In plain terms: Rapamycin (Sirolimus) has been tested in human trials aimed at the relevant outcome and did not show benefit at the doses and durations studied. The animal research may be encouraging, but it has not yet translated to humans in these trials.
Rapamycin (Sirolimus)
The evidence as the record states it
Moel et al. (Aging, 2025; PMID 40188830), the PEARL trial: 48-week decentralised, double-blind, placebo-controlled RCT of compounded rapamycin 5 mg or 10 mg weekly in healthy normative-aging adults. The pre-specified primary outcome was VISCERAL ADIPOSITY by DXA, and it did not change (partial eta-squared 0.001, p=0.942). Lean tissue mass and self-reported pain improved in women on 10 mg; those are secondary outcomes after a missed primary. Stanfield et al. (J Cachexia Sarcopenia Muscle, 2026; PMID 41985884): 13-week randomized, double-blind, placebo-controlled trial in 40 sedentary adults aged 65 to 85, sirolimus 6 mg weekly alongside an identical home exercise program. The pre-specified primary outcome was change in 30-SECOND CHAIR-STAND REPETITIONS. The intention-to-treat difference was -2.13 repetitions (95% CI -4.61 to 0.34, p=0.089), and both pre-specified sensitivity analyses favored PLACEBO and reached significance: complete-case -2.46 (p=0.045) and per-protocol -3.44 (95% CI -5.86 to -0.99). Regraded C to D: tested in humans on the actual molecule, twice, and both primaries were missed. The second trial's pre-specified primary analysis was null, and the sensitivity analyses point toward placebo rather than establishing that rapamycin blunts the gains from exercise. That attenuation signal is real enough to publish and not established enough to grade, and it is discounted here on exactly the rule that discounts PEARL's positive secondaries in women. Intention to treat is the analysis a trial is judged on, in both directions. Animal lifespan data and mechanistic plausibility do not enter the grade. Kraig et al. (Exp Gerontol, 2018; PMID 29408453): randomized placebo-controlled pilot, 25 generally healthy adults aged 70 to 95, 1 mg rapamycin daily, 11 on rapamycin and 14 on placebo completing at least 8 weeks, NIH-funded; no change in cognition on three instruments, handgrip strength or 40-foot walk time; statistically significant decrements in hemoglobin, hematocrit, red cell count and red cell indices on rapamycin, and more reported side effects (rash, stomatitis, gastrointestinal). Kell et al. (Aging Cell, 2026; PMID 41524558): small placebo-controlled experimental medicine study, 1 mg/day for four months in older men, 4 on rapamycin against 5 on placebo; p21, a marker of DNA damage-induced senescence, lower in immune cells on rapamycin. A marker in nine people, not an outcome. Funding: PEARL was supported by the telehealth company that prescribes rapamycin, with authors employed there; RAPA-EX-01 and Kraig 2018 were publicly funded. Topical rapamycin and the mTOR inhibitors everolimus and RTB101 are different forms or agents and do not grade this record. Grade D is unchanged: three randomized trials, three null primaries, and no trial against a clinical aging endpoint.
Trials showing no benefit
Moderate. Randomized, placebo-controlled, 48 weeks. The primary outcome did not change (p=0.942). Rapamycin was relatively safe. Lean tissue mass and self-reported pain improved in WOMEN at 10 mg, a subgroup finding the authors explicitly frame as requiring future work to establish efficacy.
Moderate. Randomized, double-blind, placebo-controlled. The primary intention-to-treat analysis favored PLACEBO (-2.13 repetitions, p=0.089) and sensitivity analyses favored placebo and reached statistical significance. The authors conclude sirolimus "did not enhance, and in sensitivity analyses, it may have modestly attenuated" the gains from exercise, and that it "increased the burden of minor adverse events and may have contributed to one serious infection."
Low. Small pilot powered for feasibility and safety; no change in any cognitive or physical measure; hemoglobin, hematocrit and red cell indices fell on rapamycin.
Why Grade D Route 2 and not Grade C
Grade D Route 2 applies when a compound has been tested in humans and benefit was not shown. Rapamycin (Sirolimus) has been tested in 3 human trials on endpoints relevant to the claim being evaluated, and the primary endpoint was not met.
A randomized, placebo-controlled trial pre-specifying a meaningful clinical or functional endpoint and demonstrating statistically significant benefit would move this to Grade C or higher, depending on effect size, population size, and whether it is independently replicated.
What this grade covers and what it does not
What would move this grade
A randomized, placebo-controlled trial pre-specifying a clinical aging endpoint and demonstrating statistically significant benefit on that primary endpoint would be sufficient to move this to Grade C or higher, depending on effect size and population.
Citations withdrawn from this record
The two previously cited trials were authored by Novartis, which manufactures the rapalogs they tested. Withdrawn July 2026 as the wrong molecule.
How this was studied
Compounded rapamycin 5 mg or 10 mg by mouth once weekly for 48 weeks (PEARL); sirolimus 6 mg by mouth once weekly for 13 weeks (RAPA-EX-01); rapamycin 1 mg by mouth daily for 8 weeks in adults aged 70 to 95 (Kraig 2018, PMID 29408453) and for 4 months in a 9-person marker study (Kell 2026, PMID 41524558). All in adults who were not transplant recipients.