Genetic Mechanisms of Circadian Clock-Mediated Dietary Restriction in Drosophila

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Project Summary/Abstract Dietary Restriction (DR), where caloric or diet intake is reduced but not to the point of malnutrition, extends lifespan and healthspan in model organisms from single cellular yeast to non-human primates. However, the molecular mechanisms by which DR delays aging and promotes health are not fully understood. Due to their short lifespan, versatile genetic tools, and high conservation of molecular pathways for metabolism, behavior, and aging, the fruit fly, Drosophila melanogaster, has been widely used as a model organism for DR-related research. Using Drosophila, our long-term goal is to understand how the circadian clock (genetic pathway) interacts with diets and light:dark cycles (environmental factors) to optimize organismal metabolism, physiology, and behavior that ultimately promotes health and longevity. PI’s preliminary data obtained through systemic lifespan/behavior assays and tissue- and diet-dependent transcriptomic analysis suggests a critical role of the circadian clock in the peripheral fat body (functionally homologues to the liver) for the beneficial effects of DR. The overall objective of this proposal is to understand genetic mechanisms by which circadian clocks in fat body mediate DR-dependent lifespan extension and physiological changes. For this objective, we propose to leverage versatile Drosophila genetics to test our central hypothesis, formulated based on the preliminary data and literature survey, that clock-controlled genes (CCGs) in fat body promote health and longevity by coordinating time-dependent metabolic, physiological, and behavioral homeostasis. To test this hypothesis, we propose to perform three independent yet interconnected specific aims: First, by completing a large-scale tissue specific in vivo functional screening, we will determine key CCGs and molecular pathways in fat body that are important for DR response (Aim 1). Second, by employing a genomic and metabolomic profiling, we will identify molecular and metabolic signatures responsible for DR-mediated lifespan extension through clock-controlled proteasome in fat body. Third, by applying a forced circadian misalignment (similar to jet-lag), we will determine the impact of desynchrony between the external environmental time and the internal molecular clock on DR and CCGs (Aim 3). This study is meritorious because it will generate outcomes that provide insight into how the circadian clock orchestrates environmental cues to promote health and longevity. This study also strengthens the research environment of undergraduate students at the University of Louisville because it is designed to be completed by a research team primarily composed of undergraduate students at the University.