Mitochondrial theory of aging matures--roles of mtDNA mutation and oxidative stress in human aging.

Mitochondrial theory of aging, a variant of free radical theory of aging, proposes that accumulation of damage to mitochondria and mitochondrial DNA (mtDNA) leads to aging of humans and animals. It has been supported by the observation that mitochondrial function declines and mtDNA mutation increases in tissue cells in an age-dependent manner. Age-related impairment in the respiratory enzymes not only decreases ATP synthesis but also enhances production of reactive oxygen species (ROS) through increased electron leakage in the respiratory chain. Human mtDNA, which is not protected by histones and yet is exposed to high levels of ROS and free radicals in the matrix of mitochondria, is susceptible to oxidative damage and mutation in tissue cells. In the past decade, more than one hundred mtDNA mutations have been found in patients with mitochondrial disease, and some of them also occur in aging human tissues. The incidence and abundance of these mutant mtDNAs are increased with age, particularly in tissues with great demand for energy. On the other hand, recent studies have revealed that the ability of the human cell to cope with oxidative stress is compromised in aging. Comparative analysis of gene expression by microarray technology has shown that a number of genes related to oxidative stress response are altered in aging animals. We discovered that the transcripts of early growth response protein-1, growth arrest and DNA damage-inducible proteins and glutathione S-transferase genes are increased in response to oxidative stress in human skin fibroblasts. Moreover, the activities of Cu,Zn-SOD, catalase and glutathione peroxidase decrease with age, whereas Mn-SOD activity increases with age up to 65 years and slightly declines thereafter in skin fibroblasts. Such an imbalance in the function of antioxidant enzymes may result in excess production of damaging ROS in the cell. This notion is supported by the observation that intracellular levels of H2O2 and oxidative damage to DNA and lipids are significantly increased with age of the fibroblast donor. Furthermore, the mitochondrial pool of reduced glutathione declines and DNA damage is enhanced in aging tissues. Taken together, these observations and our previous findings that mtDNA mutations and oxidative damage are increased in aging human tissues suggest that mitochondrial theory of aging is mature.