The circadian system is a hierarchical organization with a master pacemaker in the hypothalamus (the SCN) and peripheral clocks in many, if not all, other tissues. Although the light-dark cycle is the primary external synchronizer of the SCN, the timing of food intake is a powerful synchronizer of many peripheral clocks. The connections between the central SCN clock, behavioral rhythms such as sleep-wake and feeding cycles, and peripheral clocks are not fully understood. These connections therefore constitute a novel, translational research focus for human health and disease. Our project will examine the effect of interventions to impact peripheral rhythms through manipulation of feeding. Previous clinical and observational research studies of circadian rhythms and chronotype indicate that misalignment of central and peripheral clocks has adverse health consequences, including an increase in cardio-metabolic risk. However, little is known about the impact of aging on the overall synchronization of central and peripheral clocks, particularly the role of dietary time cues. Age- related reductions in amplitude and regularity of external and internal synchronizing signals may adversely impact synchrony of peripheral clocks. Reduced synchrony of peripheral signals may in turn contribute to age- related changes in sleep homeostasis. Circadian disruption may accelerate metabolic aging, both directly and indirectly by affecting sleep-wake homeostasis. Conversely, behavioral strategies to optimize circadian organization may decrease the risk of weight gain, diabetes and their cardiovascular consequences. Our proposed project focuses on the impact of dietary alignment of peripheral oscillators on cardio-metabolic risk, sleep quality and the overall synchronization of the circadian system. The overall goal of the project is to determine whether there is an optimal alignment of eating behavior (?dietary chronotype?) with sleep-wake behavior (?sleep chronotype?) and the central circadian signal (as assessed via the melatonin onset [DLMO]) that minimizes cardio-metabolic risk in middle-aged (35 ? 50 y) and older (55 ? 75 y) adults. We will use a 5-day intervention to test the hypothesis that extending and anchoring the overnight fast, independently from the timing of daytime food intake, has beneficial effects on cardio-metabolic risk, sleep quality and the alignment of rhythmic outputs of central and peripheral clocks. This first intervention will be followed by a second intervention that will test the hypothesis that early versus late timing of daytime dietary intake, without change in the timing or duration of the overnight fast, have distinct and opposite effects on cardio-metabolic risk, sleep quality and overall circadian alignment. Diabetes risk will be assessed by a 5-hour oral glucose tolerance test (OGTT). Nocturnal blood pressure dipping will be our primary cardiovascular outcome. Slow-wave activity and wake after sleep onset will be our primary sleep quality outcomes. Overall circadian alignment will be assessed using phase markers of the 24-hour profiles of melatonin, cortisol and leptin. Exploratory measures will include levels and rhythmicity of NAD+ in blood cells coupled with assessment of resting metabolic rate.
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