Rapamycin — The mTOR Inhibitor
Rapamycin (sirolimus) is an FDA-approved immunosuppressant that inhibits mTOR complex 1 (mTORC1), the master regulator of cellular growth and metabolism. It is the most robust lifespan-extending drug in mammals, extending mouse lifespan by 10–25% even when started late in life.
Mechanism of Action
mTORC1 inhibition by rapamycin reduces protein synthesis, activates autophagy, and shifts cells toward a maintenance and repair mode rather than growth. This mimics the longevity benefits of caloric restriction. Rapamycin also reduces senescent cell burden and improves immune function in aging.
Human Trial Evidence
The TRIIM trial (2019, Aging) showed a 9-drug cocktail including low-dose rapamycin reversed epigenetic age by ~2.5 years in 9 healthy men. Multiple human studies show rapamycin improves immune response to flu vaccine in elderly subjects. The PEARL trial is ongoing (2023–2025) testing 5 mg/week in healthy adults.
Dosing Protocol
Clinically used longevity protocols: 5–6 mg once weekly (Attia protocol). Some practitioners use 1–2 mg/day. Weekly pulsed dosing is thought to avoid mTORC2 inhibition (which causes metabolic side effects seen with daily dosing). Prescription only in most countries.
Safety & Contraindications
Immunosuppression at high continuous doses (organ transplant dosing). At low intermittent doses, main risks are: mouth sores (aphthous ulcers), impaired wound healing, hyperlipidemia, and increased infection risk. Not for use in active infection or pregnancy. Requires physician supervision.
Key Papers
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Nature · 2009
Reversal of epigenetic aging and immunosenescent trends in humans
Aging Cell · 2019
Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice
Journals of Gerontology · 2011