Metformin as a Tool to Target Aging

Abstract

Aging has been targeted by genetic and dietary manipulation and by drugs in order to increase lifespan and health span in numerous models. Metformin, which has demonstrated protective effects against several age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial, as the initial step in the development of increasingly effective next-generation drugs.

Figure 1. Metformin Targets Multiple Pathways of Aging

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 Barzilai et al. (2012).