Rapamycin (Sirolimus)
Rapamycin (Sirolimus) — the Easter Island mTOR inhibitor and longevity's most-studied drug: the facts and the honest evidence

Class: small_molecule
Synonyms: Rapamycin
Sirolimus
Rapamune (brand)
Function tags: longevity / geroprotection (off-label)
mTOR inhibition / autophagy
immunosuppression (approved)
anticancer / LAM / epilepsy (approved or investigational)
Overall evidence grade: A
WADA prohibited: no
Last updated: 2026-07-13

In brief: Rapamycin (sirolimus) is a small-molecule mTOR inhibitor — and longevity science's flagship. Discovered in soil bacteria on Easter Island (Rapa Nui) and named after the island, it's so fundamental that the master growth-sensing protein mTOR is named after it ("mechanistic Target Of Rapamycin"). It has lived four scientific lives — antifungal, then FDA-approved transplant immunosuppressant (1999), then anticancer, then the anti-aging frontier. Its landmark credential: in the 2009 NIA Interventions Testing Program (Nature), rapamycin extended the lifespan of already-old mice — replicated in three independent labs — making it the only drug proven to extend mammalian lifespan when started in mid-life, and the most reproducible lifespan extender across yeast, worms, flies, and mice. Mechanistically it inhibits mTOR, flipping cells from growth mode into repair mode (autophagy), reducing inflammation, and improving cellular housekeeping. The honest caveats: it's a potent prescription immunosuppressant, not a supplement; the longevity protocol (low weekly dosing) differs entirely from transplant dosing and aims to spare immunity; side effects are real; and — decisively — no human trial has yet demonstrated a longevity benefit (the PEARL RCT showed weekly dosing is reasonably safe, but durable functional benefits await replication). So: the best-evidenced longevity drug we have in animals, an approved and serious medicine, a molecule with a spectacular backstory — and still without human proof that it extends healthy lifespan.

## Identity a **macrocyclic lactone (macrolide) small molecule** that inhibits **mTOR** — the cell's master growth-and-nutrient sensor. It is an **approved prescription drug** (an immunosuppressant), and simultaneously **the single most-studied and best-evidenced compound in longevity science.** It is emphatically **not a peptide** — it's included as the register's central **longevity anchor.** ## Mechanism (as proposed) **mTOR** (mechanistic target of rapamycin) is a **kinase** that acts as the cell's **nutrient-and-growth sensor**, integrating signals to decide whether the cell should **grow and divide** (protein synthesis, proliferation — high mTOR) or **conserve and repair** (low mTOR). Rapamycin **binds FKBP12**, and that complex **inhibits mTORC1** (the growth-driving arm). The downstream effects map onto major aging hallmarks: **autophagy increases** (cells clear damaged proteins/organelles), **inflammation ("inflammaging") decreases**, **mitochondrial function improves**, and **senescent-cell burden may fall.** The longevity strategy hinges on **selectivity and schedule** — intermittent low dosing to hit **mTORC1** (growth/aging) while largely **sparing mTORC2** (whose inhibition drives the glucose/immune side effects) — the pharmacological tightrope that separates "geroprotector" from "immunosuppressant."

Evidence grades by outcome:
outcome: Mammalian lifespan extension (animal)
grade: A
base: NIA ITP, Nature 2009: reproducible across 3 labs, both sexes, late-life start; most robust of any compound
caveat: The strongest lifespan data in the register — but mouse, not human
outcome: Human longevity / healthspan
grade: F
base: No RCT has hit a longevity endpoint; PEARL showed weekly-dosing safety
caveat: The decisive gap: mouse ≠ human; durable human functional benefit unproven
outcome: Immunosuppression (approved)
grade: A
base: FDA-approved 1999 (transplant); LAM 2015
caveat: This is real, powerful pharmacology — the flip side of the "spare immunity" longevity goal
outcome: Autophagy / cellular "repair mode"
grade: B
base: Well-established mechanism (mTORC1 inhibition)
caveat: Mechanistically solid; the aging payoff in humans is the unproven step
outcome: Safety (longevity dosing)
grade: C
base: PEARL RCT (weekly): reasonably safe; AEs = mouth ulcers, glucose/lipid changes, infection risk
caveat: Not benign — a real immunosuppressant; requires clinical oversight and monitoring

Legal status:
region: US
status: an approved prescription drug (sirolimus) for transplant rej
note: an approved prescription drug (sirolimus) for transplant rejection and LAM. Longevity use is entirely off-label, requiring clinical oversight; there is no approved anti-aging indication.

Cosmetic claims:

Note: The Easter Island molecule that named a protein and became longevity's best-evidenced drug. Rapamycin is the register's longevity capstone, and it's overflowing with remarkable facts. A few: (1) it was found in soil bacteria on Easter Island (Rapa Nui) — and named after the island; (2) it's so central to cell biology that a master growth-regulating protein was named after it — mTOR = "mechanistic Target Of Rapamycin"; (3) it's the only drug proven to extend mammalian lifespan even when started in mid-life, replicated across three independent labs; (4) it's a paradox — a daily-dose immunosuppressant that, dosed weekly, may be geroprotective. It's a small molecule (approved drug), not a peptide — and human longevity proof still doesn't exist.
Status note: the field's key open question: a human RCT with a genuine longevity/healthspan endpoint — none has succeeded yet; intermittent-dosing and rapalog selectivity are the active frontiers

Sources:
Harrison DE, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009 (NIA ITP; 3-lab replication; late-life start; the field-defining result).
Discovery/history: isolated from Streptomyces hygroscopicus in Easter Island (Rapa Nui) soil (Nogrady, late 1960s; Ayerst/Wyeth/Pfizer); named after Rapa Nui; mTOR = "mechanistic Target Of Rapamycin."
Approvals: FDA sirolimus 1999 (renal transplant, NDA 021083); LAM 2015 (MILES trial).
Roark KM, Iffland PH. Rapamycin for longevity: pros, cons, future perspectives. Front Aging 2025; PEARL RCT (weekly dosing safety; longevity endpoints not met). (Approved immunosuppressant; longevity use off-label and unproven in humans as of 2026.)