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.