Drugs and compounds · Research Brief
PEARL trial found no change in its main visceral-fat outcome
A 48-week randomized trial in generally healthy older adults found similar adverse-event patterns across groups and no significant change in visceral fat, its primary outcome. Smaller secondary findings remain exploratory.
Human publication approval was recorded July 31, 2026 after source, correction-status, and evidence review.
Evidence box
Mixed, limited human evidence
- Study type
- Randomized, placebo-controlled, quadruple-masked Phase 2 trial
- Studied in
- 129 enrolled; 114 completers aged 50–85 analyzed
- Publication status
- Peer reviewed
- Outcome type
- Visceral fat primary; body composition, biomarkers, surveys and safety secondary
- Development stage
- Off-label healthy-aging research
- Conflicts / funding
- All authors were AgelessRx employees/shareholders; crowdfunding and named donors
- Editorial assessment
- Mixed; primary outcome null
- Reporting confidence
- High for reported results; generalizability limited
The bottom line
PEARL randomized generally healthy adults aged 50 to 85 to placebo or compounded rapamycin advertised as 5 mg or 10 mg once weekly for 48 weeks. Visceral adiposity—the registered primary outcome—did not differ significantly between groups. Adverse and serious adverse events were reported at broadly similar frequencies, but the trial was not large enough or designed to prove that rapamycin lengthens healthy life or lifespan. (primary results; registry)
Why this matters
Rapamycin inhibits mTOR, a nutrient-sensing pathway central to geroscience. That biological rationale has encouraged off-label use even though sirolimus is not FDA-approved to slow aging. PEARL is useful because randomized human data are scarce; its null primary result is at least as important as its more favorable secondary findings.
What researchers did
ClinicalTrials.gov records 129 participants in a randomized, parallel, placebo-controlled Phase 2 study. The publication analyzed 114 completers: 40 in the 5 mg group, 35 in the 10 mg group and 39 on placebo; 11 people discontinued and were excluded from the reported analyses. Assessments occurred at baseline, 24 weeks and 48 weeks. The primary endpoint was change in visceral fat measured by DXA. Secondary and exploratory measures included lean tissue, bone measures, blood biomarkers and self-reported health and pain.
What they found
Visceral adiposity did not change significantly across the groups at 48 weeks. The paper reported a significant increase in lean tissue mass among women in the 10 mg group and improvements in some self-reported measures, including pain for women in the 10 mg group and general health in the 5 mg group. These were secondary, sex-stratified or survey findings from small subgroups; most other comparisons were not significant. Six serious adverse events occurred—one in the 10 mg group, two in the 5 mg group and three on placebo—and non-serious adverse-event totals were similar, although gastrointestinal symptoms were more frequent in rapamycin groups. (primary results)
How strong is the evidence?
Randomization and masking are strengths. The primary outcome was null, and the analysis excluded discontinuers and used available cases when data were missing. Only 40 completers were women, including eight in the 10 mg group, so sex-specific estimates are imprecise. The compounded product produced about one-third of the 24-hour blood concentration of a commercial formulation in a separate comparison, creating uncertainty about actual exposure. Together, those limits make the favorable secondary signals hypothesis-generating, not proof of benefit.
What this does not show
PEARL did not measure lifespan and did not establish reduced disability, disease incidence or mortality. It does not show that a different formulation, dose or schedule is safe or effective. Similar event counts in 114 completers over 48 weeks cannot rule out uncommon, delayed or population-specific harms.
Safety and conflicts
Sirolimus is an immunosuppressant with FDA-approved uses that do not include healthy aging. Its official label contains major warnings and describes risks that can include infection, malignancy, metabolic effects, impaired wound healing and drug interactions; clinical context and exposure matter. Every PEARL author disclosed employment and share ownership in AgelessRx, the trial sponsor. Funding came primarily from a Lifespan.io crowdfunding effort with named major donors. Those interests make independent replication especially important. (disclosures; current label)
What happens next
A stronger next test would predefine a clinically meaningful functional outcome, use a standardized formulation with measured exposure, analyze all randomized participants, enroll enough women and men for credible subgroup estimates, and report longer follow-up. Until then, PEARL is evidence about one limited regimen and trial—not a verdict on rapamycin or human longevity.
Primary and authoritative sources
Sources, roles and limits
- Moel et al., Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results
- Identifier
- DOI:10.18632/aging.206235 · PMID:40188830 · PMCID:PMC12074816
- Role
- Primary results publication
- Limitation
- Small completer analysis, missing values, low female enrollment, self-reported adherence and compounded-drug exposure limit inference.
- Checked
- 2026-07-31 · No correction or retraction relationship found in Crossref/PubMed as checked
- ClinicalTrials.gov record NCT04488601
- Identifier
- NCT04488601
- Role
- Primary registry
- Limitation
- The record defines the registered design and outcomes; ClinicalTrials.gov does not validate a study's science.
- Checked
- 2026-07-31 · No posted results; status record last updated January 24, 2024
- DailyMed prescribing information for Rapamune (sirolimus)
- Identifier
- DailyMed setid 3275b824-3f82-4151-2ab2-0036a9ba0acc · revised 03/2026
- Role
- Regulatory and safety context
- Limitation
- The label covers approved transplant and lymphangioleiomyomatosis uses, not healthy-aging use.
- Checked
- 2026-07-31 · Current branded label revised March 2026 checked; not a trial result
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Disclosures and history
- July 30, 2026 — three-pass research, evidence review and AI-assisted prose draft completed.
- July 31, 2026 — human publication approval recorded; source and correction status rechecked.
- Corrections: none as of publication.