Refining oxidative aging theories with antioxidant enzyme knockout mice





F. Muller

The University of Texas Health Science Center at San Antonio, Department of Physiology, Barshop Institute for Longevity and Aging Studies, 15355 Lambda Drive, San Antonio, TX 78245, USA



The free radical theory of aging is currently one of the most popular explanations on how aging occurs at the molecular level. Our group recently published that mice partially deficient in the antioxidant enzyme manganese superoxide dismutase (Sod2+/-), have increased DNA oxidative damage (8-oxo-dG), increased tumor burden, but do not exhibit a shortened lifespan and do not exhibit acceleration of age-related biomarkers. Adding to this argument, published data by other groups indicate that Ogg1-/- mice exhibit an up to 20-fold increase in mitochondrial 8-oxo-dG, yet their survival is apparently normal. These simple observations would seem to pose a direct contradiction to what the free radical theory predicts. However, protein oxidation, lipid peroxides, mtDNA deletions and mitochondrial H2O2 release, are not increased in the Sod2+/- mice. An update is presented here, on the lifespan and oxidative status of other antioxidant deficient mice, with a special emphasis on the Sod1-/-. Sod1-/- animals have a shortened lifespan, but no further decrease in survival is seen in triple compound Sod1-/- Gpx1-/- Sod2+/- mice. Contrary to other antioxidant deficient animals, Sod1-/- mice exhibit a dramatic increase in every marker of oxidative damage so far assayed. Several biomarkers of aging are also accelerated. Specifically, Sod1-/- mice exhibit a dramatic increase in age-related muscle atrophy, the hind-legs having lost 50% of their muscle mass by 20 months of age. Strikingly, preliminary results indicate that even the Sod1+/- mice have a decreased lifespan. The experiments with antioxidant knockout mice thus do not disprove the free radical theory but require its refinement: 8-oxo-dG is very unlikely to play a role in aging considering its dramatic elevation is apparently without effect, but other types of oxidative damages such as protein oxidation, lipid peroxidation, mtDNA deletions are not excluded by the available data, and may very well play a role in aging.




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