higher regimens up to 15 mg loading / 5 mg daily), adjusted to blood trough levels; LAM 2 mg daily to a trough of 5–15 ng/ml; topical 0.2% gel twice daily. Longevity research in humans: 0.5 mg daily or 5 mg weekly of everolimus for 6 weeks (Mannick 2014); 1 mg daily sirolimus for 8 weeks (Kraig 2018); 5 or 10 mg weekly for 48 weeks (PEARL trial). Community-reported: 3–8 mg once weekly or once every two weeks, often with "drug holidays" — not validated
Half-life: ~62 hours (range ~46–78) in healthy adults; steady state after about two weeks of daily dosing
Storage: Tablets: room temperature, in original packaging, protect from light. Oral solution: refrigerate, protect from light, use within one month of opening; may be kept at room temperature briefly
Regulatory status: Approved medicine (US, EU, UK, AU, ZA and many others) for specific indications; longevity use off-label everywhere

Doses are as reported in studies or by the community — never recommendations.

1What it is

Rapamycin was found in a soil sample from Easter Island (Rapa Nui, hence the name) in the early 1970s by Surendra Sehgal's team at Ayerst in Montreal. It was first studied as an antifungal, then found to suppress the immune system, and was approved in 1999 to prevent kidney-transplant rejection. Working out how it acts led to the discovery of its target, named mTOR ("mechanistic target of rapamycin"), which turned out to be the central hub through which cells sense nutrients, growth factors and energy and decide whether to grow.

Its longevity reputation comes from one of the most robust results in ageing biology: it extended lifespan in yeast, worms, flies and — in the US National Institute on Aging's rigorous three-site Interventions Testing Program — in genetically diverse mice, even when started at an age equivalent to a 60-year-old human (Harrison 2009, Nature). No other drug has reproduced that as consistently. Whether it does anything similar in humans is unknown, and it is the subject of trials, a large dog study and a growing off-label experiment among self-tracking adults.

2How it's thought to work

mTORC1 inhibition. rapamycin–FKBP12 binds mTORC1 and blocks most of its functions, reducing protein synthesis (via S6K and 4E-BP1), lipid synthesis and cell growth, and releasing the brake on autophagy, the process by which cells clear damaged proteins and organelles. Reduced mTORC1 signalling is a shared feature of nearly every intervention that extends lifespan in animals, including dietary restriction.

mTORC2. rapamycin was once thought to spare mTORC2, but chronic or high dosing inhibits it too. mTORC2 loss is what drives the glucose intolerance and insulin resistance seen with rapamycin (Lamming 2012, Science). This is the basis for intermittent (weekly) dosing in longevity protocols: the hope is to hit mTORC1 while letting mTORC2 recover. That hope is supported by mouse data and is unproven in humans.

Immune effects. blocks T-cell proliferation in response to IL-2 (the transplant use), but at low intermittent doses appears to improve some immune functions in older adults, possibly by reducing "exhausted" T-cell populations and improving vaccine responses.

Senescence. reduces the inflammatory secretions of senescent cells (the SASP) in culture and in mice.

Rapamycin binds FKBP12, and that pair inhibits mTORC1 — the sensor that tells a cell nutrients are plentiful. With it switched off the cell behaves as though fasting: growth slows and autophagy, the clearing of worn-out contents, begins.Schematic — not to scale

3What the research shows

Transplant rejection prophylaxis

Multiple underpin approval; sirolimus reduces acute rejection as part of combination regimens, with a distinctive side-effect profile (lipids, wound healing, proteinuria) compared with calcineurin inhibitors.

Lymphangioleiomyomatosis (LAM)

The MILES trial showed stabilisation of lung function versus decline on placebo (McCormack 2011, NEJM). [8]

Tuberous sclerosis facial angiofibromas (topical)

Phase 3 of 0.2% sirolimus gel showed significant improvement over vehicle, leading to the 2022 approval of Hyftor.

