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.
| Andrews, Zane B; Horvath, Tamas L (2009) Uncoupling protein-2 regulates lifespan in mice. Am J Physiol Endocrinol Metab 296:E621-7 |
| Horvath, Tamas L; Andrews, Zane B; Diano, Sabrina (2009) Fuel utilization by hypothalamic neurons: roles for ROS. Trends Endocrinol Metab 20:78-87 |
| Dietrich, Marcelo O; Andrews, Zane B; Horvath, Tamas L (2008) Exercise-induced synaptogenesis in the hippocampus is dependent on UCP2-regulated mitochondrial adaptation. J Neurosci 28:10766-71 |
| Deierborg, Tomas; Deierborg Olsson, Tomas; Wieloch, Tadeusz et al. (2008) Overexpression of UCP2 protects thalamic neurons following global ischemia in the mouse. J Cereb Blood Flow Metab 28:1186-95 |
| Gao, Qian; Horvath, Tamas L (2008) Neuronal control of energy homeostasis. FEBS Lett 582:132-41 |
| Coppola, Anna; Liu, Zhong-Wu; Andrews, Zane B et al. (2007) A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Cell Metab 5:21-33 |
| Rao, Yan; Liu, Zhong-Wu; Borok, Erzsebet et al. (2007) Prolonged wakefulness induces experience-dependent synaptic plasticity in mouse hypocretin/orexin neurons. J Clin Invest 117:4022-33 |
| Downs, Jodi L; Dunn, Michael R; Borok, Erzsebet et al. (2007) Orexin neuronal changes in the locus coeruleus of the aging rhesus macaque. Neurobiol Aging 28:1286-95 |
| Gao, Qian; Horvath, Tamas L (2007) Neurobiology of feeding and energy expenditure. Annu Rev Neurosci 30:367-98 |
| Andrews, Zane B; Rivera, Alicia; Elsworth, John D et al. (2006) Uncoupling protein-2 promotes nigrostriatal dopamine neuronal function. Eur J Neurosci 24:32-6 |
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