mTOR Inhibitor

mTOR (mechanistic target of rapamycin) is a serine-threonine kinase that integrates signals from nutrients, growth factors, and cellular energy status to regulate protein synthesis, cell growth, and autophagy. mTOR exists in two complexes — mTORC1 and mTORC2 — that have distinct functions and pharmacological sensitivities.

mTORC1 is acutely sensitive to rapamycin and its analogs. mTORC1 inhibition reduces protein synthesis, slows cell proliferation, and increases autophagy. mTORC2 is acutely insensitive to rapamycin but can be inhibited by chronic high-dose exposure.

FDA-approved mTOR inhibitors:

- Sirolimus (Rapamune). Approved for organ transplant rejection prophylaxis. - Everolimus (Afinitor, Zortress). Approved for transplant rejection and various cancers. - Temsirolimus (Torisel). Approved for renal cell carcinoma.

Sirolimus has the most extensive use as a longevity intervention in off-label clinical practice. The rationale is the robust mouse lifespan extension demonstrated in the 2009 NIH Interventions Testing Program. Off-label use should be discussed with your clinician.

Off-label longevity dosing typically uses 5-8 mg once weekly, vs the 2-5 mg daily transplant dose. The intermittent schedule is intended to provide periodic mTORC1 inhibition without continuous immunosuppression.

The longevity benefit in humans has not been demonstrated in completed randomized trials. Available human data is from transplant patients on continuous high-dose use and small phase 2 studies of low-dose intermittent rapamycin in older adults. The PEARL trial is one of the larger ongoing efforts to characterize this dosing pattern in healthy adults.

Side effects in transplant patients on continuous dosing include infection risk, hyperlipidemia, mouth ulcers, anemia, and rare pneumonitis. Off-label intermittent dosing in healthy adults appears better-tolerated in published case series, but long-term safety in this population is not characterized.