Does UCP2/3 Overexpression Mimic Caloric Restriction?

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DESCRIPTION (provided by applicant): Caloric restriction (CR) extends mean and maximum life span via mechanisms that are not delineated. One hypothesis is that CR acts by reducing oxidative stress [generation of and/or damage from reactive oxygen species (ROS)]. Supporting this are data showing that CR reduces oxidative stress/damage; but no causal relationship between oxidative stress and life span has been proven, due in part to lack of an appropriate animal model. We have transgenic mice that over express mitochondrial uncoupling proteins (UCP)-2 and 3, decreasing protonmotive force and presumably resulting in mitochondria that generate less ROS. In 6-month-old transgenics, brain areas with high UCP2 expression have less lipid peroxidation and neural inflammation than do the wild type; and after a neural trauma, transgenics show less apoptosis. In contrast, UCP3 knockouts have muscle mitochondria that generate more ROS and exhibit more oxidative damage. These data suggest strongly that elevated UCP2/3 expression in ad libitum-fed mice mimics CR with respect to oxidative stress. We will test this by measuring ROS generation, lipid & protein damage, and apoptosis in skeletal muscle (UCP3 expression), hypothalamus (UCP2 expression), and liver (no significant UCP2 or 3 expression) at 4 ages over the life span. We will also determine if transgenics live longer as do CR mice. While we hypothesize that this is the case, a finding to the contrary (no extension of median/maximum life span in transgenics despite less oxidative damage) would argue against causal links between the two phenomena. We will evaluate UCP2/3 transgenics, UCP2 & UCP3 knockouts, wild type fed ad lib, and CR wild type mice for median/maximum life span, mitochondrial ROS, gene expression patterns (via microarrays), oxidative damage, apoptosis/cell death, and neural inflammation. If increased expression of UCP2/3 mimics caloric restriction, changes should be qualitatively similar to those in CR wild type mice, with changes in the opposite direction for the knockouts. Finally, we hypothesize that the life- extending effects of increased UCP2/3 expression will occur without decreases in total energy expenditure or circulating glucose (i.e., that neither is critical to life extension). Our data will determine if greater expression of UCP2/3 mimics effects of CR and will increase our understanding of mechanisms that have potential to increase median and maximum life span.