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

Holly Van Remmen, Yuji Ikeno, Michelle Hamilton, Mohammad Pahlavani, Norman Wolf, Suzanne R. Thorpe, Nathan L. Alderson, John W. Baynes, Charles J. Epstein, Ting Ting Huang, James Nelson, Randy Strong, Arlan Richardson

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)29-37
Number of pages9
JournalPhysiological Genomics
Volume16
DOIs
StatePublished - Apr 1 2004

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Keywords

  • Mitochondria
  • Oxidative damage

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Van Remmen, H., Ikeno, Y., Hamilton, M., Pahlavani, M., Wolf, N., Thorpe, S. R., Alderson, N. L., Baynes, J. W., Epstein, C. J., Huang, T. T., Nelson, J., Strong, R., & Richardson, A. (2004). Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiological Genomics, 16, 29-37. https://doi.org/10.1152/physiolgenomics.00122.2003