Circadian organization of behavior and physiology is often challenged by individual choices, social/societal pressures and pathology, leading to circadian misalignment, sleep deficiency and ultimately, adverse health outcomes. Just in the past decade, advances in the scientific knowledge of circadian biology in animal model systems, as well as in humans, coupled with the evidence of circadian disruption with aging, indicate the transformative potential of circadian based strategies for maximizing healthy aging. In this Program Project application, we propose to seize this opportunity by capitalizing on our history of successful collaborations and collective and complementary expertise and experience, as well as in circadian biology, aging and clinical research to advance our understanding of the interaction between centrally regulated circadian rhythms, sleep and peripheral tissue clocks in cardiometabolic aging. Our mechanistic approach will be complemented by interventions that increase circadian synchrony to improve cardio-metabolic health in middle age and older adults. Our multi-disciplinary and multi-institutional (Northwestern and U of Chicago) approach combines novel translational, clinical (Projects 1 & 2) and basic (Project 3) studies and is uniquely poised to achieve the scientific aims of each of the three projects. Specifically, the Program will define the role and mechanisms of interplay between central and peripheral clocks in aging and dissect the contribution of age-related changes in the circadian clock system, as measured by amplitude and phase alignment, in cardiometabolic aging. Project #1 (Zee, PI) has as its primary aim to develop translatable circadian based interventions to enhance synchronization of central and peripheral rhythms through increased amplitude, and ultimately to improve cardio- metabolic function and sleep quality in older adults. Project #2 (Van Cauter and Knutson, PIs) focuses on the impact of dietary alignment of peripheral oscillators on cardio-metabolic risk, sleep quality and the overall synchronization of the circadian system. Project #3 (Bass and Turek, PIs) will use mouse models to test circadian phase-restricted feeding as a life- and health-span extending intervention and explore molecular, physiological, and behavioral mechanisms by which phase-restricted feeding may enhance circadian robustness, metabolic function, and sleep. These projects are thematically unified by the overall Program focus on the role of aging on central and peripheral clock interactions in the regulation of cardiometabolic function at the molecular, cellular and physiological levels, and the three projects will be supported by the innovative metabolic measures and analyses proposed in the Cores. In addition, the rich, molecular data and extensive and novel physiological/metabolic data (from mice and humans) will be used to explore common mechanistic hypotheses across the entire program in order to greatly enhance our understanding of the importance of chronobiology-sleep-metabolism concepts for successful aging.

P01AG011412

1994-09-01

2022-06-30