An involvement of mitochondria in aging processes has been proposed by numerous investigators. There is mounting evidence for an increasing number of mitochondrial DNA (mtDNA) deletions and other abnormalities with age in humans. These age-associated abnormalities are most pronounced in nerve and muscle and may explain many disorders of old age in these tissues. Similar increasing mtDNA deletions with age have been found in muscles of other species, including mouse and rhesus monkey. We propose to localize mtDNA abnormalities in selected skeletal muscles of three animal models and to study the influence of age and dietary restriction (DR) on the patterns of localization. Two lines of evidence suggest a role for DR on mtDNA abnormalities. There is extensive evidence that DR reduces free radical damage in aging rodents and that DR significantly increases the maximum life-span of mice. Currently, the effects of DR are being tested in rhesus monkeys.
Three Specific Aims are proposed: 1) Develop proficiency in biogerontology and the methodology of DR, 2) Determine the cellular distribution of mtDNA deletions in skeletal muscles of mice and rhesus monkeys using in situ hybridization and in situ PCR, and 3) Determine the effect of DR on the distribution of mtDNA deletions in skeletal muscle from mice and rhesus monkeys.
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