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Comparative Study
. 2009 Dec;64(12):1212-20.
doi: 10.1093/gerona/glp132. Epub 2009 Sep 23.

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

Yiqiang Zhang  1 , Yuji Ikeno, Wenbo Qi, Asish Chaudhuri, Yan Li, Alex Bokov, Suzanne R Thorpe, John W Baynes, Charles Epstein, Arlan Richardson, Holly Van Remmen
Affiliations
Comparative Study

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

Yiqiang Zhang et al. J Gerontol A Biol Sci Med Sci. 2009 Dec.

Abstract

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.

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Figures

Figure 1.
Figure 1.
Body composition of young and old wild-type (WT) and Sod2+/−Gpx1−/− (DKO) male mice. Lean body mass (lbm) and fat composition were measured by dexascan and calculated as percent of total body mass.
Figure 2.
Figure 2.
Oxidative damage in young and old wild-type (WT) and Sod2+/−Gpx1−/− (dKO) mice. (A) DNA oxidation (level of 8-oxo-dG) was quantified in liver and skeletal muscle samples as described in the Methods section (n = 6). *p < .001, as determined by analysis of variance (ANOVA). (B) Protein oxidation was measured in homogenates from brain, liver, and skeletal muscle (n = 6). *p < .05, as determined by ANOVA. Open bars represent values from wild-type mice; filled bars, values from Sod2+/−Gpx1−/− mice.
Figure 3.
Figure 3.
Life span of Sod2+/−Gpx1−/− mice. Survival curves are shown for wild-type (121 mice, solid diamond), Gpx1−/− (47 mice, solid square), Sod2+/−Gpx1+/− (25 mice, solid circle), and Sod2+/−Gpx1−/− (32 mice, open diamond). In these survival experiments, we combined both male and female mice. The mean (± standard error of the mean [SEM]), median, maximum, and top 10% (± SEM) survival of mice were determined from the age at death as described in the Methods section.
Figure 4.
Figure 4.
Changes in carboxymethyl-lysine level (CML), a biomarker for aging. Data are results for skin collagen taken from five to seven young and old mice. The level of CML clearly increased with age for the wild-type and Sod2+/−Gpx1−/− mice but was not different between the two groups. Diamond-shaped symbols represent data from the wild-type mice; squares, the Sod2+/−Gpx1−/− mice.
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