The Interventions Testing Program
Most lifespan claims come from a single lab, a single strain of mouse, and a result that nobody repeats. The Interventions Testing Program (ITP), run by the US National Institute on Aging since 2004, exists to fix that: each compound is tested at three sites at once, in genetically diverse mice of both sexes, with pre-registered doses and enough animals to detect a 10% change in lifespan. It is the most rigorous animal lifespan evidence that exists, and most of what it has tested has failed.
| Compound | ITP result | Notes |
|---|---|---|
| Rapamycin | Median lifespan +14% in females, +9% in males when started at 600 days (≈ 60 human years); up to +23% / +26% at higher doses started earlier (Harrison 2009, Nature; Miller 2014) | The only compound to extend lifespan in every ITP cohort tested, both sexes, started late. Also extends healthspan measures. |
| Metformin | No significant lifespan extension alone at 0.1% of diet (Strong 2016); a small effect combined with rapamycin | An earlier NIA study (Martin-Montalvo 2013) found +5.8% in males at 0.1% and shortened life at 1%. The ITP did not confirm it. |
| Acarbose | +22% median in males, +5% in females (Harrison 2014); robust in later cohorts | A glucose-absorption inhibitor; the male effect is one of the largest in the programme. |
| 17α-estradiol | +19% in males, nothing in females | A non-feminising estrogen; mechanism under study. |
| Canagliflozin (SGLT2 inhibitor) | +14% in males, nothing in females (Miller 2020) | A diabetes drug with human cardiovascular and kidney outcome data. |
| NDGA, glycine, captopril | Small male-only or marginal effects | — |
| Resveratrol, green tea extract, curcumin, fish oil, NR, MCT oil | No effect | The supplements that failed. |
Rapamycin: from mice to dogs to people
Rapamycin inhibits mTOR, the nutrient-sensing hub that drives growth when food is plentiful and, when dialled down, switches cells towards repair and autophagy. It is a licensed immunosuppressant used daily at high doses in transplant patients; the longevity interest is in low, intermittent dosing, which in mice selectively inhibits the mTORC1 complex while sparing the mTORC2 complex responsible for most of the metabolic side effects.
The Dog Aging Project is the bridge species. Its first trial (Urfer 2017) gave 24 middle-aged dogs rapamycin or placebo for ten weeks and found improved heart function on echocardiography with no serious side effects. The main trial, TRIAD, has enrolled around 580 dogs aged seven and over for three years of weekly rapamycin or placebo, with lifespan and heart function as outcomes; results are expected later this decade. It is the first lifespan trial of a drug in a large, genetically diverse mammal living in human homes.
In humans the evidence is small and mostly short:
- Mannick 2014 (Science Translational Medicine): 218 adults over 65 given the rapamycin analogue everolimus for six weeks had a ~20% better response to flu vaccine, with the low-dose intermittent regimen best tolerated. The first human evidence that mTOR inhibition can improve an age-related immune function.
- PEARL (Zalzala et al., 2024, pre-registered placebo-controlled trial): 114 adults aged 50–85 took 5 or 10 mg of rapamycin once weekly or placebo for 48 weeks. Safe; no difference in visceral fat (the primary outcome); women on 10 mg gained lean mass and reported better pain and general health. A real signal, modest, in a small trial.
- Observational cohorts of self-prescribing adults (Kaeberlein 2023 survey) report mouth ulcers as the main complaint and no excess infections — in people who chose to take it, with no control.
There is no human lifespan trial of rapamycin and, given the timescale, there may never be one. Anyone taking it for ageing is extrapolating from mice and dogs — intelligently, perhaps, but extrapolating.
Metformin and TAME
Metformin's longevity reputation rests on an observational study (Bannister 2014, UK CPRD) in which diabetics on metformin appeared to outlive non-diabetic controls — a comparison with well-known biases that later re-analyses did not reproduce. The ITP did not find a lifespan effect. What metformin does have is sixty years of safety data, a cardiovascular signal in the UKPDS trial, and strong mechanistic plausibility through AMPK.
TAME (Targeting Aging with Metformin) is the proposed trial that would settle it: 3,000 adults aged 65–79 without diabetes, six years, with a composite of age-related diseases as the outcome — designed as much to make "ageing" a regulatory endpoint as to test the drug. It has been designed since 2015, has FDA agreement on the endpoint, and as of this writing has not fully launched for lack of funding. Until it reports, metformin for ageing in non-diabetics is a reasoned bet, not an evidence-based intervention.
One finding that should weigh on anyone who trains: in the MASTERS trial (Konopka 2019, Aging Cell), 53 older adults did twelve weeks of aerobic training with metformin or placebo. Metformin blunted the gains in VO2max and in muscle mitochondrial respiration. For a sedentary diabetic that trade is irrelevant; for a healthy adult whose main lever is fitness, it is the wrong direction.
