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The Mitochondrial Free Radical Theory of Aging: A Critical View

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The Mitochondrial Free Radical Theory of Aging (MFRTA) proposes that mitochondrial free radicals, produced as by-products during normal metabolism, cause oxidative damage. According to MFRTA, the accumulation of this oxidative damage is the main driving force in the aging process. Although widely accepted, this theory remains unproven, because the evidence supporting it is largely correlative. For example, long-lived animals produce fewer free radicals and have lower oxidative damage levels in their tissues. However, this does not prove that free radical generation determines life span. In fact, the longest-living rodent -Heterocephalus glaber- produces high levels of free radicals and has significant oxidative damage levels in proteins, lipids and DNA.

At its most orthodox MFRTA proposes that these free radicals damage mitochondrial DNA (mtDNA) and in turn provoke mutations that alter mitochondrial function (e.g. ATP production). According to this, oxidative damage to mtDNA negatively correlates with maximum life span in mammals. However, in contrast to MFRTA predictions, high levels of oxidative damage in mtDNA do not decrease longevity in mice. Moreover, mice with alterations in polymerase gamma (the mitochondrial DNA polymerase) accumulate 500 times higher levels of point mutations in mtDNA without suffering from accelerated aging.

Dietary restriction (DR) is the only non-genetic treatment that clearly increases mean and maximum life span. According to MFRTA caloric restricted animals produce fewer mitochondrial reactive oxygen species (mtROS). However, DR alters more than free radical production (e.g. it decreases insulin signalling) and therefore the increase in longevity cannot be exclusively attributed to a decrease in mtROS generation. Thus, moderate exercise produces similar changes in free radical production and oxidative damage without increasing maximum life span.

In summary, available data concerning the role of free radicals in longevity control are contradictory, and do not prove MFRTA. In fact, the only way to test this theory is by specifically decreasing mitochondrial free radical production without altering other physiological parameters (e.g. insulin signalling). If MFRTA is true animals producing fewer mtROS must have the ability to live much longer than their experimental controls.
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Keywords: Aging; comparative biology of aging; dietary restriction; exercise; mitochondria; mitochondrial free radical theory of aging; oxidative damage; reactive oxygen species

Document Type: Research Article

Publication date: March 1, 2008

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  • Current Aging Science publishes frontier review and experimental articles in all areas of aging and age-related research that may influence longevity. This multidisciplinary journal will help in understanding the biology and mechanism of aging, genetics, pathogenesis, intervention of normal aging process and preventive strategies of age-related disorders. The journal publishes objective reviews written by experts and leaders actively engaged in research using cellular, clinical, molecular, and animal models, including lower organism models (e.g., yeast, Caenorhabditis elegans and Drosophila). In addition to the affect of aging on integrated systems, the journal also covers original articles on recent research in fast emerging areas of adults stem cells, brain imaging, calorie restriction, immunosenescence, molecular diagnostics, pharmacology and clinical aspects of aging. Manuscripts are encouraged that relate to developmental programming of aging and the synergistic mechanism of aging with cardiovascular diseases, obesity and neurodegenerative disorders.

    Book reviews, meeting reports and letters-to-the-editor and drug clinical trial studies are also published. The journal is essential reading for researchers, educators and physicians with interest in aging, age-related dementia and Alzheimer's disease and longevity. Current Aging Science provides a comprehensive coverage of the current state of aging research for gerontologists, neuroscientists, clinicians, health science planners, granting agencies and pharmaceutical scientists.

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