Genetic Mechanisms of Circadian Clock-Mediated Dietary Restriction in Drosophila - 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.
