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author:("Ikeno, fuji")
1.  Mice Deficient in Both Mn Superoxide Dismutase and Glutathione Peroxidase-1 Have Increased Oxidative Damage and a Greater Incidence of Pathology but No Reduction in Longevity 
To test the impact of increased mitochondrial oxidative stress as a mechanism underlying aging and age-related pathologies, we generated mice with a combined deficiency in two mitochondrial-localized antioxidant enzymes, Mn superoxide dismutase (MnSOD) and glutathione peroxidase-1 (Gpx-1). We compared life span, pathology, and oxidative damage in Gpx1−/−, Sod2+/−Gpx1+/−, Sod2+/−Gpx1−/−, and wild-type control mice. Oxidative damage was elevated in Sod2+/−Gpx1−/− mice, as shown by increased DNA oxidation in liver and skeletal muscle and increased protein oxidation in brain. Surprisingly, Sod2+/−Gpx1−/− mice showed no reduction in life span, despite increased levels of oxidative damage. Consistent with the important role for oxidative stress in tumorigenesis during aging, the incidence of neoplasms was significantly increased in the older Sod2+/−Gpx1−/− mice (28–30 months). Thus, these data do not support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice and do not support the oxidative stress theory of aging.
doi:10.1093/gerona/glp132
PMCID: PMC2781787  PMID: 19776219
Oxidative stress; Longevity
2.  Overexpression of Mn Superoxide Dismutase Does Not Increase Life Span in Mice 
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.
doi:10.1093/gerona/glp100
PMCID: PMC2759571  PMID: 19633237
Oxidative damage; Mn superoxide dismutase; Pathology; Aging
3.  Is the Oxidative Stress Theory of Aging Dead? 
Biochimica et biophysica acta  2009;1790(10):1005-1014.
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.
doi:10.1016/j.bbagen.2009.06.003
PMCID: PMC2789432  PMID: 19524016
Antioxidant defense; oxidative stress; oxidative damage; knockout mice; transgenic mice; longevity
4.  Reduced Incidence and Delayed Occurrence of Fatal Neoplastic Diseases in Growth Hormone Receptor/Binding Protein Knockout Mice 
Although studies of Ames and Snell dwarf mice have suggested possible important roles of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in aging and age-related diseases, the results cannot rule out the possibility of other hormonal changes playing an important role in the life extension exhibited by these dwarf mice. Therefore, growth hormone receptor/binding protein (GHR/BP) knockout (KO) mice would be valuable animals to directly assess the roles of somatotropic axis in aging and age-related diseases because the primary hormonal change is due to GH/IGF-1 deficiency. Our pathological findings showed GHR/BP KO mice to have a lower incidence and delayed occurrence of fatal neoplastic lesions compared with their wild-type littermates. These changes of fatal neoplasms are similar to the effects observed with calorie restriction and therefore could possibly be a major contributing factor to the extended life span observed in the GHR/BP KO mice.
doi:10.1093/gerona/glp017
PMCID: PMC2667132  PMID: 19228785
Growth hormone receptor/binding protein; Knockout mouse; Neoplastic disease; Aging

Results 1-4 (4)