Rapamycin has been shown to have longevity-enhancing effects in murine models, but clinical data on its gerotherapeutic effects in humans remains limited. We performed a 48-week double-blinded, randomized, and placebo-controlled decentralized study (Participatory Evaluation of Aging with Rapamycin for Longevity [PEARL]; [NCT04488601][1]; registration date 2020-07-28) to evaluate the safety and efficacy of rapamycin in mitigating clinical signs of aging in a normative aging cohort. Participants received 5 or 10 mg / week of compounded rapamycin, or placebo for 48 weeks. Safety, adverse events (AEs) and blood biomarkers were collected. Efficacy was assessed using DEXA scan-based measures and standardized surveys assessing quality of life (QoL) and frailty. We did not detect significant differences in safety blood biomarkers, or moderate to severe AEs between the rapamycin treatment groups and placebo after 48 weeks. We detected dose-dependent (10 mg group) and sex-specific improvements in lean tissue mass, pain, social functioning, overall QoL, and overall osteoarthritis score in females, and in bone mineral content in men. Additionally, some individuals receiving rapamycin experienced significant improvements in body composition metrics that were associated with beneficial changes in gut health and lipid metabolism. We conclude that low-dose, intermittent rapamycin administration over the course of 48 weeks is safe and induces sex-specific improvements in multiple aspects of healthspan, with the most robust improvements in lean tissue mass in women taking 10 mg rapamycin/week. Future work will aim to identify biometric signatures of clinical effectiveness to inform personalized treatment strategies that more broadly maximize efficacy and minimize side effects. ### Competing Interest Statement GH, VL, AN, MM, SM, AI, and SZ are employees and shareholders of AgelessRx. JH has received financial compensation from AgelessRx for their contributions. ### 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 All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04488601&atom=%2Fmedrxiv%2Fearly%2F2024%2F08%2F26%2F2024.08.21.24312372.1.atom