Identifying the pathways by which naturally-occurring genetic variants associated with nutrient response regulate longevity and health.

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 DESCRIPTION (provided by applicant): Obesity-related disorders are associated with poor health and decreased lifespan in humans1. It is well understood that environmental factors such as diet contribute to these disorders as well as genotype. As such, dietary alterations are frequently suggested to ease metabolic dysfunction2-4. It is not understood, however, why different individuals display variable phenotypic results after dietary intervention. Furthermore, t is not known why different individuals who consume the same diet show different metabolic phenotypes in general5- 10. With environmental factors remaining constant between these individuals, genetic regulation must be responsible. Although many studies have provided substantial insight into how diet can regulate molecular responses affecting longevity, aging, and health11-20, few studies take into consideration the effects of naturally- occurring genetic variation. Understanding how genetic variation affects dietary response is crucial to providing personalized treatment for obesity-related health risks. I propose to identify the variants that influence diet- related longevity and health and determine the mechanisms by which these variants regulate response. I will reveal these variants and pathways using Drosophila melanogaster as a model organism, which allows for full- length lifespan analysis with complete dietary intervention and facilitated genetic manipulations. It has been shown by the Kapahi lab and others that restricting protein intake without malnutrition induces metabolic shifts that can result in lifespan extension21-23. Although factors such as TOR and insulin-like signaling have been implicated as key to metabolic adaptations24-25, the degree to which they affect individuals varies greatly and there are undoubtedly other key metabolic, neurological, and nutrient absorption pathways regulating these phenotypes. It is known that genetic variation can affect response to diet, but specific genes or variants within them are yet to be identified26-30. Drosophila is the optimal model for identifying these genetic components, especially due to the recent development of a panel of fully-sequenced homozygous wild fly lines which is especially useful in genome-wide association studies31. I propose to undertake the following three aims: 1) Determine the genetic variants and physiological traits that influence longevity and mortality; 2) Identify genetic and phenotypic components that regulate nutrient-specific physical capability and health; and 3) Validate the genetic variants identified and reveal how they influence metabolic pathways. Considering the increasing prevalence of obesity and related disorders world-wide, particularly in the United States32-34, it is essential to determine the genetic components that predispose individuals towards disease and specific responses to nutrients. By dissecting the factors that influence these conditions and determining the resulting affected pathways, it will become possible to identify specific drug targets to allow for individualized attention and therapeutic care on a case-by-case basis for differing metabolic conditions. Together, these therapeutics combined with dietary interventions will help maximize efforts to increase health and lifespan.