Metformin

What it is

Metformin is a biguanide derived from French lilac (Galega officinalis), in clinical use since the 1950s and now the most-prescribed type-2 diabetes drug worldwide. It lowers hepatic glucose output and improves insulin sensitivity without causing hypoglycaemia.

Why it’s of interest

Observational studies of type-2 diabetics on metformin have shown all-cause mortality lower than non-diabetic controls in some analyses — striking, given diabetics typically die younger. This signal motivated the TAME trial, a planned RCT of metformin in non-diabetic older adults.

Mechanism

Multiple, debated:

• Inhibition of mitochondrial complex I → rise in AMP → AMPK activation → reduced gluconeogenesis and lipogenesis, raised autophagy.
• Direct mTORC1 inhibition.
• Microbiome-mediated effects (BSH-active species shift bile-acid pool).
• Reduction in inflammation and senescent-cell burden in pre-clinical work.

Human evidence

• Strong RCT evidence for type-2 diabetes prevention and management.
• Lifespan extension in some mouse studies; not all.
• Possible interference with the cardiometabolic benefits of exercise in some studies — an active controversy.
• TAME is the headline longevity trial; not yet fully reported.

Safety

Gastrointestinal effects (nausea, diarrhoea) are common at start of therapy. Long-term vitamin B₁₂ deficiency is well-documented. Lactic acidosis is rare but serious; avoid in significant renal impairment.

Related entries

See also: Deregulated nutrient-sensing, TAME trial, Rapamycin.