Metformin

Metformin's primary mechanism is inhibition of mitochondrial complex I in the electron transport chain in hepatocytes, reducing ATP production and activating AMPK — the cellular energy sensor. AMPK activation mimics caloric restriction at the molecular level, suppressing mTORC1, enhancing autophagy, improving insulin sensitivity, and reducing hepatic glucose production. Metformin also reduces circulating IGF-1 levels and has direct anti-inflammatory effects through NF-κB pathway inhibition. In the gut, metformin modifies the microbiome composition in ways that may contribute to its metabolic benefits. Its AMPK activation and mTOR suppression overlap mechanistically with rapamycin and caloric restriction, placing it at the center of the longevity pharmacology toolkit.