Elevation in the Ratio of Cu/Zn-Superoxide Dismutase to Glutathione Peroxidase Activity Induces Features of Cellular Senescence and This Effect Is Mediated by Hydrogen Peroxide

Abstract

Although reactive oxygen species have been proposed to play a major role in the aging process, the exact molecular mechanisms remain elusive. In this study we investigate the effects of a perturbation in the ratio of Cu/Zn-superoxide dismutase activity (Sod1 dismutases ^. O ₂⁻ to H ₂ C ₂ ) to glutathione peroxidase activity (Gpx1 catalyses H ₂ O ₂ conversion to H ₂ O) on cell growth and development. Our data demonstrate that Sod1 transfected cell lines that have an elevation in the ratio of Sod1 activity to Gpx1 activity produce higher levels of H ₂ O ₂ and exhibit well characterised markers of cellular senescence viz . slower proliferation and altered morphology. On the contrary, Sod1 transfected cell lines that have an unaltered ratio in the activity of these two enzymes, have unaltered levels of H ₂ O ₂ and fail to show characteristics of senescence. Furthermore, fibroblasts established from individuals with Down syndrome have an increase in the ratio of Sod1 to Gpx1 activity compared with corresponding controls and senesce earlier. Interestingly, cells treated with H ₂ O ₂ also show features of senescence and/or senesce earlier. We also show that Cip1 mRNA levels are elevated in Down syndrome cells, Sod1 transfectants with an altered Sod1 to Gpx1 activity ratio and those treated with H ₂ O ₂ , thus suggesting that the slow proliferation may be mediated by Cip1. Furthermore, our data demonstrate that Cip1 mRNA levels are induced by exposure of cells to H ₂ O ₂ . These data give valuable insight into possible molecular mechanisms that contribute to cellular senescence and may be useful in the evolution of therapeutic strategies for aging.