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Rapamycin

Sirolimus · Rapamune · Rapa

B
Limited human data
FDA-approvedmTOR InhibitorMacrolideSmall Molecule
RouteOralFDA-approved
B
Evidence grade: Limited human data

Pilot studies, observational data, or smaller RCTs. Grades summarize evidence quality, not whether a compound is appropriate, legal, or risk-free.

At a glance
What it is
Sirolimus — mTOR Inhibitor — FDA Approved — The Most Evidence-Supported Longevity Compound in Preclinical Biology — mTOR Inhibitor, Macrolide, Small Molecule.
Why people use it
Used primarily for longevity and anti-aging and immune support.
What the evidence supports
Rapamycin has the most dangerous drug interaction profile among compounds in this reference set. CYP3A4 interactions can convert a longevity dose into a transplant-level immunosuppressant without any change in the rapamycin dose itself.
If you only read one thing

Rapamycin is the most evidence-supported longevity compound in mammalian biology — full stop. The ITP lifespan extension data is uniquely robust: independently replicated, dose-dependent, consistent across sexes, effective even when started late in life. The mechanism (mTOR inhibition reducing the hyperactive mTOR signaling that characterizes aged tissue) is intellectually coherent and consistent with the caloric restriction literature. The PEARL trial (April 2025) provides the first 48-week placebo-controlled human longevity data and shows a favorable safety profile at weekly low doses with measurable lean mass benefit in women. And yet: the transplant medicine literature is dominated by immunosuppression complications, serious infections, impaired wound healing, metabolic effects (hyperglycemia, dyslipidemia), and ulcers — all from continuous daily dosing. The longevity community's key hypothesis is that intermittent weekly dosing produces enough mTOR inhibition for longevity benefit while avoiding the steady-state immunosuppression of continuous dosing. This hypothesis is pharmacologically plausible and supported by the PEARL safety data — but the optimal dose, the duration, the long-term safety at intermittent doses, and the actual longevity effect in humans remain unknown.

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Published literature
4human RCTs2human studies6animal4in vitro

Counts emphasize longevity/healthspan-relevant sirolimus/rapalog trials such as PEARL and immune-function studies; transplant/oncology approval trials are not treated as proof of human longevity benefit.

Evidence reality check
Human evidence
6 human studies
4 randomized; 2 observational.
Preclinical base
10 lab signals
6 animal; 4 in-vitro/mechanistic.
Evidence snapshot
Rapamycin has the most dangerous drug interaction profile among compounds in this reference set. CYP3A4 interactions can convert a longevity dose into a transplant-level immunosuppressant without any change in the rapamycin dose itself.
From the chapter quick-reference block.

Rapamycin is the most intellectually compelling longevity compound in this reference set and the one with the greatest evidence-to-certainty gap. The biology is as strong as any longevity intervention has ever been. The human longevity data is 48 weeks old and based on a small trial.

The honest summary: the preclinical case for rapamycin as a longevity intervention is uniquely robust — ITP mouse data, independently replicated, dose-dependent, effective even when started late in life. The mechanism (mTOR inhibition restoring autophagy and reducing age-related cellular dysfunction) is intellectually coherent and conserved across species. The human safety data at weekly intermittent doses is encouraging — PEARL showed adverse events comparable to placebo over 48 weeks, with lean mass benefit in women at ~3.3 mg/week commercial equivalent exposure. The Mannick studies showed immune enhancement (not suppression) with intermittent rapalog dosing. But: the optimal human dose is unknown; the longevity effect in humans is unproven; the drug interaction profile makes it genuinely dangerous to use without physician oversight; the immunosuppression risk at higher doses is real; and the bioavailability of compounded rapamycin is substantially lower than pharmaceutical Rapamune, making dose comparisons unreliable. For the community user: rapamycin at weekly doses under physician supervision with monitoring is the only appropriate context for longevity use. It is not a compound to start based on a Reddit protocol alone.

Categories
Longevity & Anti-agingImmune & Thymic
Properties
Active malignancy: caution✓ FDA-approved✓ Human RCTNot injectable
Half-life
Rapamycin has a longer half-life (~62 hours) and typically lower bioavailability from oral dosing than everolimus
Evidence
BLimited human data
The ITP Lifespan Data
Harrison DE et al. (2009, Nature): Rapamycin started at 600-day-old mice (equivalent to ~60 human years) extended median lifespan by ~9% in males and ~14% in females across three independent NIA Interventions Testing Program (ITP) laboratories. This was the first demonstration that a drug started late in life (when equivalent to already-old mice) could extend lifespan in mammals. Reproduced multiple times with different doses and start ages. The ITP result is the most replicated mammalian longevity pharmacology finding in the scientific literature. Rapamycin is the only compound with this level of mammalian lifespan extension data. The community application is built on this preclinical foundation.
The PEARL Trial (April 2025)
Moel M, Harinath G, Lee V, et al. (2025). Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results. Aging (Aging-US). 17(4). NCT04488601. 48-week double-blinded randomized placebo-controlled decentralized trial; healthy normative-aging adults; compounded rapamycin 5 mg/week or 10 mg/week vs placebo. Primary endpoint (visceral adiposity): not met. Significant finding: lean tissue mass significantly increased in women on 10 mg/week; self-reported pain improved in women; adverse events comparable to placebo; mild GI discomfort most frequent. CRITICAL: compounded rapamycin used was ~66% less bioavailable than commercial formulations — effective dose was ~1.7-3.3 mg/week of commercial equivalent. This is the most important published human longevity trial for rapamycin as of mid-2026.
Intermittent vs Continuous Dosing
Transplant immunosuppression: 2-5 mg/day continuous (steady-state mTOR inhibition; sustained immunosuppression; metabolic effects). Longevity community: 5-6 mg once weekly (or 3-10 mg depending on protocol). The pharmacological rationale for intermittent dosing: mTORC1 inhibition from a weekly dose is highest 12-24 hours post-dose and recovers substantially over the next 6 days; this allows partial mTOR recovery between doses, potentially reducing sustained immunosuppression while still producing the mTOR signaling changes hypothesized to drive longevity benefit. mTORC2 (the immunosuppressive complex) is more sensitive to continuous dosing than intermittent — weekly dosing may preferentially inhibit mTORC1 with less mTORC2 disruption.
The Most Important Drug Interactions
Rapamycin is metabolized by CYP3A4 and is a P-glycoprotein substrate. Any CYP3A4 inhibitor dramatically increases rapamycin levels — potentially to toxic immunosuppressant concentrations. MAJOR interactions: azole antifungals (fluconazole, itraconazole, voriconazole, ketoconazole) — can increase rapamycin levels 5-20x; grapefruit juice (CYP3A4 inhibitor) — increases rapamycin absorption significantly; erythromycin, clarithromycin — strong CYP3A4 inhibitors. CYP3A4 inducers reduce rapamycin levels: rifampin, carbamazepine, phenytoin. The interaction with fluconazole is particularly dangerous for community users — a routine antifungal prescription could produce iatrogenic rapamycin toxicity.
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