The relationship of mitochondrial DNA mutations to aging is still debated. Most mtDNA mutations are recessive: there are multiple copies per cell and mutation needs to clonally expand to cause respiratory deficiency. Overall mtDNA mutant loads are low, so effects of mutations are limited to critical areas where mutations locally reach high fractions. This includes respiratory chain deficient zones in muscle fibers, respiratory-deficient crypts in colon, and massive expansions of deleted mtDNA in substantia nigra neurons. mtDNA "mutator" mouse with increased rate of mtDNA mutations is a useful model, although rates and distribution of mutations may significantly deviate from what is observed in human aging. Comparison of species with different longevity reveals intriguing longevity-related traits in mtDNA sequence, although their significance is yet to be evaluated. The impact of somatic mtDNA mutations rapidly increases with age, so their importance is expected to grow as human life expectancy increases.
Keywords: Aging; Clonal expansion; Evolution of aging; Mitochondrial DNA; Mutations.
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