PMC

Metformin targets proteins involved in homeostasis and aging. Metformin downregulates mTOR to maintain protein homeostasis, including regulation of protein synthesis and degradation of damaged proteins via autophagy, which are major biological processes associated with aging.

Metformin delays aging by reducing oxidative stress. Metformin protects biological macromolecules such as proteins and DNA by reducing excessive ROS production in the mitochondria. Furthermore, metformin can activate the SKN-1 pathway through ROS, which acts as a signaling molecule to delay aging. In addition, metformin activates SIRT3, participates in mitochondrial autophagy and reduces oxidative stress, thereby delaying cell senescence. ROS, reactive oxygen species; SIRT1, sirtuin 1; SIRT3, sirtuin 3.

The figure depicts schematically the current consensus within the biology of aging community as to pathways that are important in order to target aging and indicates at which points metformin has been shown to have effects (see text). Key take-away: outside of the cell (1, top), metformin has been shown to affect the receptors for cytokines, insulin, IGF-1, and adiponectin, all pathways that are activated with aging and, when modulated, are associated with longevity. (1) Intracellular (2, middle) metformin inhibits the inflammatory pathway and activates AMPK, increasing inhibition of mTOR, which seems to be a major target to modulate aging. Through some of these mechanisms, it also modulates oxidative stress and removes senescent cells (the mitochondrial pathways are not shown, and the mechanisms by which metformin induces senescent cell removal remain unclear). (2) These processes jointly (3, bottom) affect inflammation, cellular survival, stress defense, autophagy, and protein synthesis, which are major biological outcomes associated with aging/longevity. Adapted from .

A schematic presentation of metformin targeting diseases such as diabetes, COVID-19, cancer, neurodegenerative diseases, and aging with mitochondria and their gatekeeper VDAC1 proposed as a common target.