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Lexicon
Lexicon

Sirolimus (rapamycin)

The most discussed longevity molecule - strongly documented in mice, not in humans.

3 min read 8 sources

To the sources
Large molecule model of glossy blue and white spheres with a ring floats above a white podium in a bright lab, symbolic image for sirolimus
Compound approved · since 1999, for transplantation

Summary

At a glance

Sources checked on 26 Oct 2026

Lifespan with a late start
+14 %

Mice from 600 days, females, males +9%, at three sites2

Median lifespan, threefold dose
+26 %

Females, males +23%, mice via food4

Half-life
~62 hours

after repeated dosing in kidney transplant patients6

PEARL in humans
48 weeks

primary goal of less visceral fat missed, side effects similar to placebo5

  • Sirolimus, also rapamycin, binds to FKBP-12 inside the cell. This complex inhibits mTOR, a central control enzyme for growth and cell division.68
  • In mice it extended lifespan, even with a late start and independently at three sites. At a threefold dose median lifespan rose by 23 to 26 percent.24
  • In humans this proof is missing. In PEARL with weekly dosing over 48 weeks visceral fat stayed unchanged, the primary goal was missed.5
  • The label names infections due to immunosuppression, delayed wound healing, rising blood lipids and interactions via CYP3A4. Grapefruit juice is off limits.6
  • According to ChEMBL sirolimus has been approved since 1999 to prevent rejection after transplantation. Everything here is the state of research, not a recommendation.86
Profile

Updated July 2026

How long does it stay in the body?

Share left after one dose, calculated with a half-life of ~2.6 days

Half-life ~2.6 days
After 5.2 days: 25 %
Day 2.6 · 50 %Day 5.2 · 25 %Day 7, next dose · 15.3 %Day 7.8 · 12.3 %Day 12.9 · 3.1 %

Simplified model without an absorption phase, half-life from the TPD lexicon.

Class
mTOR inhibitor

macrolide

Use
Oral, once per WEEK

longevity approach

Half-life
about 62 hours
Approved for
Immunosuppression after organ transplantation
Training conflict
Inhibits mTOR

the very switch for muscle growth

Contents 13 sections
  1. At a glance
  2. What is sirolimus?
  3. How it works
  4. Use and dosing
  5. What the research shows
  6. Research status
  7. On the skin
  8. Side effects
  9. Storage
  10. Related compounds
  11. FAQ
  12. Glossary
  13. Sources

What is sirolimus?

Sirolimus, better known as rapamycin, binds the immunophilin FKBP-12 and through that complex inhibits mTOR, the central growth and nutrient sensor of the cell. It is approved as an immunosuppressant after organ transplantation, but its reputation comes from ageing research.

There the mouse evidence is unusually strong and has been reproduced independently several times. In humans it looks different. That difference is the core of this page.

This information is for research and educational purposes only. No medical advice.

Comparison

Longevity approaches in the lexicon

Compounds linked to ageing research in the TPD lexicon, as described there. Tap a card to open its entry.

mTOR inhibitor Sirolimus (rapamycin) mTOR
Blood sugar drug with a longevity reputation Metformin (Glucophage) Senolytic peptide FOXO4-DRI Coenzyme of energy metabolism NAD+

Simplified: different paths. What is proven in humans for each is in its entry. 8

How it works

mTOR exists in two complexes. mTORC1 is the growth switch that drives cell growth and protein synthesis when nutrients are abundant, while braking autophagy, the cellular clean-up. mTORC2 matters among other things for immune function and insulin signalling.

Rapamycin acutely inhibits mainly mTORC1. Only at persistently high levels does mTORC2 get caught too. That is exactly where the typical problems of the transplant dose come from. Weekly dosing uses the long half-life of around 62 hours to hit mTORC1 regularly while letting mTORC2 go again in between.

The difference from transplant medicine is therefore not a detail, it is the entire concept. There it is dosed daily and levels are deliberately held high, with immunosuppression as the goal. Anyone transferring the approved dose to themselves is suppressing their immune system.

Where it acts

Where sirolimus acts

Tap a point or a card. Colour = mTOR, grey = observed in studies.

  1. Immune system

    Inhibits activation and division of T cells, hence immunosuppression6

    mTOR
  2. Liver and blood lipids

    Broken down via CYP3A4, cholesterol and triglycerides can rise6

    Observed in trials
  3. Skin and wounds

    Wound healing delayed6

    Observed in trials
  4. Visceral fat

    Unchanged after 48 weeks in PEARL5

    Observed in trials
  5. Lean mass

    Increased in women at the highest study dose in PEARL5

    Observed in trials

Targets in the ChEMBL database8

Compound CHEMBL413: two recorded mechanisms, type of action on each card.

FKBP-12 (immunophilin)
Gene
FKBP1A
UniProt
P62942
ChEMBL
CHEMBL1902
Action
Inhibitor, direct binding
mTOR (kinase)
Gene
MTOR
UniProt
P42345
ChEMBL
CHEMBL2842
Action
Inhibited via the complex with FKBP-12, according to the label
Translucent glass cell with a blue enzyme with a glowing core in the centre, blue molecule chains to the left and right, golden vesicles in the cell
Together with FKBP-12 sirolimus inhibits the growth switch mTOR. Symbolic image.

