Rapamycin
The only drug to have extended lifespan in mice — even when started in old age
Definition
Rapamycin (sirolimus) is a macrolide produced by the bacterium Streptomyces hygroscopicus discovered on Rapa Nui (Easter Island, from which it takes its name) in 1972. It is the most selective inhibitor of mTORC1 (the cellular growth regulator complex). Initially approved as immunosuppressant in renal transplantation, it is the only drug that has reproducibly extended lifespan in male and female mice — even when treatment starts at the equivalent of 60 human years (NIA ITP study, Harrison 2009).
Detailed explanation
Results from the Intervention Testing Program (ITP) at NIA: rapamycin increased median lifespan of mice by 9-23% depending on dose and timing of start. It is the only ITP compound that has shown robust lifespan extension in multiple cohorts and independent centres.
Use in humans for longevity (off-label):
Dosing: intermittent doses much lower than immunosuppressive: 5-10 mg weekly or biweekly (vs 2-5 mg/day in transplantation). This selectively inhibits mTORC1 without touching mTORC2 (whose inhibition causes metabolic side effects). PEARL trial (AgelessRx, 2023-2024): the first controlled trial in healthy humans. Preliminary results: well tolerated, improves strength/body composition in women, no significant adverse effects at intermittent doses. Mannick (Novartis/resTORbio) trials with rapamycin analogues (everolimus) showed improved vaccine response and reduced respiratory infections in the elderly — the first solid human evidence of functional improvement with mTOR inhibition.
Mechanisms: inhibits mTORC1 → activates autophagy → improves proteostasis and clears damaged mitochondria → reduces chronic inflammation → improves aged immune function.
Side effects to monitor (even with intermittent dosing): mouth ulcers (canker sores), hypertriglyceridemia, hyperglycaemia (relative, from mTORC2 inhibition when chronified), thrombocytopenia (rare). Contraindications: pregnancy, active infection, recent major surgery. Requires specialist medical prescription — in Spain compassionate use with specialist follow-up.
Scientific sources
- PubMed — Rapamycin fed late in life extends lifespan in genetically heterogeneous mice (Harrison, Nature)
- PubMed — mTOR inhibition improves immune function in the elderly (Mannick)
- PubMed — Rapamycin for longevity: opinion article (Blagosklonny)
- PubMed — Targeting the biology of aging with mTOR inhibitors
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