Uncoupling Proteins and Species-Dependent Longevity

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): This application is in direct response to a Request For Application by the National Institute of Aging (NIA), RFA-AG-03-003 "COMPARATIVE BIOLOGY: MECHANISMS OF AGING." We have discovered that subtle and sustained reduction of mitochondrial membrane potential by the means of increased proton transport through its inner membrane by uncoupling proteins (UCPs) diminish age associated declines in certain metabolic parameters and increase longevity in mice. We have collected preliminary evidence that baseline level of mitochondrial uncoupling is significantly elevated in the brains of longer-lived (30-40 years) non-human primates compared to that of rats and mice, and, that certain UCPs, for example UCP2, are more widespread in the brains of non-human primates than that of rodents and proptect agains neuronal degeneration. Together these observations gave impetus to our central hypothesis that differential level of mitochondrial uncoupling contributes to species differences in longevity. In our application we propose to provide further evidence for the role of mitochondrial uncoupling proteins in the aging process with particular emphasis on species differences. Specific Aim 1: We hypothesize that species with greater longevity have elevated basal mitochondrial uncoupling levels in different tissue types, including brain, heart, muscle, liver and kidney. Specific Aim 2: We propose that key mitochondrial enzymes controlling inner mitochondrial membrane potential are differentially expressed in species with longer versus shorter longevity. Specific Aim 3: We predict that the growth hormone-dependent changes in age related processes are directly associated with uncoupling proteins and changes in inner mitochondrial membrane potential. Our attempts to provide comparative analyses of age related molecular mechanisms in rodents and nonhuman primates, will provide novel therapeutic targets, UCPs, to increase longevity without compromising tissue function.