Use and dosing

Dosing

Dosing, titration and syringe

Loading the dosing information …

  • Getting started and stepping up, drawn as a staircase
  • Units on the U-100 syringe for every step
  • How long one vial lasts
White folding box with the TPD logo next to a blister of ten round white tablets, two loose tablets in front on a bright lab bench
Tablets in a blister. Symbolic image.

What the research shows

In mice the evidence is extraordinary. In the Interventions Testing Program of the American ageing research institute, rapamycin extended lifespan even when started late in life: plus 14 percent in females and 9 percent in males, reproduced across three independent sites (Nature 2009).

The follow-up analysis (J Gerontol A 2011) confirmed plus 10 to 18 percent, while resveratrol and simvastatin in the same programme showed no effect at all. That matters, because the same testing system produced both results. The dose investigation (Aging Cell 2014) found plus 23 to 26 percent at triple dose, meaning a clear dose dependence.

In humans that proof is missing. The PEARL trial (Aging 2025) is the largest and longest investigation in normally ageing humans: 48 weeks, randomised and placebo-controlled. The primary endpoint, reduction of visceral fat, was missed. What PEARL demonstrated is safety over a year of weekly dosing, not benefit. Safety is not efficacy. That sentence belongs at the start of any consideration of this substance.

Study results

What the trials measured

Interactive: switch tabs, tap points, show or hide arms. Arms are named relative to each other, no dosing advice.

Longer life in three studies234

Gain over untreated mice in percent, Interventions Testing Program

Late start at 600 days2 Age at 90% mortality
Females 14%
Males 9%
Start at 9 months3 median lifespan, average of three sites
Females 18%
Males 10%
Threefold dose4 median lifespan
Females 26%
Males 23%

The mice received rapamycin in their food. In the same testing programme resveratrol and simvastatin showed no effect. Proof in humans is missing.

Cut glass kidney model with red and blue vessels next to an hourglass on a bright table
Approved for transplantation, for ageing proven only in mice. Symbolic image.

Research status

Where the research stands

Sirolimus has been approved since 1999, on ClinicalTrials.gov 2,391 trials list sirolimus or rapamycin. Shown are the trials on ageing in people without a transplant. As of 26 Oct 2026. 7

  1. Preclinical Longer lifespan in genetically heterogeneous mice
  2. Phase 1 2 trials, 1 completed
  3. Phase 2 6 trials, 2 completed
  4. Phase 3 1 trial, 0 completed
  5. Approval since 1999, for transplantation
0 participants in phase 3 Planned figures for running trials Approved: ChEMBL lists sirolimus with phase 4 as the highest phase and first approval in 1999. It is approved to prevent rejection after kidney transplantation, not for ageing.8
Show all 7 phase 2 and 3 trials on a timelineHide timeline 2 completed 5 running 1 with results
Phase 2
Phase 3

Bar: start to primary endpoint (planned for running trials). Green = completed, blue = progress until 26 Oct 2026. Phase 1: 2 trials on safety and pharmacokinetics, not shown as bars.

On the skin

Sirolimus has also been studied as a gel applied to the skin: for benign facial skin nodules (angiofibromas) in the inherited disease tuberous sclerosis. In a randomised study with 62 participants the nodules improved after twelve weeks in 60 percent on the gel and in no one on placebo. Side effects were mostly mild but more frequent on the gel (Wataya-Kaneda 2018). This has nothing to do with the longevity approach.

Hand touching a swirl of white cream on a light marble slab with water droplets and white flowers
Symbolic image.

Side effects

  • Mouth ulcers: the most common report and a direct sign of too much. Dose-dependent.
  • Inhibited muscle growth: not a side effect, it is the mechanism. In a building phase you are working against your goal.
  • Delayed wound healing: stop before planned procedures.
  • Shifts in the lipid profile: cholesterol and triglycerides can rise.
  • Immunosuppression: real with daily dosing or too high a weekly dose. The approved dose is made for exactly that.
  • Interactions: runs through CYP3A4, correspondingly sensitive to grapefruit and some antibiotics and antifungals.

Storage

Store dry, at room temperature and protected from light. Keep out of reach of children.

Three white tablet bottles on a bright shelf next to a folded light blue towel
Dry, at room temperature and away from light. Symbolic image.
Level · Sirolimus (rapamycin)

How the level builds up

One dose per week: each dose adds to what is left of the previous one.

Lexicon: Oral, once per WEEK (longevity approach)
Peak 1.18×Trough 0.18×
Day 7 · 2. dose
1.15× of the first dose
Plateau
from Day 7

98 % of the plateau after dose 2

Peak
1.18×

of the first dose

Trough
0.18×

before the next dose

Simplified model, values relative to the first dose, no dosing information. Dashed: the first dose alone, green: the plateau.

Related

Related compounds

A different path: all in the TPD lexicon.

