Metformin
The longevity drug. Metformin has been used for type 2 diabetes since the 1950s. It lowers blood sugar primarily by reducing liver glucose production and increasing insulin sensitivity. But its effects on AMPK and cellular metabolism have made it a subject of intense longevity research. The TAME trial (Targeting Aging with Metformin) is studying whether it can slow aging itself.
How Metformin Works
Complex I Inhibition
Mild mitochondrial inhibition. Reduces ATP production. Increases AMP:ATP ratio.
AMPK Activation
Consequence of low ATP. Metabolic sensor activated. Downstream benefits.
Liver Glucose Reduction
Decreases gluconeogenesis. Less glucose output. Primary diabetes mechanism.
Insulin Sensitization
Improves cellular response. Muscles take up glucose better. Lower insulin needed.
mTOR Inhibition
Through AMPK. Reduces growth signaling. Longevity pathway connection.
Gut Microbiome Effects
Changes bacterial composition. May contribute to GI side effects and benefits.
Beyond Blood Sugar
Longevity Interest
Diabetics on metformin outlive non-diabetics in some studies. AMPK, mTOR effects. TAME trial underway.
Cancer Prevention
Lower cancer rates in metformin users. mTOR inhibition. Growth suppression. Active research area.
PCOS
Polycystic ovary syndrome. Insulin sensitization helps. Hormone balance. Off-label use.
Cardiovascular
Reduces heart disease risk. Beyond glucose control. Vascular effects. Anti-inflammatory.
Considerations
GI Side Effects
Nausea, diarrhea common initially. Extended-release form may help. Usually improves with time.
B12 Depletion
Long-term use reduces B12 absorption. Monitor levels. Supplement if needed.
Exercise Interference
May blunt some exercise adaptations. Mitochondrial biogenesis concern. Debate ongoing.
Lactic Acidosis (Rare)
Very rare but serious. Kidney function matters. Contraindicated in severe kidney disease.