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.
Zhang
Yiqiang
Y
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245, USA.
Ikeno
Yuji
Y
Qi
Wenbo
W
Chaudhuri
Asish
A
Li
Yan
Y
Bokov
Alex
A
Thorpe
Suzanne R
SR
Baynes
John W
JW
Epstein
Charles
C
Richardson
Arlan
A
Van Remmen
Holly
H
D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight; D001921:Brain / Q000201:enzymology / Q000473:pathology; D004249:DNA Damage; D004195:Disease Models, Animal; D005979:Glutathione Peroxidase / Q000172:deficiency* / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008136:Longevity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009929:Organ Size; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D011336:Probability; D011897:Random Allocation; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2
D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2; C000722068:Gpx1 protein, mouse