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

Background Low-dose rapamycin promotes longevity in mice, but clinical safety and longevity data effects in humans remain limited.

Evaluate the long-term safety of intermittent low-dose rapamycin in a healthy, normative-aging human cohort. Design This 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.

Adverse and serious adverse events were similar across all groups. Visceral adiposity did not change significantly (ηp2=0.001, p=0.942), and changes in blood biomarkers remained within normal ranges. Lean tissue mass (ε2=0.202, p=0.013) and self-reported pain (ε2=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 (ε2=0.221, p=0.061), but no other significant effects were observed.

Low-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. Competing Interest Statement GH, VL, AN, MM, SM, AI, and SZ are employees and shareholders of AgelessRx. Clinical Trial NCT04488601 Funding Statement This study was funded by crowd sourced private donations. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The IRB of the Institute of Regenerative and Cellular Medicine gave ethical approval for this work in May 2020 (approval number IRCM-2020-252) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Peer reviewers made a significant number of suggestions that have prompted substantial revisions of this work. Notably, the statistical analysis approach has been revised and simplified, and the interpretation of findings tempered. Data Availability All data produced in the present study are available upon reasonable request to the authors