Rapamycin (Sirolimus)
A macrolide mTOR inhibitor approved as an immunosuppressant and in drug-eluting stents, repurposed off-label as the flagship geroprotector. It has the strongest and most reproducible lifespan-extension data of any small molecule in mammals, but human longevity outcome trials do not yet exist; interest rests on animal data and short-term human biomarker work.
01 Overview
Rapamycin (sirolimus) is a natural product isolated from Streptomyces hygroscopicus on Rapa Nui, FDA-approved in 1999 to prevent organ-transplant rejection and later used to coat coronary stents. It inhibits mTORC1, a central nutrient-sensing kinase, which slows anabolic growth and upregulates autophagy — the same pathway modulated by caloric restriction.
In the NIA Interventions Testing Program it extended median and maximal lifespan in genetically heterogeneous mice even when started late in life, a result replicated across multiple labs and species. Human longevity use is off-label and typically low-dose intermittent (weekly) to spare mTORC2 and limit immunosuppression. There are no completed human trials showing it extends human lifespan or prevents age-related disease; the PEARL trial and similar efforts report on tolerability and biomarkers, not hard outcomes.
02 Mechanism
Binds FKBP12; the complex inhibits mTORC1, reducing cap-dependent translation and cell growth while inducing autophagy. Chronic dosing can also inhibit mTORC2, impairing glucose homeostasis.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Transplant (labelled) | 2–5 mg/day | Oral | Daily immunosuppressive dosing per label, with trough monitoring. |
| Longevity (off-label, intermittent) | 5–8 mg/wk | Oral | Once-weekly pulsing is the common off-label protocol; not validated for outcomes. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Lifespan extension (animal)Robustly extends median and maximal lifespan in mice across multiple independent studies, including late-life dosing. | +10-25% median (mice) | Preclinical | |
| Enhanced autophagy / mTOR suppressionReliably suppresses mTORC1 signalling and raises autophagic flux in human tissue at clinical doses. | measurable p70S6K reduction | Clinical | |
| Improved immune response to vaccination (elderly)Low-dose mTOR inhibition improved influenza vaccine responses in older adults in a controlled trial (RTB101/everolimus programme). | ~20% higher antibody titre | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Mouth ulcers / stomatitisPainful aphthous ulcers are the most common dose-limiting complaint even with intermittent dosing. | Mild | Common at higher doses | Clinical | |
| Impaired glucose tolerance / insulin resistanceChronic daily dosing can raise fasting glucose and lipids via mTORC2 inhibition; intermittent dosing largely avoids this. | Moderate | Dose- and frequency-dependent | Clinical | |
| Immunosuppression / infection riskAt immunosuppressive exposure, increases susceptibility to infections and impairs wound healing. | Severe | Higher at daily transplant doses | Clinical |