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. Author manuscript; available in PMC: 2020 Jul 10.
Published in final edited form as: Cell Metab. 2020 Apr 24;32(1):15–30. doi: 10.1016/j.cmet.2020.04.001

Figure 1-. Mechanisms of metformin action in attenuating hallmarks of biological aging.

Figure 1-

The cellular uptake of metformin is via the organic cationic transporter 1 (OCT1), after which it exerts three arms of action- 1) metabolic; 2) oxidative and 3) inflammatory.

1) Metformin inhibits mitochondrial complex I and thereby oxidative phosphorylation leading to an increased AMP:ATP ratio, causing a direct activation of AMPK. AMPK-dependent mechanisms (blue) contribute to the downstream inhibition of mTORC1 (improved nutrient-sensing and autophagy), activation of PGC-1α (improved mitochondrial biogenesis), transcriptional regulation via DNA/histone modifications and miRNAs. Extracellularly, metformin downregulated Insulin/IGF1 signaling, also leading to mTORC1 inhibition.

2) The inhibition of mitochondrial ETC also leads to AMPK-independent effects (red) including reduced reactive oxygen species (ROS), reduced advanced glycation end-products (AGEs) and thereby reduced macromolecular damage.

3) The AMPK-independent (red) anti-inflammatory and senotherapeutic effects of metformin are evident via the downregulation of pro-inflammatory cytokines, NF-κB signaling, and activation of Nrf2-Gpx7 and ATM-signaling, respectively.

These three arms work to mitigate the aging-induced dysregulation in cells, thereby attenuating hallmarks of aging.