Role of dS6 phosphorylation in dTORC1/dS6K mediated longevity in Drosophila

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DESCRIPTION (provided by applicant): Obesity is a worldwide epidemic that accounts for more than 300,000 deaths per year in the United States alone. Moreover, it is the major reason behind the explosion in health care costs and the disquieting observation that, for the first time in decades, human life span is decreasing for North Americans. A direct consequence of obesity is the enhanced probability of a number of age-related pathologies including diabetes, cardiovascular disease, neurodegenerative disorders, and cancer. The epidemic has been fueled by the availability, abundance, and relatively low cost of food. The critical barrier in controlling the disease has been the inability to overcome dominant human genetic traits that promote the acquisition of food and the storage of energy reserves in the form of adipose depots. It is hypothesized that these traits were selected for during evolution as a consequence of the chronic scarcity of food and that, over time, they have prevailed over those traits that suppress food intake. Given these limitations and the magnitude of the obesity epidemic, it is critical to develop novel intervention strategies, such as targeted drug therapies. The success of such strategies will depend on a basic understanding of the molecular mechanisms that drive these responses. In contrast, to nutritional overload, dietary restriction is a robust environmental manipulation that increases "healthspan", as it not only prolongs life span but also delays the onset of age-related diseases. Although under intense investigation, the underlying molecular mechanisms that lead to obesity-induced pathologies associated with age-related diseases versus those of dietary restriction-induced increases in healthspan have remained difficult to resolve. Nonetheless, one signaling pathway that has emerged as a major player in both responses is that mediated by mTORC1. Under conditions of nutritional overload, this pathway is fully activated and known to contribute to obesity and insulin resistance. In contrast, under conditions of dietary restriction this signaling pathway is suppressed, which has been demonstrated to contribute to increased healthspan. Importantly, conservation of signaling pathways in simpler eukaryotes and the rapidity with which healthspan studies can be carried out make research in model organisms such as Drosophila invaluable in elucidating healthspan-related diseases in humans. Moreover, studies in different organisms have shown that the nutrient arm of the mTORC1 signaling pathway is highly conserved from yeast to man and is a central mediator of the effect of dietary restriction. S6K1 is a well established downstream target of mTORC1 whose deficiency in the mouse has been shown to increase insulin sensitivity, increase resistance to diet-induced obesity, and increase life span, while sparing animals from much age-related pathology. Several downstream substrates of S6K1 have been identified; however, those mediating healthspan are unknown. We propose that phosphorylation of dS6, the first-identified downstream substrate of S6K1, is an essential player in dietary restriction-mediated healthspan extension. We provide preliminary data to support this novel hypothesis. PUBLIC HEALTH RELEVANCE: Obesity, which has recently become a worldwide epidemic, is well recognized for its deleterious effects on health whereas dietary restriction increases healthspan, as it delays the onset of age- related diseases. The mTORC1/S6K1 signaling pathway has emerged as a major player in both states: under conditions of nutritional overload, this pathway contributes to obesity and insulin resistance while under conditions of dietary restriction it is suppressed and increases healthspan. The proposed project will use Drosophila model and analyze a downstream effector of this signaling pathway, the phosphorylation of S6, to reveal the mechanisms by which it affects dietary restriction mediated healthspan extension.