Graded C (exceptionally strong for C)

Lifespan and healthspan in animals

Lifespan extension of roughly 9–14% in mice started at 20 months (Harrison 2009, Nature), confirmed in later ITP cohorts and dose-response studies (Miller 2014, Aging Cell), with improvements in several age-related pathologies. Intermittent dosing and short mid-life courses also extended lifespan in some studies (Bitto 2016, eLife). Consistent across sexes and genetic backgrounds, which is rare. [1][2][7]

Graded A (surrogate endpoints)

Immune ageing in humans

A 6-week RCT of the rapalog everolimus (0.5 mg daily or 5 mg weekly) in 218 adults over 65 improved antibody response to influenza vaccine by about 20% and reduced exhausted PD-1-positive T cells (Mannick 2014, Sci Transl Med). A follow-up combination (RTB101 ± everolimus) reduced reported respiratory infections in Phase 2 (Mannick 2018, Sci Transl Med) but the Phase 3 programme failed its primary endpoint in 2019. [4][5]

Graded A (small)

Safety of low dose in healthy older adults

An 8-week placebo-controlled pilot of 1 mg daily sirolimus in 25 adults aged 70–95 found no serious adverse events and no clear change in cognitive, physical or immune measures (Kraig 2018, Exp Gerontol). The 48-week PEARL trial (around 115 participants, 5 or 10 mg weekly compounded sirolimus vs placebo) reported acceptable safety with modest improvements in lean mass and pain in women on 10 mg and no significant change in the primary visceral-fat outcome (Harinath 2025, Aging) †. [6][11]

Graded B/—

Observational and community data

Surveys of self-prescribing adults (Kaeberlein 2023, GeroScience) report mostly mild side effects (mouth ulcers) and self-perceived benefits that cannot be separated from expectation. The Dog Aging Project's TRIAD trial of weekly rapamycin in companion dogs is ongoing, after a small pilot suggested improved cardiac function (Urfer 2017, GeroScience). [9][10]

Graded C/B

Cancer, Alzheimer's, periodontal disease, ovarian ageing

Rapalogs are approved cancer drugs (everolimus, temsirolimus). Small human pilots exist in periodontal ageing and in ovarian function; mouse data in Alzheimer's models are positive; none is established in humans.

4Reported side effects and interactions

Literature-reported

Literature (approved doses, daily, with trough monitoring). mouth ulcers and stomatitis (the most common complaint at every dose), raised cholesterol and triglycerides, raised glucose and new-onset diabetes, low platelets and anaemia, impaired wound healing and lymphocele, peripheral oedema, acne-like rash, proteinuria, interstitial pneumonitis (uncommon but serious), increased infections including opportunistic ones, reduced testosterone and sperm count in men (reversible), and, in transplant populations, increased risk of certain cancers and lymphoma over years of combined immunosuppression. Not for use in pregnancy; effective contraception advised.

Community-reported

Community-reported (intermittent low dose). mouth ulcers, transient fatigue or "flu-like" feeling on dose day, raised LDL and triglycerides on blood tests, raised fasting glucose, acne, slower healing of cuts, occasional bacterial skin infections; most report the regimen as tolerable, which is a selected population of people who continued.

Theoretical. long-term immune suppression even at intermittent doses; metabolic harm via mTORC2 that may not show up for years; masking of infections; unknown interaction with the cancer-promoting and cancer-suppressing effects of mTOR inhibition in healthy people.

Interactions. sirolimus is cleared by CYP3A4 and P-glycoprotein, so blood levels can rise sharply with ketoconazole, itraconazole, voriconazole, clarithromycin, erythromycin, diltiazem, verapamil, HIV protease inhibitors and grapefruit juice, and fall with rifampicin, carbamazepine, phenytoin and St John's wort. Combined with cyclosporine, take at a fixed interval. Live vaccines should be avoided. ACE inhibitors increase angioedema risk. The community practice of taking it with grapefruit juice to "stretch" a dose deliberately exploits an interaction that makes blood levels unpredictable.

