SNEV, DNA Reparatur und gesundes Altern

The long average life span that we currently are facing is one of the big success stories of advances in medicine, hygiene and nutrition. However, the reaching of such old ages also poses challenges to our health care systems in terms of age related diseases and frailty. Still molecular mechanisms that underlie the disposition to develop diseases at old age are not well understood. Identification of factors that promote healthy aging is therefore one of important topics of our future. One factor, that is widely acknowledged to have a negative impact on healthy aging, is defective DNA repair, since mutations in DNA repair factors lead to accelerated and premature aging, as observed in segmental progeroid syndromes in humans as well as in several mouse models where DNA repair factors had been knocked-out. However, the opposite, namely if improved DNA repair also increases the health span is unclear. No studies are available on overexpression of DNA repair factors in multicellular organisms, where modulation of the life and health span have been analysed. Recently, we identified and characterized the DNA repair factor SNEV and observed a doubling of the replicative life span of endothelial cells upon ectopic overexpression concomitant to lower basal DNA damage and apoptosis levels as well as an increased resistance to oxidative stress. In keeping with this, decreased SNEV protein, as observed in fibroblasts of SNEV+/- mice, accelerates entry into cellular senescence. Therefore, we hypothesise that modulating DNA repair will also modulate the health/life span of organisms. Using SNEV as a model protein, we will test this hypothesis. Heterozyogus SNEV+/- mice that show low SNEV levels will be compared to wild type litter mate controls. Furthermore, we will generate single copy, conditional, tetracycline inducible transgenic (SuperSNEV) mice that overexpress SNEV to defined levels. These mice will be compared in terms of resistance to DNA damage, oxidative stress and life span.