Metformin — The Longevity Drug Candidate
Metformin is the world's most prescribed diabetes drug (>150 million users) and the leading candidate for a longevity pharmaceutical. It activates AMPK, inhibits mTOR, and reduces mitochondrial complex I activity. Epidemiological studies show metformin users have lower rates of cancer, cardiovascular disease, and all-cause mortality than non-diabetics not taking metformin — suggesting it may extend healthspan.
Mechanism of Action
Metformin inhibits mitochondrial complex I, reducing ATP production and activating AMPK (the cellular energy sensor). AMPK activation inhibits mTOR, activates autophagy, reduces hepatic glucose production, and improves insulin sensitivity. Metformin also reduces IGF-1 signalling, activates SIRT1, and has direct anti-inflammatory effects via NF-κB inhibition.
Human Trial Evidence
The TAME trial (Targeting Aging with Metformin) is the first FDA-approved longevity trial, testing 1,500 mg/day metformin in 3,000 non-diabetic adults aged 65–79 (results expected 2025–2026). Observational data from 180,000 diabetics shows metformin users have ~15% lower all-cause mortality than matched non-diabetics. The MILES trial showed metformin reversed gene expression patterns of aging in muscle.
Dosing Protocol
500–1,500 mg/day (longevity protocols). Standard diabetes dose: 500 mg twice daily with meals, titrated to 1,000 mg twice daily. Extended-release (ER) formulation reduces GI side effects. Prescription only. Peter Attia has moved away from metformin due to concerns about blunting exercise adaptation.
Safety & Contraindications
Well-established safety profile over 60 years. Main side effects: GI (nausea, diarrhoea, metallic taste) — minimised with ER formulation and dose titration. Rare but serious: lactic acidosis (contraindicated in renal impairment, eGFR <30). Depletes vitamin B12 — supplement B12 with long-term use. Avoid in iodinated contrast procedures.