The timing, duration, and quality of sleep are influenced by circadian rhythmicity and sleep homeostasis, and both processes are disrupted with age. Older adults are at greater risk for metabolic disorders, and research links circadian disruption and sleep deficiency with risk for obesity, insulin resistance and Type 2 diabetes, although little of that work was conducted in older adults. In young adults, sleep restriction for week reduces insulin sensitivity, and acute circadian misalignment increases post-prandial glucose levels (despite increased insulin), suggesting reduced insulin sensitivity. A combined stimulus of recurrent circadian disruption coupled with sleep restriction for 3 weeks elicits increased glucose and decreased insulin levels following a standard meal in young and older adults, even when that meal is consumed at a normal circadian time, suggesting that chronic combined exposure to these challenges causes inadequate pancreatic beta- cell compensation. Building on this, the central theme of this Program is to differentiate the consequences of circadian disruption (while minimizing sleep loss) and sleep deficiency (while minimizing circadian disruption) on glucose regulation. We will test specific hormonal, cellular, and autonomic mechanisms that may lead to the observed changes in glucose levels and insulin secretion in response to meals. We will examine in older adults the dynamics of metabolic changes across 3 weeks of recurrent circadian disruption (RCD) when sleep loss is minimized (Project 1), or sleep restriction when circadian disruption is minimized (Project 2), assessing metabolic response to standard meals, insulin sensitivity (both systemic and cellular), and energy balance. In parallel studies in mice (Project 3), we will examine long-term exposure to sleep loss without circadian disruption (by genetic ablation of VLPO neurons) and circadian disruption without sleep loss (using a 10:10 LD cycle to create RCD). We will assess metabolic function (feeding, body weight, metabolic hormones, glucose tolerance) in response to these experimental manipulations and whether responses differ in young vs. older mice. Furthermore, we will test whether the metabolic abnormalities associated with RCD are due to temporal disarray of rhythms in cells and tissues involved in glucose homeostasis. The Cores will provide support across projects, and will facilitate overall analysis and interpretation of the results of he across the Program. This research has important implications for the development of strategies to prevent, and therapies to treat, obesity and diabetes in older adults.

Public Health Relevance

Sleep is regulated by circadian rhythmicity and sleep homeostasis, and both are disrupted with age. Sleep deficiency and circadian disruption are risk factors for obesity and Type 2 diabetes, which increase with age. This Program seeks to differentiate the distinct consequences of circadian disruption (while minimizing sleep loss) and sleep loss (while minimizing circadian disruption) on age-related impairments of glucose regulation, and to reveal the mechanisms by which glucose regulation is impaired.

National Institute of Health (NIH)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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Mackiewicz, Miroslaw
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Brigham and Women's Hospital
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