The aim of the proposal is to gain novel insight into molecular mechanisms of healthy ageing. Based on a proteomic analysis of ageing processes in a variety of ageing models including model organisms and model systems (e.g. human cell cultures), we will address the question how (1) changes in protein concentration and protein modification, (2) protein-protein interactions and protein networks, (3) signaling mediated by extracellular proteins, and (4) protein turnover and degradation via the proteasomal system play a functional role in the ageing process. To this aim we have assembled a consortium of 15 highly experienced European research laboratories, one Chinese high technology Institute and 3 SME's with complementary expertise in the fields of cellular and molecular biology of ageing, proteomics analysis and MS, structural biology and bioinformatics. By using a centralized cutting-edge proteomic technological platform available in two world-class centres that form part of this consortium and a new platform for cell culture at physiological low oxygen pressure, a high resolution proteomic analysis of unmatched precision will be applied to well-established in vitro models of replicative and stress-induced senescence and cells and tissues from people of different age including centenarians. Novel technology will also allow identification of age-associated post- translational modifications and cleavage events that are known to influence greatly the activity of proteins. Trans-species comparisons will reveal candidates for proteins that play a functional role in driving ageing processes, allowing for the first time a delineation of cause-effect relationships (instead of mere correlations) governing proteome changes that lead to age- associated phenotypes. The work described above will also lead to new protocols for early diagnosis and prevention of age- associated dysfunctions, based for example on strategies to reactivate proteasome #
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