Abstract
Since its inception more than four decades ago, the Mitochondrial Free Radical Theory of Aging (MFRTA) has served as a touchstone for research into the biology of aging. The MFRTA suggests that oxidative damage to cellular macromolecules caused by reactive oxygen species (ROS) originating from mitochondria accumulates in cells over an animal’s lifespan and eventually leads to the dysfunction and failure that characterizes aging. A central prediction of the theory is that the ability to ameliorate or slow this process should be associated with a slowed rate of aging and thus increased lifespan. A vast pool of data bearing on this idea has now been published. ROS production, ROS neutralization and macromolecule repair have all been extensively studied in the context of longevity. We review experimental evidence from comparisons between naturally long- or short-lived animal species, from calorie restricted animals, and from genetically modified animals and weigh the strength of results supporting the MFRTA. Viewed as a whole, the data accumulated from these studies have too often failed to support the theory. Excellent, well controlled studies from the past decade in particular have isolated ROS as an experimental variable and have shown no relationship between its production or neutralization and aging or longevity. Instead, a role for mitochondrial ROS as intracellular messengers involved in the regulation of some basic cellular processes, such as proliferation, differentiation and death, has emerged. If mitochondrial ROS are involved in the aging process, it seems very likely it will be via highly specific and regulated cellular processes and not through indiscriminate oxidative damage to macromolecules.
Highlights
The basis for the mitochondrial free radical theory of aging (MFRTA) was provided by Denham Harman [1,2], who recognized the possibility of a connection between mitochondrial oxidative phosphorylation, oxygen free radical formation, cellular damage and the general degenerative phenotype of aging
By the 21st century, the basic ideas espoused in the MFRTA had grown to include a vast array of connections between mitochondrial free radical production
Predictions based on the MFRTA The modern version of the MFRTA proposes that the progenitor reactive oxygen species (ROS) superoxide (O2·-) originating from several mitochondrial enzymes, including respiratory complexes I, II and III [8] enters into a number of secondary reactions leading to other ROS that react with and indiscriminately damage cellular macromolecular structures
Summary
The basis for the mitochondrial free radical theory of aging (MFRTA) was provided by Denham Harman [1,2], who recognized the possibility of a connection between mitochondrial oxidative phosphorylation, oxygen free radical formation, cellular damage and the general degenerative phenotype of aging. One exception to this general rule has been the targeting of human catalase to mitochondria in mice, which does appear to increase both mean and maximum lifespan, the effect on lifespan was apparently reduced when the transgenic mice were backcrossed to control for differences in genetic background [56] Interpretation of this experimental model from the perspective of mitochondrial ROS and intracellular oxidative damage leading to aging and tissue dysfunction (reviewed in Wanagat et al [62]) is complicated by the fact that human catalase expression in these mouse tissues is mosaic, with the human protein being detectable in only 10 to 50% of all cells ([56], and unpublished results from skeletal muscle). Once these ROSaffected pathways have been clearly identified, their redox-stimulated changes during aging and contribution to lifespan can be addressed
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