ATM dependent phosphorylation of SNEV in stress and longevity

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 negatively 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 human patients as well as in several mouse models where DNA repair factors had been knocked-out. However, the opposite, namely if improved DNA repair will also increase the health span is unclear, very limited data is available on overexpression of DNA repair factors, 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. Recently, we found that SNEV might be a potential phosphorylation substrate of ATM, a kinase that directs the cellular response to DNA double strand breaks and, in part, to oxidative stress, and that phosphorylation of SNEV is triggered by oxidative stress. Therefore, we hypothesise that phosphorylation of SNEV might be modulating DNA repair and might also modulate the health/life span of cells. This project will elucidate novel and substantially refine known pathways in the cellular stress response and their contribution to aging and age-related pathologies and provide insight into how SNEV`s multiple role in diverse cellular pathways are interconnected. Furthermore, by testing the mutants that cannot be phosphorylated by ATM or that mimick constitutive phosphorylation, we might be able to attribute the life span extension activity to its ATM dependent DNA repair activity. With this detailed molecular and physiological knowledge it might be possible to eventually design diagnostic and interventive strategies counteracting or at least retarding functional decline that accompanies late life as well as malignancies caused by defective DNA repair, thereby possibly leading to improvement of public health and thus to decreased public health care cost.

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 old ages also poses challenges to our health care systems in terms of increasing age related diseases and frailty. Still molecular mechanisms that during normal aging nourish the development of diseases at old age are not well understood. Identification of factors that promote healthy aging is therefore one of the important topics of our future.One factor that is widely acknowledged to negatively impact on healthy aging is defective DNA repair, since mutations in DNA repair factors lead to accelerated and premature aging. However, the opposite, namely if improved DNA repair will also increase the health span is unclear, and very limited data is available on overexpression of DNA repair factors, 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 with lower basal DNA damage as well as an increased resistance to oxidative stress. This project set out to elucidate pathways in the cellular stress response and their contribution to aging and age-related pathologies and provide insight into how SNEVs multiple roles in diverse cellular pathways are interconnected. In addition we elucidated the function of a SNEV interacting protein, Nsun5, as well as miRNAs in the context of aging and stress resistance. Thereby we found that Nsun5 is able to extend the life span of fly, worm and yeast in a highly conserved manner by programming the cellular protein synthesis machine to increased stress resistance. Finally, we found that miRNAs can also modulate the life span and stress resistance of human cells. With such knowledge it is possible to eventually design strategies counteracting or at least retarding functional decline that accompanies late life and lead to diseases including malignancies caused by defective DNA repair.