"Genetic manipulations of Mn superoxide dismutase (MnSOD), SOD2 expression have demonstrated that altering the level of MnSOD activity is critical for cellular function and life span in invertebrates. In mammals, Sod2 homozygous knockout mice die shortly after birth, and alterations of MnSOD levels are correlated with changes in oxidative damage and in the generation of mitochondrial reactive oxygen species. In this study, we directly tested the effects of overexpressing MnSOD in young (4–6 months) and old (26–28 months) mice on mitochondrial function, levels of oxidative damage or stress, life span, and end-of-life pathology. Our data show that an approximately twofold overexpression of MnSOD throughout life in mice resulted in decreased lipid peroxidation, increased resistance against paraquat-induced oxidative stress, and decreased age-related decline in mitochondrial ATP production. However, this change in MnSOD expression did not alter either life span or age-related pathology."
http://biomedgeronto...abstract/glp100
"Methionine sulfoxide reductase A (MsrA) repairs oxidized methionine residues within proteins and may also function as a general antioxidant. Previous reports have suggested that modulation of MsrA in mice and mammalian cell culture can affect the accumulation of oxidized proteins and may regulate resistance to oxidative stress. Thus, under the oxidative stress theory of aging, these results would predict that MsrA regulates the aging process in mammals. We show here that MsrA-/- mice are more susceptible to oxidative stress induced by paraquat. Skin-derived fibroblasts do not express MsrA, but fibroblasts cultured from MsrA-/- mice were, nevertheless, also more susceptible to killing by various oxidative stresses. In contrast to previous reports, we find no evidence for neuromuscular dysfunction in MsrA-/- mice in either young adult or in older animals. Most important, we found no difference between MsrA-/- and control mice in either their median or maximum life span. Thus, our results show that MsrA regulates sensitivity to oxidative stress in mice but has no effect on aging, as determined by life span.—Salmon, A. B., Pérez, V. I., Bokov, A., Jernigan, A., Kim, G., Zhao, H., Levine, R. L., Richardson, A. Lack of methionine sulfoxide reductase A in mice increases sensitivity to oxidative stress but does not diminish life span.
"http://www.fasebj.or.../fj.08-127415v1
"We evaluated the effect of overexpressing antioxidant enzymes on the lifespans of transgenic mice that overexpress copper zinc superoxide dismutase (CuZnSOD), catalase, or combinations of either CuZnSOD and catalase or CuZnSOD and manganese superoxide dismutase (MnSOD). Our results show that the overexpression of these major antioxidant enzymes, which are known to scavenge superoxide and hydrogen peroxide in the cytosolic and mitochondrial compartments, is insufficient to extend lifespan in mice."
"The oxidative stress theory of aging offers a credible explanation of a molecular mechanism underlying the aging process. One of the most direct tests of the oxidative stress theory of aging has been to alter oxidative stress/damage and then determine how this alteration affects lifespan (e.g. to genetically manipulate the expression of antioxidant enzymes and observe the effects on lifespan). Based on studies to date, the effect of oxidative stress as a lifespan determinant has been dependent upon the type of animal model tested. Transgenic Drosophila overexpressing either CuZnSOD (Sun & Tower, 1999; Phillips et al., 2000) or MnSOD (Sun et al., 2002) have extended longevity.Although several studies have shown that overexpression of antioxidant enzymes in mice has a protective effect against oxidative stress, with a diminished accumulation of oxidative damage in macromolecules (Muller et al., 2007), Huang et al. (2000) reported that transgenic mice overexpressing CuZnSOD (two- to five-fold increase) did not show any increase in lifespan (Huang et al., 2000). In contrast, Schriner et al. (2005) targeted catalase to mitochondria and observed a 21% extension in the lifespan of transgenic mice."
"Our data might appear to conflict with the study by Schriner et al. (2005), which showed that the overexpression of catalase increased the lifespan of transgenic mice. However, whereas Schriner et al. overexpressed catalase in mitochondria, catalase overexpression in our transgenic mouse occurred in the peroxisomes (Chen et al., 2003), where catalase is normally expressed (Zamocky & Koller, 1999)."
http://www.pubmedcen...i?artid=2667893
"Glutathione peroxidase 4 (Gpx4) is an antioxidant defense enzyme that plays an important role in detoxification of oxidative damage to membrane lipids. Because oxidative stress is proposed to play a causal role in aging, we compared the life spans of Gpx4 heterozygous knockout mice (Gpx4+/– mice) and wild-type mice (WT mice). To our surprise, the median life span of Gpx4+/– mice (1029 days) was significantly longer than that of WT mice (963 days) even though the expression of Gpx4 was reduced approximately 50% in all tissues of Gpx4+/– mice. Pathological analysis revealed that Gpx4+/– mice showed a delayed occurrence of fatal tumor lymphoma and a reduced severity of glomerulonephritis. Compared to WT mice, Gpx4+/– mice showed significantly increased sensitivity to oxidative stress-induced apoptosis. Our data indicate that lifelong reduction in Gpx4 increased life span and reduced/retarded age-related pathology most likely through alterations in sensitivity of tissues to apoptosis."
http://biomed.geront...stract/62/9/932
"Although there is a consensus that mito-chondrial function is somehow linked to the aging process, the exact role played by mito-chondria in this process remains unresolved. The discovery that reduced activity of the mitochondrial enzyme CLK-1/MCLK1 (a.k.a. COQ7) extends lifespan in both C. elegans and mice has provided a genetic model to test mitochondrial theories of aging. We have recently shown that the mitochondria of young, long-lived, Mclk1+/- mice are dysfunctional, exhibiting reduced energy metabolism and a substantial increase in oxidative stress. Here we demonstrate that this altered mitochondrial condition in young animals paradoxically results in an almost complete protection from the age-dependent loss of mitochondrial function, as well as in a significant attenuation of the rate of development of oxidative biomarkers of aging. Moreover, we show that reduction in MCLK1 levels can also gradually prevent the deterioration of mitochondrial function and associated increase of global oxidative stress that is normally observed in Sod2+/- mutants. We hypothesize that the mitochondrial dysfunction observed in young Mclk1+/- mutants induces a physiological state that ultimately allows for their slow rate of aging. Thus, our study provides for a unique vertebrate model in which an initial alteration in a specific mitochondrial function is linked to long-term beneficial effects on biomarkers of aging and, furthermore, provides for new evidence that indicates that mitochondrial oxidative stress is not causal to aging."
http://www.jbc.org/c...t/M109.006569v1
