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; 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.