Ultimate Longevity Bible

Intervention

Rapamycin

Last updated Sun May 17 2026 00:00:00 GMT+0000 (Coordinated Universal Time)

title: Rapamycin slug: rapamycin category: interventions summary: An mTOR inhibitor, originally an immunosuppressant, that extends lifespan in every mammalian model tested. Off-label use for longevity is investigational. lastUpdated: 2026-05-17 tags: [rapamycin, sirolimus, mTOR, longevity drug] references:

  • "Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009)."
  • "Kaeberlein, M. & Galvan, V. Rapamycin and Alzheimer's disease. Sci. Transl. Med. 11, eaar4289 (2019)."

What it is

Rapamycin (sirolimus) is a macrolide produced by Streptomyces hygroscopicus, first isolated from a soil sample on Easter Island (Rapa Nui). It binds FKBP12 and the resulting complex inhibits mTORC1, the master regulator of cellular growth and nutrient signalling. It is FDA-approved as an immunosuppressant for organ transplant.

Why it’s of interest

Rapamycin (and its analog everolimus) is the most reproducible lifespan-extending pharmaceutical in mammals. The NIA’s Interventions Testing Program showed median-lifespan extension in genetically heterogeneous mice across multiple independent sites and at multiple ages, including late-life dosing.

Mechanism

mTORC1 inhibition reduces protein synthesis, raises autophagy, and shifts cellular state from growth to maintenance — the conserved “dietary restriction” programme acting downstream of nutrient sensing.

Human evidence

  • Approved as immunosuppressant; safety profile at transplant doses well characterised.
  • Low-dose intermittent dosing (e.g. 5–6 mg once weekly) is under investigation for healthspan; the PEARL trial and follow-on protocols are the most-cited human studies.
  • Off-label use is reported in longevity-medicine clinics but lacks long-term RCT data.

Safety

Even at low doses: stomatitis (mouth ulcers), impaired wound healing, glucose intolerance/hyperglycaemia, dyslipidaemia, increased infections, and (rarely) interstitial pneumonitis. Drug interactions via CYP3A4 are significant. Not appropriate during attempts to conceive.

Related entries

See also: Disabled macroautophagy, Deregulated nutrient-sensing, ITP trial, PEARL trial.

References

  • Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
  • Kaeberlein, M. & Galvan, V. Rapamycin and Alzheimer's disease. Sci. Transl. Med. 11, eaar4289 (2019).

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