Sirolimus (rapamycin)
Metformin (Glucophage) Different longevity approach, blood sugar drug FOXO4-DRI Different path: remove ageing cells NAD+ Coenzyme, level falls with age Epitalon Peptide from longevity research MOTS-c Mitochondrial peptide, metabolism

FAQ

Common questions about Sirolimus (rapamycin)

Short answers, each backed by the sources below.

What is sirolimus approved for?

To prevent rejection after a kidney transplant, plus for the rare lung disease lymphangioleiomyomatosis. ChEMBL lists sirolimus with first approval in 1999. It is not approved for ageing.68

How does sirolimus work?

It binds to the protein FKBP-12 inside the cell. This complex inhibits mTOR, a key kinase for growth and cell division. Among other things sirolimus thereby slows the division of T cells, which is the basis of its effect after a transplant.68

What do the mouse studies show?

In the Interventions Testing Program rapamycin extended lifespan even when started at 600 days, by 14 percent in females and 9 percent in males, at three sites. When started at 9 months it was 18 and 10 percent, resveratrol and simvastatin did not work there. At a threefold dose median lifespan rose by 26 and 23 percent.234

What did PEARL show in humans?

PEARL gave healthy adults placebo or one of two doses once a week for 48 weeks. Visceral fat, the primary goal, did not change. Side effects were similar in all groups. Women at the highest study dose had more lean mass and less pain. According to the full text, the pharmacy-made form used reached only about a third of the blood level of a commercial tablet.5

How long does sirolimus stay in the body?

After repeated dosing in kidney transplant patients the half-life was about 62 hours. The label stresses that the level therefore only settles after days.6

Which risks does the label name?

Due to immunosuppression more infections and a possible risk of lymphoma and other cancers, especially of the skin. In addition delayed wound healing and rising cholesterol and triglyceride levels. These data come from transplantation with daily dosing.6

Why do grapefruit juice and some antibiotics matter?

Sirolimus is broken down via CYP3A4. Strong inhibitors such as certain antifungals and macrolide antibiotics raise the level, the label advises against the combination. Grapefruit juice inhibits the same breakdown and must not be taken with it according to the label.6

Glossary

Terms explained briefly

Dotted words in the text open these explanations directly.

Autophagy
The cell's clean-up: old components are broken down and recycled.
CYP3A4
Liver enzyme that breaks down many compounds. If something inhibits it, the level of other drugs rises.
FKBP-12
Small protein in the cell that sirolimus binds to. Only the complex of both inhibits mTOR.
Half-life
Time after which only half of a substance is left in the blood.
Immunosuppression
Dampening of the immune system, for example so a transplanted organ is not rejected. Infections become more likely.
Interventions Testing Program
Programme of the US ageing research institute that tests compounds in parallel at three sites on genetically mixed mice.
Mouth ulcers
Small, painful open sores on the lining of the mouth.
mTOR
Kinase in the cell that controls growth, protein synthesis and cell division. It works in two complexes, mTORC1 and mTORC2.
Placebo
Dummy preparation without active substance. Comparing against it shows what is due to the substance itself.
Visceral fat
Fat in the abdomen around the organs, as opposed to fat under the skin.

Evidence

Sources

Show all 8 sourcesHide sources 5 Studies1 Trial registry2 Database checked 26 Oct 2026

Studies

  1. Sirolimus gel versus placebo for facial angiofibromas

    Wataya-Kaneda et al., JAMA Dermatology, 2018

    DOI 10.1001/jamadermatol.2018.1408 PMID 29800026 NCT02635789
    Checked 26 Oct 2026 via doi.org, Crossref, PubMed
  2. Rapamycin extends mouse lifespan even when started late

    Harrison et al., Nature, 2009

    DOI 10.1038/nature08221 PMID 19587680
    Checked 26 Oct 2026 via doi.org, Crossref, PubMed
  3. Rapamycin works, resveratrol and simvastatin do not

    Miller et al., Journal of Gerontology Series A, 2011

    DOI 10.1093/gerona/glq178 PMID 20974732
    Checked 26 Oct 2026 via doi.org, Crossref, PubMed
  4. Lifespan increase depends on dose and sex

    Miller et al., Aging Cell, 2014

    DOI 10.1111/acel.12194 PMID 24341993
    Checked 26 Oct 2026 via doi.org, Crossref, PubMed
  5. PEARL: weekly rapamycin in healthy adults over 48 weeks

    Moel et al., Aging, 2025

    DOI 10.18632/aging.206235 PMID 40188830 NCT04488601
    Checked 26 Oct 2026 via doi.org, Crossref, PubMed, PMC (Volltext)

Trial registry

  1. Trials on rapamycin and ageing on ClinicalTrials.gov

    ClinicalTrials.gov, U.S. National Library of Medicine

    Checked 26 Oct 2026 via ClinicalTrials.gov API v2

Database

  1. US prescribing information for sirolimus

    DailyMed, U.S. National Library of Medicine (Stand 30.09.2023)

    Checked 26 Oct 2026 via DailyMed, openFDA
  2. Mechanism and approval in ChEMBL

    ChEMBL, EMBL-EBI (CHEMBL413)

    Checked 26 Oct 2026 via ChEMBL