Benefits of Metformin in Attenuating the Hallmarks of Aging

Abstract

Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging. Metformin, a biguanide that combats age-related disorders and improves health span, is the first drug to be tested for its age-targeting effects in the large clinical trial-TAME (targeting aging by metformin). This review focuses on metformin's mechanisms in attenuating hallmarks of aging and their interconnectivity, by improving nutrient sensing, enhancing autophagy and intercellular communication, protecting against macromolecular damage, delaying stem cell aging, modulating mitochondrial function, regulating transcription, and lowering telomere attrition and senescence. These characteristics make metformin an attractive gerotherapeutic to translate to human trials.

Keywords: TAME; aging; aging hallmarks; health span; longevity; metabolism; metformin.

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

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.

Figure 2-. The primary and secondary targets of metformin among the hallmarks of aging

Metformin attenuates hallmarks of aging to varying degrees and in turn, contributes to its gerotherapeutic effects. We classified the hallmarks in the inner circle (deregulated nutrient-sensing, genomic instability, loss of proteostasis and altered intercellular communication) as primary, reflective of them being direct targets of metformin via its action on AMPK, SIRT1, mTORC1, IIS pathways, protection against macromolecular damage, improved autophagy response and reduced inflammation, respectively. The hallmarks in the outer circle (stem cell exhaustion, cellular senescence, mitochondrial dysfunction, epigenetic alterations, telomere attrition) are secondary targets, due to their attenuation being mediated by metformin’s role on a primary target. Due to the high degree of interconnectedness between the hallmarks of aging, metformin’s attenuation of any single hallmark has a major influence on several others, thereby leading to a widespread response against aging.