Somatic tissues progressively deteriorate over time, giving rise to a range of phenotypic changes associated with aging. This deterioration likely results from the accumulation of damage to cellular DNAs and other macromolecules. In this Project we propose to evaluate the contribution of accumulated nuclear DNA (nDNA) mutations to aging. Our approach is to genetically engineer mice with varying levels of spontaneous mutator and antimutator phenotypes and to examine these animals for altered rates of aging. These studies will take advantage of our ability to make allelic replacements (""""""""knockins"""""""") in mice that modify the fidelities of the nuclear DNA polymerases delta and epsilon (pols delta and epsilon).
The specific aims are: 1) determine the effects of pol delta and pol epsilon mutators on aging, 2) determine the effects of pol delta antimutators on aging, and 3) asses the combined effects of pol delta and pol gamma antimutators and mitochondrial catalase (mCAT). Together, these experiments will allow us to critically and directly evaluate the effect of somatic mutation burden on aging. Since pol delta participates in both mitotic DNA replication and post-mitotic repair, changes in the fidelity of this essential enzyme are expected to alter the cumulative mutation levels in a broad spectrum of tissues and cell types. By using a series of low-to-high mutator and antimutator alleles, we will be able to titrate the somatic mutation burden in mice and thus directly assess the impact of nDNA mutation on aging.
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