Is the oxidative stress theory of aging dead?

Abstract

Currently, the oxidative stress (or free radical) theory of aging is the most popular explanation of how aging occurs at the molecular level. While data from studies in invertebrates (e.g., C. elegans and Drosophila) and rodents show a correlation between increased lifespan and resistance to oxidative stress (and in some cases reduced oxidative damage to macromolecules), direct evidence showing that alterations in oxidative damage/stress play a role in aging are limited to a few studies with transgenic Drosophila that overexpress antioxidant enzymes. Over the past eight years, our laboratory has conducted an exhaustive study on the effect of under- or overexpressing a large number and wide variety of genes coding for antioxidant enzymes. In this review, we present the survival data from these studies together. Because only one (the deletion of the Sod1 gene) of the 18 genetic manipulations we studied had an effect on lifespan, our data calls into serious question the hypothesis that alterations in oxidative damage/stress play a role in the longevity of mice.

Figure 1. Lifespans of knockout mice with a deficiency in various antioxidant enzymes

The survival curves of Sod2^+/- (Graph A; [17]), Sod1^-/- (Graph D; unpublished), Gpx1^-/- (Graph C; [43], Gpx4^+/- (Graph B; [16]), MsrA^-/- (Graph E; [42], and Trx2^+/- (Graph F; unpublished) mice are shown compared to their WT cohorts. The genetic background, number, sex and survival data for these curves are given in Table 2.

Figure 2. Lifespans of transgenic mice overexpressing different antioxidant enzymes

The survival curves of SOD1 Tg (Graph A; [103], CAT Tg (Graph B; [103]), Sod2 Tg (Graph C; [53]), GPX4 Tg (Graph D; unpublished), SOD1/CAT Tg (Graph E; [103]), and SOD1/Sod2 Tg (Graph F; [103]) mice are shown compared to their WT cohorts. The genetic background, number, sex and survival data for these curves are given in Table 3.

Figure 3. Sensitivity to transgenic mice to oxidative stress

The sensitivity of embryonic fibroblasts isolated from WT, SOD1 Tg, Sod2 Tg, and SOD1/Sod2 Tg mice to paraquat (48 hrs) was determined as previously described [59]. The data are the mean ± SEM of experiments repeated with fibroblasts derived from three animals and were analyzed by two-way ANOVA. Values that are significant different (p< 0.05) from each other are shown with different subscripts.

Figure 4. Oxidative damage to macromolecules in knockouts mice

The levels of DNA oxidation measured as 8-oxodG/2dG in livers from young WT, Gpx1^-/-, Sod1^-/-, and Sod2^+/- mice was determined as described previously [85]. The data are expressed as the mean ± SEM from 3 to 5 mice and were analyzed by the non-parametric test of ANOVA. Values that are significant different (p< 0.05) from each other are shown with different subscripts.