This proposal is based on the premise that oxygen free radicals are involved in mitochondrial aging and in turn, aging of the whole organism. Superoxide radicals generated in the mitochondria can lead to damage of macromolecules and result in defective mitochondria. This process ultimately leads to the state of senescence and the demise of the organism. We hypothesize that factors that can protect the mitochondria from free radical damage have the potential to maintain energy production and tissue function, and ultimately to delay the onset of senescence and prolong the lifespan of the organism. MnSOD deficient mice (Sod2-/-) represent an animal model with increased mitochondrial superoxide radicals, accelerated tissue damage, and early demise. We have showed that genetic modifiers play an important role in the determination of the life expectancy of Sod2-/- mice. Thus, Sod2-/- mice on a long-lived genetic background have a lifespan 5 times longer than that of the mutant mice on a short-lived background. We designated the genetic modifiers KOLEGs (KnockOut Life-Extending Genes) and designed a series of experiments to map the KOLEG loci and to identify putative modifier genes. To date, we have generated congenic KOLEG-containing mice on an otherwise pure B6 background, mapped the major KOLEG to a 10 cM region, and identified a putative modifier gene in the KOLEG-containing region. The modifier gene encodes the nicotinamide nucleotide transhydrogenase (NNT), which is a membrane-bound protein located in the inner membrane of the mitochondria. To build upon our current findings and ultimately identify novel genetic modifiers capable of """"""""modulating mitochondrial resistance to increased oxidative stress and extending the lifespans of mutant as well as wild type mice, the following specific aims are proposed.
Aim 1 : Identification of additional modifier genes by fine mapping and functional annotation.
Aim 2 : Mechanistic analysis of Nnt as the genetic modifier of Sod2-/-.
Aim 3 : Validation of Nnt as a longevity assurance gene (LAG).
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