A letter describes the human evidence, not the product, the manufacturer, or the intervention's worth.
Grade D, tested: a human randomized trial looked for a benefit on the endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score. graded and did not find one. How to read a grade →
See the full evidence record →Rapamycin (Sirolimus)
Compare this record with another, side by side →
How this letter has changedLatest: October 2026 · Corrected.
The record said rapamycin had been given to humans twice on aging questions and that no trial had tested daily dosing. Kraig et al. (Exp Gerontol, 2018; PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 29408453) randomized 25 adults aged 70 to 95 to 1 mg daily and found no change in cognition, grip strength or walking, with falls in hemoglobin and red cell indices; it is now the third tested-null payload and its safety signal is in the cautions. The Kell 2026 study (PMID 41524558) is restated as a 4-against-5 marker study reporting lower immune-cell p21, not a white-cell-count study. The best-use line no longer says one trial found attenuation of exercise benefit, which the basis itself discounts. PEARL's support by the telehealth company that prescribes rapamycin, with authors employed there, is stated. D Route 2 Human randomized trials have been run and did not show benefit on the stated outcome. One of the two routes to the lowest letter on EBL's scale. unchanged. Applied the written grade definition under the editor's standing instruction of October 2026 (Arnold Sandlow, D.C.).PMID 29408453 PMID 41524558
Kell et al. (Aging Cell, 2026; PMID 41524558) randomized healthy older men to 1 mg/day or placebo An inactive substitute made to look like the real treatment, so participants cannot tell which one they received. for four months and reported no difference in white cell counts at eight weeks. A safety and mechanism result in a small randomized sample. No randomized human trial has tested rapamycin against a clinical aging endpoint, so the grade does not move.PMID 41524558
Every change to a letter on this site is dated and published. The full evidence log →
Rapamycin is a drug used after organ transplants and widely discussed for slowing aging. It has been tested three times against a dummy pill on aging questions. It did not improve thinking, grip strength or walking, belly fat, or leg strength when added to exercise. One of the studies was run by a company that prescribes it. So in people, it has not shown a benefit.
This was not skipped. A human randomized trial has tested it and did not find a benefit on the endpoint below. That is a different statement from an untested intervention, which may still turn out to work. A Route 1 No human randomized trial has been run, so the record rests on animal or mechanistic evidence only. One of the two routes to the lowest letter on EBL's scale. Grade D means nobody has looked. A Route 2 Grade D means somebody looked and the answer was no.
Population Healthy normative-aging adults, low-dose intermittent rapamycin, 48 weeks (PEARL)
Certainty 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.
PMID 40188830 →
Population 40 sedentary adults aged 65-85, sirolimus 6 mg once weekly, 13 weeks (RAPA-EX-01)
Certainty Moderate. Randomized, double-blind Neither the participants nor the people assessing them know who received the real treatment until the trial ends., placebo-controlled. The primary intention-to-treat Analyzing everyone in the group they were assigned to, even if they stopped the treatment, so the comparison stays randomized. 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."
PMID 41985884 →
Population 25 generally healthy adults aged 70 to 95, randomized placebo-controlled pilot, 1 mg rapamycin daily, 8 weeks or more
Certainty 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.
PMID 29408453 →
mTOR inhibitor · Immunomodulator · Prescription only
The most discussed prescription drug in longevity medicine. Extensive lifespan data in every animal model studied. One human RCT Randomized controlled trial: people are assigned to the treatment or a comparison by chance, so the groups differ only in what they received. It is the design that can show cause and effect. using a rapamycin analog demonstrating improved immune function in elderly adults. The leap from animal data to human longevity benefit is plausible but not yet established by hard human endpoint evidence.
Why this gradeGrade D, tested, no benefit. The reasoning, and what the grade does not cover.
