Rethinking the mitochondrial theory of aging: the role of mitochondrial gene expression in lifespan determination.

The Mitochondrial Theory of Aging postulates that accumulation of mtDNA mutations and mitochondrial dysfunction are responsible for generating aging phenotypes and limiting lifespan. Although widely accepted, this theory remains unproven because the evidence supporting it, while substantial, is largely correlative. Furthermore, recent experimental results in mice with accelerated rates of mtDNA mutagenesis have challenged the traditional formulation of the Mitochondrial Theory, perhaps warranting a reevaluation of some of its core principles. In this perspective, we summarize recent work suggesting that both the quantity and the quality of mitochondrial gene expression play a much greater role in the aging process than previously appreciated. We speculate that this form of mitochondrial dysfunction may operate independently or in concert with mtDNA mutations to promote age-related pathology and limit lifespan.