Knockout and Transgenic Mouse Models to Define the Role of Oxidative Stress in Aging
H. Van Remmen, J. Vijg, X. Chen, J. Mele, M. Hamilton and A. Richardson
Departments of Physiology and Cellular and Structural Biology, Univ. of Texas Health Science Center and GRECC, South Texas Veterans Health Care System, San Antonio, TX, 78229.
Knockout and transgenic mice with alterations in antioxidant defense capacity provide good models to investigate the role of oxidative stress in the decline in physiologic function that occurs during the aging process. We have recently studied the relationship between oxidative damage and aging in Sod2+/- knockout mice, which have approximately 50% of the Mn-Superoxide dismutase (MnSOD) activity of wildtype (WT) mice in all tissues. Sod2+/- mice show a significant increase in oxidative damage to both nuclear and mitochondrial DNA and an increase in the incidence of pathology; however, there is no alteration in lifespan. We are currently examining the effect of a more severe antioxidant depletion on oxidative stress and aging in mice deficient in both MnSOD and glutathione peroxidase (GPx1). The Sod2+/- x GPx1-/- mice are characterized by a 50% reduction in MnSOD activity in combination with a very low to non-detectable activity of GPx1 in all tissues we have studied. Oxidative damage to nuclear and mitochondrial DNA in a variety of tissues is elevated to levels several fold higher than in WT or Sod2+/- knockout mice. Fibroblasts isolated from the Sod2+/- x GPx1-/- mice show increased cell death in response to t-butyl hydroperoxide or g-irradiation in vitro. The Sod2+/- x GPx1-/- mice are also highly sensitive to oxidative stress induced in vivo by whole body g-irradiation. In contrast, to examine the effect of increased antioxidant protection and reduced oxidative damage on physiologic function and lifespan we are studying two transgenic mouse models that were generated using P1 clones isolated from a human genomic library (hCat-Tg and hSod-Tg). These transgenic mouse lines exhibit at least 2 to 4-fold increased activity of either catalase or CuZn superoxide dismutase, respectively in all tissues. Our preliminary data using hepatocytes and fibroblasts isolated from the hCat-Tg mice or hSod-Tg mice show an increased resistance to induction of oxidative stress by agents such as H2O2 and paraquat compared to WT mice. By using knockout and transgenic mouse models with modified antioxidant defense systems and altered sensitivity to oxidative stress and damage, we hope to be able to better define the role that oxidative stress plays in aging and age-related physiologic declines.
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