The integrated goal of this program project application is to apply approaches in both humans (Projects 1 and 2) and experimental male and female mouse models (Project 3) to determine the impact of circadian phase- restricted feeding on age-related disorders of sleep, circadian rhythms, and metabolism. In Project #3, we aim to dissect the molecular mechanisms by which circadian phase-restricted feeding acts as a countermeasure to prevent the age-related decay in circadian robustness, sleep, and metabolic health by exploiting integrated systems level physiological analyses and genome-based approaches. New preliminary data using whole animal calorimetry, feeding monitoring, and RNA analyses support the concept that feeding time plays a key role in the integration of energetics and metabolism throughout life, and that mis-timing in behavioral, energetic, and transcriptional rhythms in relationship to the light cycle represents a hallmark of aging. Our lab and others have also shown that circadian control of NAD+ biosynthesis impacts both core clock function and activity of the sirtuins, key enzymes involved in gene regulation and energetic homeostasis during aging. Yet, a gap remains in understanding whether decay in peripheral clock control of NAD+ biosynthesis and sirtuin function during aging contributes to alterations in circadian behavioral rhythms, sleep, and metabolic homeostasis. We have also recently performed integrated RNA and chromatin immunoprecipitation sequencing (Science, Nov 2015) to reveal cell-type specific functions of the molecular clock in glucose metabolism, and we aim to apply these methodologies to further investigate the global effects of mis-timed feeding on peripheral clock transcription cycles and the impact of such cycles on circadian behavior and sleep homeostasis. We will further perform both chronologic and lifespan-extension analyses to dissect the role of the clock-NAD+-SIRT pathway and application of next-generation sequencing as a discovery platform will uncover how dampened oscillations of clock- controlled metabolic gene regulation contributes to alterations in cell-type specific metabolic dysfunction, and in turn, to alterations in circadian behavior and sleep. Finally, we will also assess whether NAD+ biosynthesis in peripheral tissues is both necessary and sufficient to prevent the age-related decline in sleep and metabolic function. Collectively, results of Project #3 will determine whether circadian phase-restricted feeding is an effective means to attenuate misalignment between oscillations in bioenergetics, metabolic, and transcriptional pathways important in aligning oxidative and reductive phases of physiology with the sleep-wake cycle and will establish new mechanistic insights into feeding time manipulation as an anti-aging intervention in humans.
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