An Objective Appraisal of the Free Radical Theory of Aging

Publisher Summary This chapter presents a review of the literature that suggests that increasing the antioxidant concentration, whether exogenously through the diet or through use of transgenic mouse models, is not sufficient to extend the life span of mice bred under optimal animal husbandry conditions. It suggests that the first premise of the free radical theory of aging, i.e., that an increase in antioxidants should extend life span, appears to be true only when short lived animal models are used, whether it is because they are genetically short-lived or because of suboptimal husbandry conditions. With regard to the second premise of the free radical theory of aging, that an increase in oxidants should shorten life span, the data accumulated so far leave little doubt that uncontrolled levels of reactive oxygen species are incompatible with mammalian life. The deleterious phenotypes of Sod2–/– and Gpx4–/– mice make this point very clearly. In addition, the increased levels of oxidative damage brought about by the absence of Sod1 are clearly sufficient to result in an increase in oxidative damage and a significant reduction in life span as well as to accelerate the course of several age-related pathologies. However, the effect of high levels of oxidative damage on aging is difficult to interpret because Sod1–/– mice also have a significant increase in cancer, which may contribute to the reduction in life span.