Metformin

Mechanism of Action

Metformin activates AMP-activated protein kinase (AMPK) via inhibition of mitochondrial Complex I, increasing the AMP/ATP ratio. AMPK activation triggers a cascade of metabolic effects: inhibition of hepatic gluconeogenesis, enhanced glucose uptake in skeletal muscle via GLUT4 translocation, and suppression of mTORC1 signaling. In the longevity context, metformin's mTOR inhibition mimics caloric restriction signaling, activating autophagy, reducing inflammatory cytokines (IL-6, TNF-a), decreasing insulin and IGF-1 signaling, and modulating the gut microbiome (increasing Akkermansia muciniphila). It also reduces AGE formation and mitochondrial ROS production.

Dosing Protocol

Notes

Metformin is the most discussed longevity pharmaceutical, with the TAME trial representing the first FDA-acknowledged attempt to classify aging as a treatable condition. IMPORTANT CAVEAT: The exercise-blunting concern — some studies show metformin may attenuate mitochondrial adaptations to exercise (VO2max, muscle protein synthesis). Some longevity practitioners recommend metformin only on non-training days. Required bloodwork: Fasting glucose, fasting insulin, HbA1c, basic metabolic panel (BMP) with creatinine/eGFR, vitamin B12 and methylmalonic acid (annually), lactate (if symptomatic), CBC. Monitor renal function every 6-12 months. Supplement B12 (1000 mcg/day) prophylactically. Medical supervision required.

Stacking

• Berberine (alternating — similar AMPK activation, not concurrent)
• Rapamycin (complementary mTOR pathway targeting)
• NAD+ precursors (NMN/NR)
• Vitamin B12 (metformin depletes B12)

Interactions

• Alcohol [HIGH] — Increased risk of lactic acidosis, especially with binge drinking or chronic alcohol use.
• Iodinated contrast dye [HIGH] — Discontinue metformin 48 hours before and after contrast procedures; risk of lactic acidosis from acute kidney injury.
• Insulin / Sulfonylureas [MEDIUM] — Additive hypoglycemia risk when combined with insulin or insulin secretagogues.
• Rapamycin [LOW] — Complementary mechanisms (AMPK vs. mTOR) but potential for additive immunosuppression and insulin sensitivity effects.

Contraindications

• eGFR <30 mL/min/1.73m2 (contraindicated) or <45 (use with caution)
• Acute or chronic metabolic acidosis including lactic acidosis
• Heavy alcohol consumption
• Acute decompensated heart failure
• Hepatic failure
• Planned procedures with iodinated contrast dye

Side Effects

• GI distress: nausea, diarrhea, bloating, metallic taste (common initially, improves with XR formulation)
• Vitamin B12 deficiency (with chronic use — monitor annually)
• Lactic acidosis (rare but serious — primarily in renal impairment)
• Potential blunting of exercise-induced mitochondrial adaptations (debated)
• Weight loss (often considered a benefit)

Key Papers

• 10.1016/j.cmet.2016.05.011
• 10.1111/acel.12898
• 10.3389/fendo.2021.718942

Source Quality

FDA-approved pharmaceutical (Glucophage, Glucophage XR). Generic metformin HCl widely available. Extended-release formulation strongly preferred for longevity use (better GI tolerance). Verify NDMA levels are within FDA limits.

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