The mitochondria are hypothesized to play a major role in mammalian aging. As a byproduct of making ATP via oxidative phosphorylation (OXPHOS), electrons are donated prematurely to O2 to generate oxygen radicals. These radicals damage mitochondrial membranes and mutate mitochondrial DNA (mtDNA) resulting in partial respiratory deficiency. In an attempt to compensate, the cell nucleus synthesizes more mitochondria, but inadvertently amplifies the mutant mtDNAs, ultimately leading to cellular respiratory failure. Over time respiratory deficient cells accumulate in organs, resulting in bioenergetic decline and senescence. To test this hypothesis, this application proposes five specific aims. First, the investigator proposes to examine the association between aging, mitochondrial functional decline oxygen radical production and mtDNA mutation accumulation in human skeletal muscle. Second, they will define the nature and severity of mtDNA mutations that accumulate with aging. Third, the investigator will analyze the tissue distribution and frequency of respiratory deficient cells and correlate the amplification of mutant mtDNAs with the coordinate induction of OXPHOS gene expression. Fourth, they will determine if the increased longevity and decreased oxygen radical production of diet restricted mice is associated with sustained mitochondrial function and reduced mtDNA mutations. Finally, the investigator proposes to prepare transgenic mice with increased mitochondrial and cytosolic oxygen radical detoxification systems to determine if mitochondrial damage is decreased and longevity increased.
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