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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG009975-17S2
Application #
8917613
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Mackiewicz, Miroslaw
Project Start
1999-05-15
Project End
2018-06-30
Budget Start
2014-09-15
Budget End
2015-06-30
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Leise, Tanya L; Goldberg, Ariella; Michael, John et al. (2018) Recurring circadian disruption alters circadian clock sensitivity to resetting. Eur J Neurosci :
Zitting, Kirsi-Marja; M√ľnch, Mirjam Y; Cain, Sean W et al. (2018) Young adults are more vulnerable to chronic sleep deficiency and recurrent circadian disruption than older adults. Sci Rep 8:11052
McHill, Andrew W; Hull, Joseph T; McMullan, Ciaran J et al. (2018) Chronic Insufficient Sleep Has a Limited Impact on Circadian Rhythmicity of Subjective Hunger and Awakening Fasted Metabolic Hormones. Front Endocrinol (Lausanne) 9:319
Li, Peng; Yu, Lei; Lim, Andrew S P et al. (2018) Fractal regulation and incident Alzheimer's disease in elderly individuals. Alzheimers Dement 14:1114-1125
Todd, William D; Fenselau, Henning; Wang, Joshua L et al. (2018) A hypothalamic circuit for the circadian control of aggression. Nat Neurosci 21:717-724
Naganuma, Fumito; Bandaru, Sathyajit S; Absi, Gianna et al. (2018) Melanin-concentrating hormone neurons contribute to dysregulation of rapid eye movement sleep in narcolepsy. Neurobiol Dis 120:12-20
Asgari-Targhi, Ameneh; Klerman, Elizabeth B (2018) Mathematical modeling of circadian rhythms. Wiley Interdiscip Rev Syst Biol Med :e1439
Kroeger, Daniel; Absi, Gianna; Gagliardi, Celia et al. (2018) Galanin neurons in the ventrolateral preoptic area promote sleep and heat loss in mice. Nat Commun 9:4129
Gottlieb, Daniel J; Ellenbogen, Jeffrey M; Bianchi, Matt T et al. (2018) Sleep deficiency and motor vehicle crash risk in the general population: a prospective cohort study. BMC Med 16:44
Biello, Stephany M; Bonsall, David R; Atkinson, Lynsey A et al. (2018) Alterations in glutamatergic signaling contribute to the decline of circadian photoentrainment in aged mice. Neurobiol Aging 66:75-84

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