Grade D on Route 2: tested, no benefit demonstrated. Rapamycin has been given to humans in three randomized placebo-controlled trials on aging-adjacent questions and found nothing each time: Kraig 2018 (PMID 29408453) at 1 mg/day in adults aged 70 to 95, null on cognition, grip strength and walking, with falls in hemoglobin and red cell indices; and the two below. PEARL pre-specified visceral adiposity by DXA, which did not move (p=0.942). RAPA-EX pre-specified 30-second chair-stand repetitions, where the intention-to-treat difference was -2.13 (p=0.089) and did not reach significance, though both pre-specified sensitivity analyses favored placebo and did.
WHY THIS READS NO BENEFIT RATHER THAN HARMintention to treat is the analysis a trial is judged on, and it was null. The attenuation signal is real enough to publish and not established enough to grade. The same discount falls on PEARL's positive secondaries in women, which also arrived after a missed primary. FUNDING: PEARL was run and supported by the telehealth company that prescribes rapamycin, with authors employed there; the other two trials were publicly funded.
WHAT THIS GRADE DOES NOT COVERnone of the three trials tested rapamycin against a clinical aging outcome, and PEARL was powered for safety rather than efficacy by its own authors' description. The Kell 2026 study (PMID 41524558) reports a senescence marker lower in immune cells in 4 men against 5 on placebo, a mechanism signal and not an outcome. Topical rapamycin and the related drugs everolimus and RTB101 are different forms or agents. This D says that on the questions these three trials asked, rapamycin did not deliver. It does not say rapamycin fails as a geroprotector, because no trial has yet asked that question with an endpoint that could answer it.
A grade describes the human evidence for a named use. It is not advice, and it is not a judgment on any individual prescription. How the letters are decided →
As studiedDose, form, population and duration for every use.
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.
A grade describes the intervention that was tested. Where the product on the shelf differs from it, this says so.
The trial that would change this grade.
A positive trial of this shape would move this entry to C.
Why the current trials fall short
Three randomized trials have given rapamycin to people on aging-adjacent questions, and none found benefit on its primary measure. None asked whether rapamycin slows aging with an endpoint that could answer it, and the largest was powered for safety by its own authors' description.
Why people believe itTwo human sources; one published case report of benefit; no reports of harm.
The case for rapamycin is the strongest animal evidence of any drug in this field: it extended lifespan in mice at three independent test sites. In people, a related drug improved vaccine responses in older adults, and some physicians now prescribe it off-label.
What supporters point to, and what each source actually shows. None of it is enough to move this letter higher; the trial described above under Evidence wanted is what would.
- Human trial, blood or body markerIn older adults, everolimus, a drug closely related to rapamycin, improved the response to a flu vaccine by about 20 percent. An immune marker, with a related drug. PMID 25540326
- Self-reported survey, not a trialA survey of 333 adults using rapamycin off-label, with 172 non-users for comparison. Self-reported and not randomized; the authors present it as early safety information. PMID 37191826
A case report describes what happened to one or a few patients. It cannot show the treatment caused the change, and reports of success are published more often than reports of failure.
- A 52-year-old woman with low bone density whose spine bone density rose 15.9 percent over two years after taking low-dose rapamycin in a trial and then starting low-dose naltrexone. Two drugs, one patient. PMID 39958011
Searched PubMed, October 2026: 17 case report record(s) returned. One report describes a possible benefit linked to rapamycin taken for aging and is listed. The rest concern transplant, cancer, rare diseases or topical use.
Animal and laboratory workOne study in animals or cells. Not counted toward the letter.
None of this is human evidence and none of it counts toward the letter. It is listed so the reader can see what the idea rests on. Most findings in animals do not hold up when tested in people.
- MouseRapamycin added to the diet from 600 days of age extended median and maximal lifespan in male and female mice at three independent test sites; measured at 90 percent mortality, lifespan rose 14 percent in females and 9 percent in males. PMID 19587680
Rapamycin is FDA-approved for organ transplant rejection prevention, certain cancers, and tuberous sclerosis complex. Its use for longevity is off-label and not FDA-approved. EBL presents the published human evidence for educational purposes only. No content on this page constitutes medical advice or a recommendation to seek a prescription. It is a decision for a qualified physician who knows your full clinical picture.
