Aging: A mitochondrial DNA perspective, critical analysis and an update

Abstract

The mitochondrial theory of aging, a mainstream theory of aging which once included accumulation of mitochondrial DNA (mtDNA) damage by reactive oxygen species (ROS) as its cornerstone, has been increasingly losing ground and is undergoing extensive revision due to its inability to explain a growing body of emerging data. Concurrently, the notion of the central role for mtDNA in the aging process is being met with increased skepticism. Our progress in understanding the processes of mtDNA maintenance, repair, damage, and degradation in response to damage has largely refuted the view of mtDNA as being particularly susceptible to ROS-mediated mutagenesis due to its lack of “protective” histones and reduced complement of available DNA repair pathways. Recent research on mitochondrial ROS production has led to the appreciation that mitochondria, even in vitro, produce much less ROS than previously thought, automatically leading to a decreased expectation of physiologically achievable levels of mtDNA damage. New evidence suggests that both experimentally induced oxidative stress and radiation therapy result in very low levels of mtDNA mutagenesis. Recent advances provide evidence against the existence of the “vicious” cycle of mtDNA damage and ROS production. Meta-studies reveal no longevity benefit of increased antioxidant defenses. Simultaneously, exciting new observations from both comparative biology and experimental systems indicate that increased ROS production and oxidative damage to cellular macromolecules, including mtDNA, can be associated with extended longevity. A novel paradigm suggests that increased ROS production in aging may be the result of adaptive signaling rather than a detrimental byproduct of normal respiration that drives aging. Here, we review issues pertaining to the role of mtDNA in aging.

Keywords: Mitochondrial DNA, Reactive oxygen species, DNA damage, DNA repair, Somatic mtDNA mutations, Antioxidants, Reactive oxygen species signaling, Mitochondrial DNA degradation, Electron transport, Aging

Core tip: The notion of reactive oxygen species (ROS) -mediated accumulation of mutations in mitochondrial DNA (mtDNA) as a driving force behind aging is increasingly losing ground forcing a revision of the Mitochondrial Theory of Aging. While mitochondrial involvement remains in the center of attention of aging research, the focus is shifting from mtDNA mutations to mitochondrial physiology. The positive effect of increased ROS production on longevity is increasingly viewed as evidence that increased ROS production in aging may be adaptive rather than maladaptive. This novel paradigm explains failure of antioxidants to delay aging in clinical trials.