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1 MRC-Dunn Human Nutrition Unit, Cambridge, United Kingdom; School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom
2 MRC-Dunn Human Nutrition Unit, Cambridge, United Kingdom
* To whom correspondence should be addressed. E-mail: adrian.lambert{at}mrc-dunn.cam.ac.uk.
To gain insight into the anti-aging mechanisms of caloric restriction (CR), mitochondria from liver tissue of male Brown Norway rats were used to study the effects of CR and insulin on mitochondrial reactive oxygen species production and bioenergetics. As assessed by hydrogen peroxide measurement, CR resulted in a decrease in the production rate of reactive oxygen species. This decrease was attributed to a decrease in protonmotive force in mitochondria from the CR animals. The decrease in protonmotive force resulted from an increase in proton leak activity and a concomitant decrease in substrate oxidation activity. Each of these effects of CR was reversed by subjecting CR animals to 2 weeks insulin treatment. To achieve continuous and stable insulin delivery, animals were placed under temporary halothane anesthaesia and mini-osmotic pumps were implanted subcutaneously. To gain further insight into how CR and insulin exerted its effects on mitochondrial bioenergetics, the effects of CR and insulin were quantified using modular metabolic control analysis. This analysis revealed that the effects of CR were transmitted through different reaction branches of the bioenergetic system, and insulin reversed the effects of CR by acting through the same branches. These results provide a plausible mechanism by which mitochondrial reactive oxygen species production is lowered by CR, and a complete description of the effects of CR on mitochondrial bioenergetics. They also indicate that these changes may be due to lowered insulin concentrations and altered insulin signaling in the CR animal.
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