Bioenergetics of Metformin Action and Aging

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Abstract. Metformin has been used as a medication for the treatment of diabetes for approximately 70 years. Besides diabetes, biguanides are associated with a number of other beneficial effects prevention/treatment of cancer, cardiovascular disease, neurodegenerative disease, and weight loss. Metformin has also been shown to increase health span and prolong life span. Despite these wide-ranging pleotropic effects, the primary molecular mechanism of action is still unresolved. Aging is arguably the single greatest risk factor for most diseases. This application is based on the premise that deciphering metformin's molecular mechanism of action will provide a better understanding of how the aging process and aging-related diseases may be more effectively targeted. Based on extensive preliminary data and fundamental, yet often underappreciated, thermodynamic and bioenergetic principles, the central hypothesis of this project is that a mild reduction in mitochondrial bioenergetic efficiency is the primary molecular mechanism by which metformin, and other organic cations, extend health span and/or lifespan. It is further hypothesized that the efficacy of metformin on health span depends on the chronic metabolic state – beneficial under caloric surplus but detrimental under caloric deficit conditions. State-of-the-art in vivo and in vitro approaches will be used: to establish the interaction of aging and metformin (and other organic cations) on mitochondrial bioenergetic efficiency in mitochondria isolated from heart, skeletal muscle, liver, kidney, intestine and brain from 3, 12, and 24 month old Fischer 344 rats (Aim 1); to establish the acute interaction of metformin and metabolic state (low or high fat diet, fed or fasted) in vivo in 12 month old rats (Aim 2); and to determine the context specific impact of metformin on health span and lifespan in male and female rats. The outcomes of this project are expected to demonstrate that metformin, similar to other organic cations, dose-dependently decreases mitochondrial bioenergetic efficiency, revealing a primary mechanism that can account for the numerous downstream cellular and physiological effects, including protection from aging-related diseases.