SUMMARY
Metformin, the most widely prescribed medication for treating type 2 diabetes, is increasingly recognized for
healthspan effects that resemble exercise. The beneficial effects of metformin, like aerobic exercise, appear to
be mediated through an energetic and/or redox stress mechanism, raising the prospect that the two approaches
could exert additive or even synergistic effects. Surprisingly, our recently published clinical trial showed that
metformin inhibits the beneficial effects of aerobic exercise training (AET) on skeletal muscle mitochondrial
function and whole-body insulin sensitivity. Interestingly, subjects who entered the study with the highest
mitochondrial complex I supported OXPHOS function and insulin sensitivity were the most negatively affected
by metformin treatment. How metformin inhibits the positive effects of AET, why this effect is most pronounced
in those with the highest mitochondrial function, and how these interactions ultimately impact healthspan and
lifespan are unknown. The hypothesis of this proposal is that the effects of metformin on healthspan and lifespan
are context specific; beneficial in the context of low energy demand/mitochondrial capacity but detrimental in the
context of high energy demand/mitochondrial capacity. To test this hypothesis, the study will leverage a rat model
with divergent selection for intrinsic aerobic capacity, referred to as high capacity and low capacity runners
(HCR/LCR). By selecting for maximal treadmill running capacity, LCR and HCR rats diverged in intrinsic
mitochondrial function, lifespan and metabolic traits that increase or decrease risk for chronic disease. Changes
in mitochondrial function will be assessed using ex vivo respirometry that measures the interplay among three
thermodynamic forces. Further, the proposal uses targeted kinetic and quantitative mitochondrial proteomics to
understand appropriate or aberrant cellular remodeling, and novel in vivo imaging approaches to understand
changes in mitochondrial morphology and dynamics. The Specific Aims are to: 1) establish if mitochondrial
changes to metformin treatment are context specific, 2) establish if the effects of metformin on adaptations to
aerobic exercise training are context specific, and 3) determine whether the beneficial effects of metformin on
healthspan and lifespan are context specific. It is expected that with metformin treatment, remodeling of
mitochondria will be consistent with improved outcomes in LCR rats, but have no effect or will be detrimental in
HCR, with or without exercise training. Further it is expected that metformin will extend healthspan and lifespan
in LCR rats, but not HCR rats. Successful completion of these aims will reveal the importance of context
specificity on metformin action and the mechanisms underlying its positive and potentially negative impacts on
healthspan and lifespan. This information is critical given the ever expanding off-target use of metformin in
healthy individuals without chronic disease and/or overt metabolic dysfunction. Results from this project will help
inform who can benefit from metformin treatment, and more importantly, who should avoid it.