It has been well documented that calorie restriction (CR) without malnutrition is an effective strategy to improve health and extend lifespan in a variety of species. The mechanisms underlying CR are unclear. We proposed that a reduction in proton leak-dependent respiration could play a central role in the action of CR by inhibiting reactive oxygen species (ROS) production. In support of this hypothesis, we found that CR resulted in a rapid and sustained reduction in both maximum leak-dependent respiration and ROS production in skeletal muscle mitochondria. We also demonstrated that CR appears to decrease ROS production by different mechanisms in the acute and chronic settings. To further pursue the mechanism governing these adaptations, we also examined the effect of acute CR in Uncoupling Protein-3 knockout mice (Ucp3-KO mice) and wild-type mice. We found that CR decreased skeletal muscle mitochondrial proton leak-dependent respiration in the wild-type, but not in the Ucp3-KO mice. The kinetic response of the proton leak reactions in Ucp3-KO mice subjected to CR indicated increased proton conductance, whereas no CR-induced differences were observed in wild-type mice. Further assessment of these differences suggest that alterations in proton leak with acute CR occur via a UCP3-independent mechanism, that to some extent, involves the Adenine Nucleotide Translocator (ANT). In summary, this dissertation demonstrates that the benefit of CR is mediated, at least in part, by a decrease in the production of ROS. However, the mechanisms underlying the action of CR are complex and involve several processes, including hypometabolism and mitochondrial proton leak. Further in vitro and in vivo research is warranted to better understand these mechanisms. Research in this area has important implications as it may lead to novel treatment strategies (e.g., nutraceuticals or pharmaceuticals) that could improve the quality of life for an increasing aging population.

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