Recently, we and others have revealed that, in the nematode Caenorhabditis elegans, reduction of protein synthesis rates in somatic cells extends lifespan. Based on this, we postulate that the molecular factors and mechanisms that control the mRNA metabolism in post-mitotic cells are critical determinants of ageing. This project will validate this hypothesis using C. elegans as main model system, but parallel studies in Saccharomyces cerevisiae and Drosophila melanogaster will prove the conservation of our observations. The cellular factors involved in mRNA metabolism (degradation/storage) are localized at specific particles in the cytoplasm of all eukaryotic cells, termed mRNA processing (P) bodies. Additionally, stress granules are cytoplasmic sites of mRNA-metabolism that are formed under stress conditions in mammalian cells. The objectives of this project include: -Monitoring of both P bodies and stress granules in adult worms and characterization of the age-related alterations in their profile, by immunostaining and real-time fluorescence imaging -Direct alterations in the expression of genes encoding factors of each particle in wild-type worms and analysis of the effects on lifespan and stress resistance -Comparison of the age-related changes in the profile of P bodies and stress granules between wild-type and long- or short-lived mutant worms -Direct alterations in the expression of genes encoding factors of each particle in worms with altered lifespan and investigation of the effects on lifespan and stress resistance -Observation of the age-related alterations in the profile of P bodies in yeast and flies, both in wild-type and long-lived strains. The rationale for this project is to provide insight into the modulation of ageing and stress resistance at the level of mRNA metabolism, which is a yet unexplored field of the biology of ageing and global stress response.
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