Safety and efficacy of rapamycin on healthspan metrics after one year: PEARL Trial Results

BackgroundLow-dose rapamycin promotes longevity in mice, but clinical safety and longevity data effects in humans remain limited. ObjectivesEvaluate the long-term safety of intermittent low-dose rapamycin in a healthy, normative-aging human cohort. DesignThis decentralized double-blinded, randomized, placebo-controlled trial (NCT04488601, registered 2020-07-28) was performed over 48 weeks. Participants received placebo, 5mg or 10mg compounded rapamycin (equivalent to 1.43mg or 2.86mg of generic formulations) weekly. The primary outcome measure was visceral adiposity (by DXA scan), secondary outcomes were blood biomarkers, and lean tissue and bone mineral content (by DXA scan). Established surveys were utilized to evaluate health and well-being. Safety was assessed through adverse events and blood biomarker monitoring. ResultsAdverse and serious adverse events were similar across all groups. Visceral adiposity did not change significantly ({eta}p2=0.001, p=0.942), and changes in blood biomarkers remained within normal ranges. Lean tissue mass ({varepsilon}2=0.202, p=0.013) and self-reported pain ({varepsilon}2=0.168, p=0.015) improved significantly for women using 10mg rapamycin. Trends of improvement in bone mineral density were observed in males using 10mg rapamycin ({varepsilon}2=0.221, p=0.061), but no other significant effects were observed. ConclusionsLow-dose, intermittent rapamycin administration over 48 weeks is relatively safe in healthy, normative-aging adults, and was associated with significant improvements in lean tissue mass and pain in women. Future work will evaluate benefits of a broader range of rapamycin doses on healthspan metrics for longevity, and will aim to more comprehensively establish efficacy.