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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences Advance Access originally published online on September 23, 2009
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2009 64A(12):1212-1220; doi:10.1093/gerona/glp132
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© The Author 2009. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

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 Zhang1,2, Yuji Ikeno2,3,4,5, Wenbo Qi2, Asish Chaudhuri2,3,6, Yan Li2, Alex Bokov2,5, Suzanne R. Thorpe7, John W. Baynes7,8, Charles Epstein9, Arlan Richardson1,2,3,5 and Holly Van Remmen1,2,3,5

1 Department of Cellular and Structural Biology
2 Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio
3 South Texas Veterans Health Care System, San Antonio
4 Department of Pathology
5 Department of Physiology
6 Department of Biochemistry, University of Texas Health Science Center, San Antonio
7 Department of Chemistry and Biochemistry
8 Department of Exercise Science, University of South Carolina, Columbia
9 Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco

Address correspondence to Holly Van Remmen, PhD, Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245. Email: vanremmen{at}uthscsa.edu


  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.

Keywords Oxidative stress; Longevity

Received: April 29, 2009; Accepted: August 13, 2009

Decision Editor: Huber R. Warner, PhD


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