Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results

Abstract

Design: This 48-week decentralized, double-blinded, randomized, placebo-controlled trial (NCT04488601) evaluated the long-term safety of intermittent low-dose rapamycin in a healthy, normative-aging human cohort. Participants received placebo, 5 mg or 10 mg compounded rapamycin 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.

Results: Adverse and serious adverse events were similar across all groups. Visceral adiposity did not change significantly (η_p² = 0.001, p = 0.942), and changes in blood biomarkers remained within normal ranges. Lean tissue mass (η_p² = 0.202, p = 0.013) and self-reported pain (η_p² = 0.168, p = 0.015) improved significantly for women using 10 mg rapamycin. Self-reported emotional well-being (η_p² = 0.108, p = 0.023) and general health (η_p² = 0.166, p = 0.004) also improved for those using 5 mg rapamycin. No other significant effects were observed.

Conclusions: 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.

Keywords: aging; geroscience; healthspan; longevity; rapamycin.

Figure 1

Changes in body composition measures in response to rapamycin use. Females using 10 mg of rapamycin had significant improvements in lean tissue mass at 24 and 48 weeks relative to both placebo (24 week: md = 3.60472 (95% CI = 0.0913–7.1182), p = 0.043; 48 week: md = 6.194 (95% CI = 0.8773–11.5105), p = 0.018) and 5mg groups (24 week: md = 3.774 (95% CI = 0.3271–7.2212), p = 0.028; 48 week: md = 5.565 (95% CI = 0.5311–10.5979), p = 0.026) (A). Improvements in visceral adiposity (measured by VAT) were clear for males in the 5 mg cohort relative to the 10 mg cohort (md = -19.520 (95% CI = −37.6513–−1.3893), p = 0.031) but not placebo (md = −11.866 (95% CI = −30.4152–6.6813), p = 0.362) at 24 weeks, but reverted to non-significance after 48 weeks (B). While no other measures showed significant differences (C, D), trending differences were observed in BMC for males at 48 weeks in 10 mg versus 5 mg groups (md = 2.580 (95% CI = −0.0600–5.2198), p = 0.057) but not placebo (md = 1.383 (95% CI = −1.1092–3.8757), p = 0.527) (C). md = mean difference, ^*=p ≤ 0.05. Error bars represent standard error of the mean.

Figure 2

Changes in self-reported survey scores of quality of life and health. Females using 10 mg of rapamycin again had significant improvements in self-reported measures of pain at both 24 and 48 weeks (24 weeks: md = 6.765 (95% CI = 1.315–12.215), p = 0.011; 48 weeks: md = 8.071 (95% CI = 3.044–13.098), p < 0.001) (A). Additionally, improvements in measures of General Health reports were specific to the 5mg rapamycin group, increasing at 24 weeks and remaining relatively constant thereafter (24 weeks: md = 5.882 (95% CI = 0.388–11.376), p = 0.033; 48 weeks: md = 5.882 (95% CI = 1.350–10.415), p = 0.007) (B), however, improvements in Emotional Well-being were only seen for 5mg rapamycin users and placebo groups after 48 weeks (5mg: md = 5.176 (95% CI = 0.056–10.297), p = 0.047; placebo: md = 4.267 (95% CI = 0.432–8.102), p = 0.025) (C). md = mean difference, ^*=p ≤ 0.05, ^**p ≤ 0.01. Error bars represent standard error of the mean.