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/

Although reactive oxygen species have been proposed to play a major ro le in the aging process, the exact molecular mechanisms remain elusive , In this study we investigate the effects of a perturbation in the ra tio of Cu/Zn-superoxide dismutase activity (Sod1 dismutases -O-2(-) to H2O2) to glutathione peroxidase activity (Gpx1 catalyses H2O2 convers ion to H2O) on cell growth and development, Our data demonstrate that Sod1 transfected cell lines that have an elevation in the ratio of Sod 1 activity to Gpxl activity produce higher levels of H2O2 and exhibit well characterised markers of cellular senescence viz.slower prolifera tion and altered morphology, On the contrary, Sod1 transfected cell li nes that have an unaltered ratio in the activity of these two enzymes, have unaltered levels of H2O2 and fail to show characteristics of sen escence, Furthermore, fibroblasts established from individuals with Do wn syndrome have an increase in the ratio of Sod1 to Gpx1 activity com pared with corresponding controls and senesce earlier, Interestingly, cells treated with H2O2 also show features of senescence and/or senesc e earlier, We also show that Cip1 mRNA levels are elevated in Down syn drome cells, Sod1 transfectants with an altered Sod1 to Gpxl activity ratio and those treated with H2O2 thus suggesting that the slow prolif eration may be mediated by Cip1. Furthermore, our data demonstrate tha t Cip1 mRNA levels are induced by exposure of cells to H2O2 These data give valuable insight into possible molecular mechanisms that contrib ute to cellular senescence and may be useful in the evolution of thera peutic strategies for aging.