Milena Pinto, Carlos T. Moraes

In the last century, considerable efforts were made to understand the role of mtDNA mutations and of oxidative stress in aging. The classic mitochondrial free radical theory of aging, in which mtDNA mutations cause genotoxic oxidative stress, which in turn creates more mutations, has been a central hypothesis in the field for decades. In the last few years, however, new elements have discredited this original theory. The major source of mitochondrial DNA mutations seems to come from replication errors and failure of the repair mechanisms, and the accumulation of these mutations as observed in aged organisms appears to occur by clonal expansion and are not caused by a reactive oxygen species-dependent vicious cycle. New hypotheses of how age-associated mitochondrial dysfunction may lead to aging are based on the role of reactive oxygen species as signaling molecules and on their role in mediating stress responses to age-dependent damage. Here, we review the changes that mtDNA undergoes during aging, and the past and most recent hypotheses linking these changes to the tissue failure observed in aging.