This is an application for renewal of a program project that has, from its inception 1978, the persistent theme of elucidation of gene action capable of modulating the rate of aging in mammalian cells. For the present competitive renewal we are pursuing this theme by studying genetic models of enhanced longevity through augmented resistance to oxidative and DNA damage. Two projects capitalize on work in the past funding cycle that shows that over expression of catalase targeted to mitochondria leads to lifespan extension in mice, and that while over expression of wild type catalase (targeted to peroxisomes) and Cu-Zn superoxide dismutase (type 1) have little effect on murine lifespan by themselves, the combination of over expression of both produces a significant extension of mean lifespan in mice. Improved genetic models of lifespan extension through enhanced antioxidant defense in mice will be developed and characterized. Two projects study the mouse models of altered fidelity of DNA polymerases gamma and delta, respectively. This includes the study of aging in mice with """"""""antimutator"""""""" polymerases with enhanced fidelity in the face of oxidative stress. This project requests support of Cores for administration, mitochondrial assays, animal assays and maintenance, and DNA damage assays.
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