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.

Public Health Relevance

The current rapid growth of the aged population and of the prevalence of age-related chronic disorders, such as diabetes and cardiovascular disease, coupled with advances in the scientific knowledge of circadian biology and 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 build on this growing knowledge and on our history of successful collaborations with collective and complementary expertise and experience 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 and to translate these findings to interventions to enhance circadian rhythmicity, and thus improve sleep and cardiometabolic health of older adults.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG011412-18A1
Application #
9220509
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Mackiewicz, Miroslaw
Project Start
1997-02-01
Project End
2022-05-31
Budget Start
2017-09-15
Budget End
2018-05-31
Support Year
18
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Neurology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Broussard, Josiane L; Wroblewski, Kristen; Kilkus, Jennifer M et al. (2016) Two Nights of Recovery Sleep Reverses the Effects of Short-term Sleep Restriction on Diabetes Risk. Diabetes Care 39:e40-1
Grimaldi, Daniela; Carter, Jason R; Van Cauter, Eve et al. (2016) Adverse Impact of Sleep Restriction and Circadian Misalignment on Autonomic Function in Healthy Young Adults. Hypertension 68:243-50
Mokhlesi, Babak; Grimaldi, Daniela; Beccuti, Guglielmo et al. (2016) Effect of One Week of 8-Hour Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea on Glycemic Control in Type 2 Diabetes: A Proof-of-Concept Study. Am J Respir Crit Care Med 194:516-9
Broussard, Josiane L; Kilkus, Jennifer M; Delebecque, Fanny et al. (2016) Elevated ghrelin predicts food intake during experimental sleep restriction. Obesity (Silver Spring) 24:132-8

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