Yeast Mother Cell-Specific Aging: The Relation to Apoptosis and to Regulation of Oxidative Metabolism

The emphasis of this project is on studying molecular and cellular mechanisms that are engaged with a defined set of aging processes in eukaryotes, which can be studied at the cellular level. Our working hypothesis pinpoints oxidative stress to induce damage and cause changes in cellular signalling that both drive senescence and apoptotic cell death. In line with this, we assume that regulation of apoptotic signalling contributes to the senescence phenotype in a cell type-specific manner. The participants of this project work on representative eukaryotic cellular model systems for aging, ranging from yeast to humans. The joint projects will combine approaches to investigate cellular aging in vitro with ex vivo studies of human origin and with a mouse model of accelerated senescence. The prime interest of the joint research program is to analyze functional changes that can be observed in cells during aging processes. We expect that studying aging processes in the context of various complementary experimental systems will shed new light on universal versus species specific (or tissue-specific) mechanisms of aging. Based on experimental results obtained previously by network partners, a strong emphasis of the present proposal is on the role of apoptotic processes for aging. Under defined circumstances, both apoptosis resistance and increased sensitivity for apoptosis are known to be associated with cellular aging. However, a conceptual framework to solve this apparent ambiguity is largely missing and will now be investigated in this joint project. Both senescence and apoptosis can be experimentally induced by increasing the concentration of reactive oxygen species (ROS) at the cellular level and there is increasing evidence that in many organisms concentrations of ROS rise with age. However, the role of oxidative stress for apoptosis and senescence may differ between species and even between different cell types of the same species. To allow a valid comparison of aging processes in species as different as yeast and humans, a commonly applicable strategy will be developed, including tools for a systematic and uniform analysis of the pro-oxidant status of the cell and oxidative damage caused by ROS. We will also apply bioinformatics approaches to define genes and gene sets with similar function in the model systems described here that contribute to either the senescence phenotype or to age-associated cell death. From these experiments we expect New major insights into the process of cellular senescence in various species and tissues a distinction between unique and common pathways leading to the senescent phenotype a clarification of the role of apoptosis for cellular aging The elucidation of molecular pathways that are triggered by ROS generation, which lead to molecular damage and changes in signal transduction to cause senescence and eventually apoptotic cell death.