Role of mRNA translation in the effects of dietary restriction on lifespan

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DESCRIPTION (provided by applicant): Dietary restriction (DR), a reduction of nutrients in the diet, provides the most robust method of lifespan extension and slowing of age-related diseases in species as diverse as yeast, worms, fruit flies, and rodents. Given the universally protective effects of DR, investigating its molecular mechanisms will promote a greater understanding of the pathogenesis of various human age-related diseases. This will in turn help advance the development of therapies for these disorders. Due to their short life spans and the ease of genetic manipulation, invertebrate models continue to be useful as models for understanding human diseases and in providing therapeutic targets. Given the conservation of biological processes and signaling pathways, studies in model organisms are likely to make the greatest contributions to our understanding of biological mechanisms of lifespan extension by DR. The Kapahi laboratory previously identified the TOR (target of rapamycin) pathway as a critical regulator of nutrient modulated lifespan changes in flies. This genetic pathway plays a conserved role in sensing nutrients in yeast, worms, flies and humans. Recently, the Kapahi laboratory showed that modulating mRNA translation is a key mechanism downstream of the TOR pathway that determines lifespan extension by dietary restriction. The lab has established a method for translational profiling that measures the mRNA translation state at the genome wide level. The lab has identified differentially translated genes that regulate metabolism upon DR, some of which are required for lifespan extension by DR. However, the role of tissue-specific changes and their respective contribution to extending lifespan upon DR remains unknown. In this proposal we aim to examine the role of tissue-specific changes in mRNA translation in mediating lifespan extension by DR by undertaking the following aims: 1) To examine tissue- specific genome-wide translation changes upon DR and 2) To characterize the effects of differentially translated genes on various age-related functional declines. This proposal will create tools that allow tissue specific assessment of mRNA translation state in D. melanogaster. The proposal will critically examine whether tissue-specific changes in mRNA translation and transcription play a role in age-related decline in various functions. The complex body plan, relatively short life span and the powerful genetic tools that allow the rapid discovery of new genes associated with a phenotype are some of the strengths of D. melanogaster that make it ideal for this proposal. The availability of the GAL4-UAS system to manipulate gene expression will allow comprehensive testing of the role of tissue-specific gene expression on given phenotypes. Further, there is a rich set of physiological and behavioral phenotypes that can be examined in D. melanogaster, including changes in metabolism, body composition, kidney function, memory, and mobility. Together this makes D. melanogaster an ideal system to examine the functional significance of tissue-specific changes on healthspan and aging. PUBLIC HEALTH RELEVANCE: Dietary restriction is the most robust environmental method of lifespan extension in various species and has been shown to protect against various age related diseases including diabetes, cancer and neurodegeneration. This proposal investigates the mechanism by which tissue specific changes in mRNA translation mediates the lifespan extension effects by dietary restriction using Drosophila. Our findings will have a significant effect on understanding the role of nutrition in aging and age related diseases in humans.