. Longterm calorie restriction reduces proton leak and hydrogen peroxide production in liver mitochondria. Am J Physiol Endocrinol Metab 288: E674 -E684, 2005. First published November 23, 2004 doi: 10.1152/ajpendo.00382.2004.-Calorie restriction (CR) without malnutrition increases maximal life span in diverse species. It has been proposed that reduction in energy expenditure and reactive oxygen species (ROS) production could be a mechanism for life span extension with CR. As a step toward testing this theory, mitochondrial proton leak, H 2O2 production, and markers of oxidative stress were measured in liver from FBNF 1 rats fed control or 40% CR diets for 12 or 18 mo. CR was initiated at 6 mo of age. Proton leak kinetics curves, generated from simultaneous measures of oxygen consumption and membrane potential, indicated a decrease in proton leak after 18 mo of CR, while only a trend toward a proton leak decrease was observed after 12 mo. Significant shifts in phosphorylation and substrate oxidation curves also occurred with CR; however, these changes occurred in concert with the proton leak changes. Metabolic control analysis indicated no difference in the overall pattern of control of the oxidative phosphorylation system between control and CR animals. At 12 mo, no significant differences were observed between groups for H 2O2 production or markers of oxidative stress. However, at 18 mo, protein carbonyl content was lower in CR animals, as was H 2O2 production when mitochondria were respiring on either succinate alone or pyruvate plus malate in the presence of rotenone. These results indicate that long-term CR lowers mitochondrial proton leak and H 2O2 production, and this is consistent with the idea that CR may act by decreasing energy expenditure and ROS production. energy expenditure; aging; oxidative stress; food restriction CALORIE RESTRICTION (CR) without malnutrition is the only intervention that has consistently been shown to increase maximum life span in laboratory rodents (60). In addition to increasing life span in rodents, CR also delays the onset of diabetes, hypertension, and many types of cancer as well as other age-related physiological and pathological conditions (60). This shows that CR not only extends life span but also retards the rate of biological aging. The mechanism(s) responsible for the actions of CR, however, is still unknown.Two theories of aging, the rate of living theory (42) and the free radical theory (24), have been proposed as possible mechanisms for the retardation of aging and diseases by CR (56). However, both of these theories may contain the same mechanism, since mitochondria are central to both energy metabolism and reactive oxygen species (ROS) production. Because both processes contain a common mitochondrial link, it is reasonable to assume that alterations in energy expenditure (defined here as any process that converts food or stored energy to heat and work) could influence ROS production. Thus both theories may be linked by common reduction in mitochondrial ROS pr...

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