The primary human RCT (Mannick 2014, PMID 25540326) used everolimus (RAD001), a rapamycin analog, not rapamycin (sirolimus) itself. The two drugs share a mechanism but differ in pharmacokinetics and binding selectivity. The human evidence is for the class, not the specific drug being used off-label.
The primary outcome was influenza vaccine response as a proxy for immunosenescence reversal. This is a scientifically meaningful surrogate. It is not a hard longevity endpoint. No human RCT has demonstrated that rapamycin reduces mortality, extends lifespan, or prevents age-related disease in healthy adults.
The longevity community uses approximately 1 to 6 mg once weekly based on observational Research that watches what people already do rather than assigning a treatment. It can show that two things travel together, not that one causes the other. data and extrapolation from the ITP mouse studies. Three randomized placebo-controlled trials of rapamycin on aging questions have now reported, two weekly and one daily at 1 mg (Kraig et al., Exp Gerontol 2018, PMID 29408453), and all three were null on their pre-specified primary endpoints The one outcome a trial names in advance as its main test. Results on other outcomes carry less weight.; in one, sensitivity analyses suggested it attenuated rather than enhanced the gains from exercise.
The human evidenceThree papers, each linked to its PubMed record.
Elderly volunteers aged 65 and older received everolimus (RAD001) at low doses for 6 weeks, followed by influenza vaccination. RAD001 enhanced the vaccine response by approximately 20 percent and reduced the percentage of PD-1 expressing CD4 and CD8 T cells, a marker of immunosenescence. The primary finding: partial mTOR inhibition improved immune function in elderly humans. This is the most important human data point for the entire rapamycin longevity hypothesis.
Phase 2a trial in 264 elderly subjects. TORC1 inhibition with RTB101 alone or in combination with everolimus enhanced antiviral gene expression and showed a trend toward reduced respiratory tract infection incidence. The annualized infection rate difference was not statistically significant Unlikely to be explained by chance alone at the threshold the study set. It says nothing about whether the difference is large enough to matter., suggesting the study may have been underpowered. Supportive but not conclusive.
The National Institute on Aging Interventions Testing Program has demonstrated rapamycin extends lifespan in genetically diverse mice by 10 to 25 percent even when initiated late in life (equivalent to 60 years in humans). This is among the most replicated The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away. lifespan findings in aging biology. Animal data does not enter EBL grades, but this is the biological rationale behind the human investigation.
PEARL has reported (PMID 40188830). A 48-week decentralized, double-blind, placebo-controlled trial of compounded rapamycin at 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 (p=0.942). Lean tissue mass and self-reported pain improved in women on 10 mg, both secondary outcomes after a missed primary. The trial was run by AgelessRx, which sells rapamycin prescriptions, and still reported its primary as null. A second trial has since reported and is described above.
The dosing used in longevity medicine is not derived from a powered human RCT. It is based on physician observational data, primarily from Mikhail Blagosklonny and others, and extrapolation from the ITP mouse studies and the Mannick human immune trials.
Any physician prescribing rapamycin off-label for longevity should monitor at baseline and every 3 to 6 months:
Most primary care physicians won’t prescribe this.
Rapamycin for longevity is off-label, requires comfort with the evolving evidence base, and demands appropriate monitoring. Most internists and family physicians are unfamiliar with the longevity dosing protocol.
EBL’s clinical practitioner network includes physicians trained in evidence-based longevity medicine who are experienced with off-label Rx evaluation, will review your full clinical picture before any prescription decision, and can monitor appropriately. This is the conversation the evidence warrants. EBL helps you get there prepared.
Educational use only · Not medical advice · Prescription medication · Consult a qualified clinician
Primary evidenceFour papers, each linked to its PubMed record.
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 Age-related loss of muscle mass and strength. 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.
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