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1 Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
2 Molecular Biosciences, University of California, Davis, CA, USA
3 Medicine, University of Wisconsin, Madison, WI, USA
* To whom correspondence should be addressed. E-mail: mharper{at}uottawa.ca.
Calorie restriction (CR) without malnutrition increases lifespan and delays the onset of a variety of diseases in a wide range of animal species. However, the mechanisms responsible for the retardation of aging with CR are poorly understood. We proposed that CR may act, in part, by inducing a hypometabolic state characterized by decreased reactive oxygen species (ROS) production and mitochondrial proton leak. Here we examine the effects of long-term CR on whole animal energetics as well as muscle mitochondrial energetics, ROS production and ROS damage. CR was initiated in male FBNF1 rats at 6 months of age and continued for 12 or 18 months. Mean whole body oxygen consumption was 34.6% (P<0.01) and 35.6% (P<0.001) lower in CR rats than in controls after 12 and 18 months CR, respectively. Body mass-adjusted oxygen consumption was 11.1% and 29.5 % lower (both P<0.05) in the CR rats than in controls after 12 and 18 month CR. Muscle mitochondrial leak-dependent (state 4) respiration was decreased after 12 months compared to controls; however, following 18 months of CR there were slight but not statistically significant differences. Proton leak kinetics were affected by 12 months CR such that leak-dependent respiration was lower in CR mitochondria only at protonmotive force values exceeding 170mV. Mitochondrial H2O2 production and oxidative damage were decreased by CR at both time points and increased with age. Muscle UCP3 protein content increased with long-term CR, consistent with a role in protection from ROS, but inconsistent with the observed decrease or no change in proton leak.
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