Metformin

Metformin for longevity: from diabetes drug to anti-aging candidate

Metformin is the world's most prescribed medication for type 2 diabetes, taken by over 150 million people. Derived from the French lilac plant (Galega officinalis), it has been in clinical use since the 1950s. In recent years, metformin has attracted enormous attention in the longevity community because observational studies suggest that diabetics taking metformin live as long as, or even longer than, matched non-diabetics despite their underlying metabolic disease ^[1]. This finding sparked a provocative question: could metformin slow aging itself?

The idea isn't as far-fetched as it sounds. A 2024 study in Signal Transduction and Targeted Therapy showed that metformin decelerates epigenetic aging clocks, and a 2025 review in Molecules mapped out the molecular pathways connecting metformin to cellular aging mechanisms [6, 2]. But the gap between observational data and randomized proof remains wide, and the scientific community is increasingly acknowledging that uncertainty.

How metformin works: AMPK, mTOR, and mitochondrial signaling

Metformin partially inhibits Complex I of the mitochondrial electron transport chain, which raises the AMP-to-ATP ratio inside cells. This activates AMP-activated protein kinase (AMPK), the cell's master energy sensor. Once AMPK switches on, it triggers a cascade of effects that overlap with what happens during caloric restriction: mTORC1 gets suppressed (promoting autophagy and reducing growth signaling), chronic inflammation drops via NF-kB suppression, oxidative stress decreases, and insulin sensitivity improves ^[2].

A 2022 Nature study identified a more specific mechanism: at low doses, metformin activates lysosomal AMPK through a protein called PEN2 without fully shutting down mitochondrial respiration ^[7]. This may explain why lower doses seem to offer geroprotective benefits with fewer side effects, and it has shifted some researchers toward advocating dose ranges of 500-1000 mg rather than the 1500-2000 mg used in diabetes treatment.

The TAME trial: can aging become a treatable condition?

The Targeting Aging with Metformin (TAME) trial is the most important clinical study in the geroprotection field right now. Led by Dr. Nir Barzilai at the Albert Einstein College of Medicine, it aims to enroll over 3,000 participants aged 65 to 79 who will take 1,500 mg of metformin daily for six years ^[4]. The primary endpoint is time to first occurrence of any age-related disease: cardiovascular disease, cancer, cognitive decline, or death.

If TAME succeeds, it would be the first clinical trial to establish aging itself as a treatable condition, a regulatory milestone that could open the door for other geroprotective drugs. The trial is now managed within ARPA-H and uses the NIH-funded Geroscience Network. Barzilai has stated publicly that Eli Lilly plans a parallel TAME-like study using their GLP-1 agonist, viewing metformin's framework as a template for testing longevity drugs at scale.

What the evidence actually shows (and where it falls short)

A systematic review of 53 studies found that metformin reduced all-cause mortality (HR 0.93 compared to non-diabetics), cancer incidence (31% relative risk reduction), and cardiovascular events independently of glucose lowering ^[1]. A 2024 meta-analysis confirmed lower cancer risk overall (RR 0.72), with the strongest reductions in breast cancer (RR 0.68) and colorectal cancer (RR 0.62) ^[8]. A 2025 study linked metformin use to exceptional longevity in postmenopausal women with type 2 diabetes.

The problem: these are all observational findings in diabetic populations. A 2025 review in Ageing Research Reviews titled "Emerging uncertainty on the anti-aging potential of metformin" points out that randomized trials in non-diabetics have generally failed to replicate these benefits ^[9]. Time-related biases in observational data, healthy-user effects, and the absence of large RCTs in healthy populations mean we don't yet know whether metformin genuinely slows aging in people who aren't diabetic. This is exactly why TAME matters so much.

Metformin dosage for longevity

There's no FDA-approved dosage for longevity, because metformin isn't approved for that indication. In diabetes, standard doses range from 1,000 to 2,000 mg daily. The MILES trial (Metformin in Longevity Study) used 1,700 mg/day. Most longevity physicians start patients at 500 mg once daily and titrate up to 1,000 mg over several weeks, monitoring for GI tolerance ^[3]. Some practitioners use intermittent protocols, skipping doses on exercise days to avoid blunting training adaptations.

The PEN2/lysosomal AMPK pathway data from 2022 suggests that lower doses (500 mg) may activate beneficial aging pathways without the full mitochondrial suppression seen at higher doses ^[7]. This is still speculative, but it has influenced the dosing philosophy of several prominent longevity clinicians.

Side effects and the exercise trade-off

The most common side effects are gastrointestinal: nausea, diarrhea, and abdominal discomfort, affecting roughly 30% of new users. These typically improve within weeks or with extended-release formulations. Up to 30% of long-term users develop vitamin B12 deficiency, which can cause fatigue, neuropathy, and cognitive problems. Annual B12 monitoring and supplementation are recommended for anyone on metformin ^[10]. Lactic acidosis is a rare but serious risk, primarily in people with kidney impairment.

The biggest concern for the longevity community is exercise interference. The MASTERS trial (a randomized, double-blind, placebo-controlled study in older adults) showed that metformin blunted muscle hypertrophy from resistance training: the placebo group gained significantly more lean body mass, thigh muscle area, and muscle density ^[5]. Since sarcopenia is itself a major driver of frailty and mortality in aging, this trade-off is real. Peter Attia has publicly stated he no longer recommends metformin for non-diabetic patients who exercise regularly, and many longevity physicians now advise skipping metformin on strength-training days.

Metformin vs. berberine

Berberine, a plant alkaloid from goldenseal and barberry, activates AMPK through a mechanistically distinct pathway. Clinical trials show comparable glucose-lowering efficacy, and some data suggests better effects on lipid profiles. Berberine is available without prescription and some users report fewer GI side effects. David Sinclair has publicly said he switched from metformin to berberine due to GI intolerance. However, berberine lacks metformin's decades of safety data and large-scale epidemiological evidence, and as a supplement it's not regulated for quality or purity ^[11].

Bottom line

Metformin is cheap, well-studied, and has a plausible mechanism of action against aging. It's the closest thing to a proven geroprotective drug in humans, but "closest" still isn't "proven" for healthy non-diabetics. The TAME trial should provide real answers. Until then, the decision to take metformin for longevity comes down to individual risk tolerance, exercise habits, and a physician's guidance. It is a prescription medication and should only be used under medical supervision.