Rapamycin
Quick Definition
Rapamycin (sirolimus) is an mTOR inhibitor FDA-approved for organ transplant rejection prophylaxis and several other niche indications. It is widely used off-label at low weekly doses for longevity-focused interventions, based on extensive preclinical lifespan extension data in animals — though human longevity outcomes are not established.
In Depth
Rapamycin was originally isolated from soil bacteria on Easter Island (Rapa Nui) in the 1970s. It received FDA approval as sirolimus in 1999 for prevention of organ transplant rejection. It is also approved for lymphangioleiomyomatosis (LAM) and as a coating on coronary stents.
Rapamycin specifically inhibits mTORC1 (mechanistic target of rapamycin complex 1), a central nutrient-sensing and protein-synthesis hub in the cell. mTORC1 inhibition mimics caloric restriction in many model organisms.
Rapamycin has demonstrated lifespan extension in yeast, C. elegans, Drosophila, and most importantly mice. The 2009 NIH Interventions Testing Program showed rapamycin extends median and maximal lifespan in genetically heterogeneous mice when started in middle age — the first pharmacologic intervention to do so robustly in mammals.
The longevity benefit in humans has not been demonstrated in any randomized clinical trial. Available human data is from transplant patients on chronic high-dose sirolimus and small phase 2 studies of low-dose rapamycin in older adults. Off-label longevity dosing typically uses 5-8 mg once weekly, vs 2-5 mg daily for transplant patients, intended to provide intermittent mTORC1 inhibition without continuous immunosuppression.
Side effects in transplant patients on continuous dosing include infection risk, hyperlipidemia, mouth ulcers, anemia, and rare pneumonitis. Side effects in healthy adults on intermittent dosing are dominated by mouth ulcers and mild lipid changes in published case series. Off-label use should be discussed with your clinician.