Cellular and molecular determinants of vertebrate lifespans

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This proposal outlines a research program that will lead to a better understanding of the biology of animal lifespan. Experiments over the last two decades have shown us that increased or naturally long lifespans are associated with increased cellular stress resistance. Greater cellular stress resistance promotes the maintenance of cell and tissue functions over longer periods of time. In highly oxidative tissues (e.g. brain and heart) of particularly long-lived species, individual cells may persist for 80+ years. However, we know surprisingly little about how this is achieved. In this research proposal, I describe a strategy for identifying components of cellular stress resistance that have co-evolved with longevity in mammalian and avian species. This approach makes use of a wide range of species, including some that are exceptionally long-lived (e.g. bats and birds). Proteins that function in maintaining cellular machinery in a functional state, removing mutagenic DNA damage, and regulating mitochondrial function will be assayed. In addition to the multi-species approach taken, I will also investigate these same cellular functions in a strain of mice possessing a single gene mutation that extends their lifespan by 50% (the Snell dwarf). Physiological stressors cause cell death, which underlies the tissue degeneration of aging. Long-lived animals may counter this by maintaining populations of stem cells within tissues of adults that can replicate and differentiate to replace lost cells. I will determine whether longer-lived animals have more or more robust adult stem cells in heart tissue. Finally, the information generated in studies of this nature is of benefit to people. I recently discovered a potentially important interaction between the dietary polyphenol resveratrol and the mitochondrial antioxidant enzyme Mn-superoxide dismutase. Treatment of human cells or live mice with resveratrol induces increased production of this enzyme that is coincident with increased stress resistance. In this proposal, I outline experiments that will elucidate the interaction of resveratrol with cells that lead to Mn-superoxide dismutase induction, as well as experiments that will lead to improved delivery of resveratrol to cells to facilitate this effect.