The oxidative stress hypothesis of aging (or the free radical hypothesis as it was first proposed) is currently one the most popular explanations for how aging occurs at the biochemical level. The basic tenet of the oxidative stress hypothesis is that the age-related loss of physiological function is due to the progressive and irreversible accumulation of oxidative damage.

The basic object of the research described in this application is to test the oxidative stress hypothesis of aging using transgenic mouse models in which the balance between prooxidants and antioxidants is altered so that the steady state accumulation of oxidative damage is accelerated. If the accumulation of oxidative damage is an important mechanism in the aging process as predicted by the oxidative stress hypothesis of aging, one should observed that the increase in the steady state accumulation of oxidative damage leads to an accelerated rate of aging, i.e., the mice should show a reduced life span and an earlier incidence of pathological lesions. In this proposal, transgenic mice that show reduced expression of either Mn-SOD (Sod2+/-) or both Mn-SOD and the selenium-dependent glutathione peroxidase (Sod2+/-XGpx1+/-F1) will be used to test the following hypothesis: An imbalance between prooxidants and antioxidants that results in an increased steady state accumulation of oxidative damage will result in an accelerated loss of function and therefore accelerated aging.

The basic object of the research described in this application is to test the oxidative stress hypothesis of aging using transgenic mouse models in which the balance between prooxidants and antioxidants is altered so that the steady state accumulation of oxidative damage is accelerated, If the accumulation of oxidative damage is an important mechanism in the aging process as predicted by the oxidative stress hypothesis of aging, one should observed that the increase in the steady state accumulation of oxidative damage leads to an accelerated rate of aging, i.e., the mice should show a reduced life span and an earlier incidence of pathological lesions. In this proposal, transgenic mice that show reduced expression of either Mn-SOD (Sod2+/-) or both Mn-SOD and the selenium-dependent glutathione peroxidase (Sod2+/-XGpx1+/-F1) will be used to test the following hypothesis: An imbalance between prooxidants and antioxidants that results in an increased steady state accumulation of oxidative damage will result in an accelerated loss in function and therefore accelerated aging. The specific aims of this study are: 1. To establish a breeding colony of transgenic mice to generate wild type, Sod2+/- and Sod2+/-XGpx1+/-F1 mice. 2. To measure the survival and pathology and selected physiological parameters of wild type Sod2+/-, and Sod2+/-XGpx1+/-F1 mice. 3. To measure the antioxidant status and the level of oxidative damage in tissues of wild type, Sod2+/-, and Sod2+/-XGpx1+/-F1 mice at 5, 14, and 26 months of age. 4. To measure parameters of mitochondrial function (e.g., mitochondrial respiration, hydrogen peroxide generation, and permeability transition) in tissues of wild type, Sod2+/-, and Sod2+/-XGpx1+/-F1 mice at 5, 14 and 26 moths of age.

R01AG015908

1998-07-15

2002-06-30