Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging

1 Departments of Cellular and Structural Biology at the University of Texas Health Science Center at San Antonio, San Antonio 78229 2 Physiology at the University of Texas Health Science Center at San Antonio, San Antonio 78229 3 Pharmacology at the University of Texas Health Science Center at San Antonio, San Antonio 78229 4 Barshop Center for Longevity Studies at the University of Texas Health Science Center at San Antonio, San Antonio 78229 5 Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, San Antonio, Texas 78284 6 Department of Pathology, University of Washington, Seattle, Washington 98195 7 Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208 8 Department of Pediatrics, University of California, San Francisco 94143 9 Neurology and Neurological Sciences, Stanford University, Palo Alto, California 94304 Mice heterozygous for the Sod2 gene ( Sod2 +/- mice) have been used to study the phenotype of life-long reduced Mn-superoxide dismutase (MnSOD) activity. The Sod2 +/- mice have reduced MnSOD activity ( 50%) in all tissues throughout life. The Sod2 +/- mice have increased oxidative damage as demonstrated by significantly elevated levels of 8-oxo-2-deoxyguanosine (8oxodG) in nuclear DNA in all tissues of Sod2 +/- mice studied. The levels of 8oxodG in nuclear DNA increased with age in all tissues of Sod2 +/- and wild-type (WT) mice, and at 26 mo of age, the levels of 8oxodG in nuclear DNA were significantly higher (from 15% in heart to over 60% in liver) in the Sod2 +/- mice compared with WT mice. The level of 8oxodG was also higher in mitochondrial DNA isolated from liver and brain in Sod2 +/- mice compared with WT mice. The increased oxidative damage to DNA in the Sod2 +/- mice is associated with a 100% increase in tumor incidence (the number of mice with tumors) in old Sod2 +/- mice compared with the old WT mice. However, the life spans (mean and maximum survival) of the Sod2 +/- and WT mice were identical. In addition, biomarkers of aging, such as cataract formation, immune response, and formation of glycoxidation products carboxymethyl lysine and pentosidine in skin collagen changed with age to the same extent in both WT and Sod2 +/- mice. Thus life-long reduction of MnSOD activity leads to increased levels of oxidative damage to DNA and increased cancer incidence but does not appear to affect aging. oxidative damage; mitochondria