Sleep, Aging and Circadian Rhythm Disorders

描述(申请人提供)：睡眠的时间、持续时间和质量受到昼夜节律性和睡眠动态平衡的影响，这两个过程都会随着年龄的增长而中断。老年人患代谢紊乱的风险更大，研究将昼夜节律紊乱和睡眠不足与肥胖、胰岛素抵抗和2型糖尿病的风险联系起来，尽管这些工作很少在老年人身上进行。在年轻人中，一周的睡眠限制降低了胰岛素敏感性，而急性昼夜节律失调会增加餐后血糖水平(尽管胰岛素增加)，这表明胰岛素敏感性降低。反复出现的昼夜节律紊乱加上睡眠限制3周的组合刺激，会导致年轻人和老年人在标准膳食后血糖升高和胰岛素水平下降，即使这顿饭是在正常的昼夜节律时间消费的，这表明长期联合暴露在这些挑战中会导致胰岛β细胞代偿不足。在此基础上，本计划的中心主题是区分昼夜节律紊乱(同时将睡眠损失降至最低)和睡眠不足(同时将昼夜节律紊乱降至最低)对血糖调节的影响。我们将测试特定的激素、细胞和自主神经机制，这些机制可能会导致观察到的血糖水平和胰岛素分泌的变化。我们将检查老年人在睡眠损失最小化时的3周反复昼夜节律紊乱(RCD)或当昼夜节律紊乱最小化时的睡眠限制(项目2)的代谢变化动态，评估对标准膳食的代谢反应、胰岛素敏感性(全身和细胞)和能量平衡。在小鼠的平行研究中(项目3)，我们将研究长期暴露在没有昼夜节律干扰的睡眠不足(通过基因消融VLPO神经元)和没有睡眠丢失的昼夜节律干扰(使用10：10 LD周期来创建RCD)。我们将评估代谢功能(摄食、体重、代谢激素、葡萄糖耐量)对这些实验操作的响应，以及幼鼠和老年鼠的反应是否不同。此外，我们将测试与RCD相关的代谢异常是否由于参与葡萄糖稳态的细胞和组织的时间节律紊乱所致。这些核心将提供跨项目的支持，并将促进对整个方案的卫生与环境监测结果的全面分析和解释。这项研究对制定预防和治疗老年人肥胖和糖尿病的策略具有重要意义。

DESCRIPTION (provided by applicant): 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.