application): An age-related decline in the ability of a cell/organism to maintain the integrity of its genome has been proposed to be a fundamental mechanism underlying the aging process, and it has been suggested that dietary restriction extends the longevity of rodents and reduces the incidence of age-related pathological lesions by reducing the levels of DNA damage and mutations that accumulate with age in a cell's genome. This hypothesis is attractive because the integrity of the genome is essential to a cell/organism and because it is supported by several lines of research. Unfortunately, all of the evidence supporting the premise that the accumulation of DNA damage/mutations plays a role in aging and dietary restriction is correlative. The goal of the research described in this project is to use transgenic animal models to test more directly the role that DNA damage plays in the anti-aging action of DR. The objective of this project is to test the following hypothesis: changes in DNA repair that alter the age-related accumulation of DNA damage/mutations will alter the survival and aging of the animals. In this project, two transgenic approaches will be taken to alter the age-related accumulation of DNA damage/mutations: the DNA polymerase B heterozygous (p-po1 -/+) knockout mouse will be used to accelerate the accumulation of DNA damage/mutations and transgenic mice that over-express genes involved in DNA base excision repair will be used to retard the accumulation of DNA damage/mutations. This project consists of three specific aims: (1) to study the effect of reduced base excision repair on the accumulation of DNA damage/mutations and aging using the DNA polymerase p knockout mouse, 92) to study the effect of dietary restriction on the accumulation of DNA damage/mutations and aging in B-po1 -/+ transgenic mice, and (3) To generate and characterize stably transfected cell lines, and subsequently transgenic mice, with enhanced base excision repair actively.
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