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

Moel M, Harinath G, Lee V, Nyquist A, Morgan SL, Isman A, Zalzala S · 2025 · Aging (Albany NY) · Atlas ID MOE2025

What this study shows

First completed long-term RCT of rapamycin for healthy human aging (NCT04488601, 48 weeks, n=114). Primary endpoint (visceral fat by DXA) showed NO significant change (p=0.942) - a null result exactly as pre-registered. Secondary endpoints were more promising: women on the 10mg/week dose had significant improvements in lean muscle mass and self-reported pain. A textbook example of why the pre-registered primary endpoint, not the most exciting secondary finding, is what should drive the headline conclusion.

Abstract

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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.

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At a glance

Evidence type	H Human study Marked H because it is direct evidence from a human clinical trial or human cohort; the code names the kind of study, not its quality -- a small, well-run trial is still H.
Study type	2 - Human Clinical Trial
Model system	Humans, RCT, ages 50-85 (n=114 completed)
Journal	Aging (Albany NY)
Year	2025
Peer reviewed	Yes
Record last updated	2026-08-22
Source	DOI 10.18632/aging.206235 · PMID 40188830 · Free full text (PMC12074816)

Extracted findings

Intervention	Intermittent low-dose rapamycin (5/10 mg weekly, 48 wk)
Target	mTOR
Model	Human – RCT (PEARL, ages 50-85, n=114 completed)
Effect	Intermittent low-dose rapamycin was safe over 1 year; some healthspan gains (e.g. lean tissue in women at 10 mg)
Dose	Rapamycin (compounded), 5 mg/week or 10 mg/week orally, 48 weeks; randomized double-blind placebo-controlled. Note: compounded effective dose ~66% lower than the advertised dose.
Sample size	114 completed: 40 at 5 mg/wk, 35 at 10 mg/wk, 39 placebo. Low female enrollment (35.1%).
Effect size	Primary endpoint (visceral adipose tissue) NOT met. Secondary: decreased bone mineral density (OR 0.24, 95% CI 0.06-0.93, p=0.04); increased lean tissue (esp. women at 10 mg); small HbA1c rise in 5 mg males (p=0.010). Overall safe/well tolerated over 1 year.
Limitations	Small n -> wide 95% CIs / underpowered; low female enrollment; compounded-dose uncertainty; minor changes in RBC / BUN / HbA1c; human gerotherapeutic data still limited.

In the Atlas

Open questions that cite this study

Cited as supporting evidence for the open question mTORC1-selective (mTORC2-sparing) dosing captures longevity without insulin resistance.
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Cited as supporting evidence for the open question A sensor/autophagy biomarker panel as a surrogate endpoint for human trials.
Cited as supporting evidence for the open question Rapamycin + AMPK-axis drugs (acarbose / metformin): additive via distinct pathways, and untested as a combination in humans.

Answers that reference this study

Discussed in the plain-language answer How is rapamycin dosed in the longevity studies?.
Discussed in the plain-language answer Does rapamycin extend lifespan in humans?.
Discussed in the plain-language answer What are rapamycin's side effects?.

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