The risks
| Drug | Common | Serious or important |
|---|---|---|
| Rapamycin (weekly, low dose) | Mouth ulcers (the commonest), raised triglycerides and LDL, mild rise in glucose, slower wound healing | Immunosuppression at higher doses; interstitial lung disease (rare); interactions via CYP3A4 (grapefruit, some antifungals and antibiotics); a live vaccine during use. |
| Metformin | GI upset, metallic taste | B12 deficiency with long use (check yearly); lactic acidosis if kidney function is poor — cystatin C first; blunts training adaptation. |
| Acarbose | Flatulence, bloating | Hypoglycaemia only with other glucose-lowering drugs. |
| SGLT2 inhibitors | Genital thrush, more urination | Euglycaemic ketoacidosis, especially on a low-carbohydrate diet; dehydration. |
Why we do not prescribe
Three reasons, in increasing importance. First, these are prescription medicines in every jurisdiction we operate in, and Longevity Bros is a coaching and research-protocol company, not a medical practice. Second, the evidence for ageing is animal and pilot evidence, and the right person to weigh an extrapolation against an individual's kidneys, lipids, immune status and goals is the physician who can see all of them. Third, in a healthy adult the proven levers — fitness, muscle, sleep, metabolic health — are large, and these drugs at best add to them and at worst (metformin and training) subtract. So this page is educational. If, having read it, you want to discuss rapamycin or metformin with your doctor, a protocol can make sure the labs that conversation needs are already on the table.
What to measure
If a physician does prescribe one of these, the monitoring the trials used:
- Before: cystatin C, liver enzymes, full lipid panel with ApoB, HbA1c and fasting insulin, full blood count, B12 (metformin), and a baseline of the thing you hope to change — VO2max, DEXA, hsCRP.
- Rapamycin, every 3 months: lipids, glucose, full blood count; a note of any ulcers or slow-healing cuts; vaccination timing.
- Metformin, every 6–12 months: cystatin C, B12, HbA1c — and VO2max, to see whether it is costing you fitness.
- Anything: a stop rule written down before the first dose.
Where peptides and therapies fit
They do not fit next to these drugs; they fit instead of the question. The longevity goal page describes what a protocol for someone over forty actually contains — the training, sleep, labs and, where they are earned, the compounds studied for recovery and body composition — and that plan is what most people asking about rapamycin are missing. The baseline-labs guide is the panel any of these conversations should start from. For the related, over-marketed question of NAD+ and mitochondria, the NAD+ page and the mitochondria article apply the same grading.
Common mistakes
- Treating the mouse result as a human result. The ITP is the best animal evidence there is, and it is still animal evidence.
- Metformin while trying to raise VO2max. MASTERS showed it blunts the adaptation.
- Grey-market rapamycin with no physician, no lipid panel and no stop rule.
- Forgetting the CYP3A4 interactions — a course of clarithromycin or a grapefruit habit changes the rapamycin level considerably.
- Starting a longevity drug before the longevity basics. It is the smallest lever on the site, taken first.
- Reading the Bannister metformin study as proof. It was not reproduced.
Frequently asked questions
Does rapamycin extend human lifespan?
Nobody knows. It extends lifespan in every ITP mouse cohort tested, including when started late, and improved heart function in a small dog trial. In humans there is a vaccine-response trial, a 48-week safety trial of 114 adults and observational surveys. No lifespan trial exists.
What is the evidence for metformin and ageing?
Mostly an observational study that later analyses did not reproduce, mechanism, and sixty years of safety data. The ITP did not find a lifespan effect in mice. The TAME trial that would settle it has not fully launched, and the MASTERS trial found metformin blunts the fitness gains from training.
What is the ITP?
The Interventions Testing Program, run by the US National Institute on Aging: candidate compounds are tested for lifespan at three sites at once in genetically diverse mice of both sexes. Rapamycin, acarbose, 17α-estradiol and canagliflozin have extended lifespan; most supplements, including resveratrol and NR, have not.
What are the side effects of low-dose rapamycin?
Mouth ulcers most commonly, raised lipids, a mild rise in glucose and slower wound healing; immunosuppression at higher doses and interactions with drugs metabolised by CYP3A4. It is a prescription medicine and needs a physician, a lipid panel and a stop rule.
Will Longevity Bros put rapamycin or metformin in my protocol?
No. They are prescription medicines and a physician's decision; we write research protocols and coach. What a protocol does is build the training, sleep, labs and body composition underneath, and make sure the lab panel is ready if you choose to raise these drugs with your doctor.
Want a plan built on your own numbers?
A protocol can prepare the labs and the conversation; the prescription is your physician's. The longevity protocol builds everything that sits underneath it. €399, follow-up included.
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