Markers researchers commonly monitor

These follow transplant-label monitoring and the longevity trials:

Marker	Why it's watched
Sirolimus trough level	standard in transplant care (target depends on regimen); rarely done in community use, which means nobody knows their exposure. Useful at least once if dosing weekly.
Fasting lipids (LDL, triglycerides)	the most consistent metabolic change, often within weeks.
Fasting glucose, fasting insulin, HbA1c	mTORC2-related insulin resistance; the key safety marker for intermittent use.
CBC with platelets	thrombocytopenia and anaemia are dose-related.
CMP including creatinine/eGFR and urine protein	proteinuria and kidney effects, especially with any other nephrotoxic drug.
Liver enzymes	occasional elevations.
Testosterone (men)	reduced in transplant studies; reversible.
Infection and wound-healing log	mouth ulcers, skin infections, slow healing are early warnings of over-exposure.
Lung symptoms	new cough or breathlessness needs prompt review for pneumonitis.

Free for everyone. Safety information is never behind a paywall.

5Formulation and handling

Approved as 0.5 mg, 1 mg and 2 mg tablets, a 1 mg/ml oral solution (refrigerate, protect from light, use within one month of opening, dilute in water or orange juice — not grapefruit juice), and a 0.2% topical gel. Tablets should be taken consistently with or without food, since fat alters absorption, and should not be crushed. Compounded capsules used in some longevity trials have shown variable bioavailability. There is no , and no injectable form outside the oncology product. Tablets store at room temperature in original packaging, protected from light and moisture.

6Commonly studied alongside

Metformin (the other most discussed "geroprotector"; combined use in longevity circles, with mouse data on additive effects); acarbose and 17α-oestradiol (other ITP successes); GH secretagogues such as ipamorelin (#4) — notable because GH/IGF-1 raises mTOR signalling, so the two pull in opposite directions and are frequently combined by the community without data; NAD precursors; senolytics (dasatinib + quercetin, fisetin); MOTS-c and epitalon in community "longevity stacks" with no combination data.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	FDA-approved (Rapamune, 1999, transplant; 2015, LAM; Hyftor gel 2022; Fyarro 2021 for PEComa). Prescription-only; longevity use off-label; widely prescribed off-label by telehealth clinics, and compounded versions exist
European Union	EMA-authorised (Rapamune) for kidney transplant and LAM; prescription-only
United Kingdom	MHRA-licensed; prescription-only
Australia	TGA-approved; Schedule 4 prescription-only
South Africa	SAHPRA-registered; prescription-only
Sport	Not on the WADA Prohibited List as of review †

8Open questions

Does rapamycin extend healthy lifespan in humans? No trial can answer this directly; surrogate-marker trials are small and mixed.
Is intermittent (weekly) dosing really safer metabolically, or does it just dilute both benefit and harm?
Optimal dose, age to start, and duration — all unknown.
Sex differences: female mice benefit more in the ITP; PEARL hinted at a female-specific effect.
Whether companion-dog results (TRIAD) will translate.

9References

1Harrison DE et al. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. PubMed · DOI
2Miller RA et al. (2014). Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell. PubMed · DOI
3Lamming DW et al. (2012). Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. PubMed · DOI
4Mannick JB et al. (2014). mTOR inhibition improves immune function in the elderly. Sci Transl Med. PubMed · DOI
5Mannick JB et al. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med. PubMed · DOI
6Kraig E et al. (2018). A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort. Exp Gerontol. PubMed · DOI
7Bitto A et al. (2016). Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. eLife. PubMed · DOI
8McCormack FX et al. (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis (MILES). NEJM. PubMed · DOI
9Urfer SR et al. (2017). A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. GeroScience. PubMed · DOI
10Kaeberlein TL et al. (2023). Evaluation of off-label rapamycin use to promote healthspan in 333 adults. GeroScience. PubMed
11Harinath G et al. (2025). Safety and efficacy of low-dose rapamycin for healthy aging (PEARL). Aging [verify details]. PubMed
12Pfizer. Rapamune prescribing information (current label). PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

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11Page history

26 Oct 2026Profile published — awaiting medical review

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