Decreased amplitude and stability of rhythmic behaviors, including the prominent fragmentation of sleep are hallmarks of aging in humans. It is now established from both laboratory and field studies that disrupted circadian function represents a significant risk factor for cardiometabolic disease (CMD) in humans. The exciting evidence of the ubiquity of circadian clocks in all tissues, and their critical role in metabolism, not only opens up new avenues for exploring the mechanistic interactions between central and peripheral clocks in cardiometabolic aging, but also to develop therapeutic interventions to re-establish synchrony between central and peripheral clocks with each other and with the external physical and social environments. Feeding has been shown to synchronize clocks in peripheral tissues and animal studies have demonstrated that restricting feeding to the active period decreases CMD risk, while in humans decreased caloric intake in the evening is associated with a lower body mass index (BMI). The amplitude of melatonin (typically decreased with advancing age), can be considered a marker of robustness of central circadian function, but melatonin also has physiological effects beyond circadian regulation throughout the body. Recent observations have demonstrated low melatonin levels are a risk factor for incident diabetes and hypertension independent of sleep duration. Together, this data suggests that strategies aimed at synchronizing feeding behavior and enhancing the nocturnal melatonin signal can positively impact cardiometabolic function in older adults. We propose to take an innovative approach that combines the recent data on the role of feed/fast patterns on clock regulated metabolic activity and the reemergence of scientific interest of the central and peripheral effects of melatonin on cardiometabolic function to improve metabolic health in late middle to old age. The primary aim of this project is develop translatable circadian based interventions that enhance synchronization of central and peripheral rhythms, to ultimately improve cardiometabolic function and sleep quality in older adults. This project will enroll 100 older adults (55-75 years) to participate in a parallel (4 arm intervention) placebo controlled study to determine whether a 6 week program of extended overnight fasting (EOF) of 12-14 hours and/or low dose (3 mg) melatonin administration will enhance circadian amplitude and improve cardiometabolic function, as well as to evaluate the potential beneficial effects of a regimen that combines both treatments. The results from this study will demonstrate novel circadian based clinically applicable approaches for maintaining circadian-metabolic health in older age. In addition, the similarity of the baseline characteristics in Project 1 and Project 2, and the complementary physiological and molecular measures and analyses of clock genes and NAD+ regulatory pathways across all 3 projects will allow us to study the links between aging, circadian rhythms, sleep and metabolism that would not be possible without the program project grant as a whole.
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