Highlight
The PEARL trial, a 48-week randomized, placebo-controlled study, showed that intermittent low-dose rapamycin therapy in healthy normative-aging adults is generally safe. Significant improvements were seen in lean tissue mass and pain reduction in women taking 10 mg weekly. Lower doses (5 mg) were associated with enhanced self-reported emotional well-being and general health. No significant changes occurred in visceral adiposity or adverse biomarker levels.
Study Background and Disease Burden
Aging is a major risk factor for chronic diseases that reduce healthspan and quality of life. The search for interventions that promote healthy aging and extend healthspan—beyond simply increasing lifespan—is a growing priority in geroscience. Rapamycin, an mTOR inhibitor, has shown promising lifespan extension and healthspan benefits in animal models but its long-term effects and safety in normative-aging humans are not well established. The PEARL trial addresses this by investigating low-dose, intermittent rapamycin in healthy adults to evaluate its potential in aging intervention while carefully assessing safety and clinically relevant health outcomes.
Study Design
The PEARL trial was a decentralized, double-blinded, randomized, placebo-controlled clinical trial registered as NCT04488601. It targeted a healthy, normative-aging population without significant comorbidities. Participants were randomized to receive placebo, 5 mg, or 10 mg compounded rapamycin weekly over 48 weeks.
The primary endpoint was visceral adiposity measured by dual-energy X-ray absorptiometry (DXA) scans, a relevant marker linked to metabolic health and aging. Secondary endpoints included blood biomarkers related to metabolic and organ function, lean tissue mass, and bone mineral content also assessed by DXA. Participant-reported outcomes evaluating health status, pain, emotional well-being, and general health were captured through validated surveys. Safety outcomes were rigorously tracked by adverse event reporting and serial blood biomarker monitoring.
Key Findings
Safety data revealed that both adverse and serious adverse events were comparable across placebo and rapamycin groups, indicating that low-dose intermittent rapamycin does not increase short-to-medium term risk in healthy aging adults.
The primary outcome, visceral adiposity, showed no significant differences between any group, with effect size near zero (ηp2 = 0.001, p = 0.942), suggesting rapamycin did not alter this aspect of fat distribution over 48 weeks.
However, significant secondary outcomes emerged in lean tissue mass and patient-reported pain specifically for women given 10 mg rapamycin weekly. Lean tissue mass improved (ηp2 = 0.202, p = 0.013), likely reflecting favorable effects on muscle mass or related maintenance, a critical factor in preventing frailty. This was accompanied by reductions in self-reported pain (ηp2 = 0.168, p = 0.015), which may further contribute to improved functional status and quality of life.
For participants receiving 5 mg rapamycin, self-reported emotional well-being (ηp2 = 0.108, p = 0.023) and general health (ηp2 = 0.166, p = 0.004) improved significantly, pointing toward possible psychological or systemic benefits potentially mediated by lower-dose rapamycin’s influence on cellular or metabolic processes.
Blood biomarkers remained stable and within normal ranges across all groups, supporting the safety profile over the study duration.
No significant effects were found on bone mineral content or other measured parameters.
Expert Commentary
The PEARL trial represents a pivotal step in translating preclinical evidence of rapamycin as a geroprotective agent into clinical applicability. The favorable safety profile addresses concerns about immunosuppression and metabolic disturbances that have limited rapamycin’s widespread use. The sexual dimorphism observed—with significant lean mass and pain benefits mainly in women—raises important mechanistic questions and the need for sex-specific analysis in future studies.
Improved self-reported emotional well-being and general health at the lower dose suggest dose-dependent nuances in rapamycin’s effects, possibly attributable to varying molecular targets and pathways modulated by different dosages.
Limitations include the moderate sample size and relatively short duration for longevity studies, as well as the lack of diverse ethnic representation, which should be addressed in future trials. The decentralized trial design is innovative but may influence compliance and assessment uniformity.
This study complements emerging evidence supporting rapamycin and related mTOR inhibitors as candidates for extending healthspan by preserving lean mass and reducing pain, key determinants of functional independence in aging.
Conclusion
In summary, intermittent low-dose rapamycin administered weekly over 48 weeks is safe in healthy normative-aging adults and confers significant benefits in lean tissue mass and pain reduction in women, alongside improved emotional well-being and general health at lower doses. These healthspan improvements highlight rapamycin’s promise as a geroprotective intervention. Larger, longer-term studies exploring a broader range of doses, mechanistic insights, and impact on other healthspan domains are warranted to establish efficacy and inform clinical translation for aging intervention strategies.
References
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2. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017 Mar 9;168(6):960-976. doi: 10.1016/j.cell.2017.02.004.
3. Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493(7432):338-345. doi: 10.1038/nature11861.
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