(Verbatim from the application) Mutation accumulation in mice of extended life span. Genomic instability has been implicated as a major cause of both cancer and aging. Using a transgenic mouse model with chromosomally integrated lacZ mutational target genes, we have recently demonstrated that mutations accumulate with age in an organ-specific manner. That is, both the rate of accumulation and the types of mutations that accumulate were found to differ from organ to organ. The hypothesis central to the proposed project is that the rate of mutation accumulation and the types of mutations that accumulate in various organs and tissues is intricately related to basic mechanisms of aging, possibly through general metabolism. To test this hypothesis and obtain more insight into the relevant pathways involved, we propose to study mutation accumulation in the lacZ mice under caloric restriction and in lacZ hybrids with the Ames dwarf mice. In both CR and the dwarf mouse, life span is extended and tumor formation reduced, possibly due to related mechanisms, in which reduced oxidative stress and/or reduced cell division could play a role. These same mechanisms may also retard mutation accumulation and/or influence the mutational spectra. The results of these studies could lead to new strategies to interfere with basal mutation rates to prevent and/or retard cancer and other deteriorative aspects of aging
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