ABSTRACT
Long-lived animals have low rates of mitochondrial reactive oxygen species (ROS) production and oxidative damage in their mitochondrial DNA (mtDNA). These two parameters also decrease in the four known manipulations that increase mammalian longevity: caloric, protein and methionine restriction, and rapamycin treatment. Oxidative damage to mtDNA is known to be repaired. And mtDNA mutations, including large deletions, do not reach levels high enough in homoplasmy to cause decrements in tissue function in old animals. However, mitochondrial ROS also cause double-strand breaks, which also cause mtDNA fragmentation simultaneously with deletions. These mtDNA fragments are now known to exit mitochondria and insert in nuclear DNA entering it via the pericentromeric region. These mtDNA fragments increase with age in yeast as well as in mice and rat tissues and accelerate chronological aging in yeast. Such mtDNA fragment accumulation in the nucleus can cause aging by various potential mechanisms by affecting nuclear genes and regulatory regions, or inducing aneuploidy and large chromosomal rearrangements due to their high levels near the centromeres.
