LYSOSMAL PROTEASES, PROTEIN TURNOVER AND AGING

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We propose to test the hypothesis that the rate of protein turnover declines with age, and that this leads to an accumulation of altered proteins. As a model organism, we are using the soil nematode Caenorhabditis elegans. We have already purified Cathepsin D, and now propose to purify and characterize lysosomal Cathepsin L. We will isolate mutants, both deficient and hyperproducing, affecting both of these proteases, and use them to determine the role of individual proteases in protein turnover, both of global protein and of specific test proteins. we are also designing delivery systems for protease inhibitors, so that these can be used to confirm results obtaine with mutants. Finally, we will assess the changes in the rate of protein turnover which occur during aging, and determine whether modulation of protease activity and/or protein turnover in vivo affects the rate of aging of C. elegans, using a multiparametric index of senescence.