Allostasis and Metabolic Resiliency in Older People

描述(申请人提供)：老年人可能对环境应激源特别敏感，因为身体能力减弱和下丘脑-垂体-肾上腺(HPA)轴敏感性增加，导致对常见日间挑战的荷尔蒙反应重复和延长。这些反复的荷尔蒙干扰强烈地促进了现在所称的平衡负荷，这反过来又阻止了一连串的原发事件和次要健康后果，如血脂异常、内脏过度肥胖和胰岛素抵抗。很少有人研究老年人对环境应激的高反应性和代谢弹性，因此，本提案的目的是确定应激反应、脂肪代谢和胰岛素抵抗在衰老过程中的关系。具体目标是：1)确定65岁及以上健康和非肥胖男性和女性对急性心理物理挑战的主观日常生活经验和皮质醇反应曲线之间的关联；2)确定皮质醇高反应对同一年龄组的脂肪分解和胰岛素抵抗的几个功能指标的影响；以及3)确定皮质醇高反应和胰岛素抵抗之间的关系在多大程度上受到生长激素(GH)对心理物理挑战的反应以及IL-6水平和老年人内脏脂肪的调节。我们计划使用最近发表的一种混合方法-白天重建方法(DRM)-来收集关于日常生活经历的情感反应的定量信息，这些情感反应可能是HPA衰老高反应的原因或后果，并将使用一种新的心理物理挑战来模拟常见的现实生活环境情景，例如驾驶汽车时遇到的任务。自动心理物理测验(APT)是一种计算机化的包括简单反应时、选择反应、视觉跟踪、静态和动态敏锐度以及信息处理的一系列计时操作测验。此外，我们将使用最先进的方法来量化内脏脂肪(CT扫描)以及脂肪分解和胰岛素抵抗的指标(带有示踪剂输注的高胰岛素-正常血糖钳，用于测定肝脏葡萄糖产生和外周脂肪分解)，以确定与常见日常挑战的负面反应相关的健康和功能后果。

DESCRIPTION (provided by applicant): Older people may be especially sensitive to environmental stressors due to diminished physical capabilities and an increased hypothalamo-pituitary-adrenal (HPA) axis sensitivity, resulting in repeated and prolonged hormonal responses to common day challenges. These repeated hormonal perturbations contribute strongly to what is now termed the allostatic load, which, in turn, precludes a cascade of primary events and secondary health consequences, such as dyslipidemia, excess visceral adiposity, and insulin resistance. Rarely is hyper-responsiveness to environmental stress and metabolic resiliency studied in older people and so, the purpose of this proposal is to determine the relation between stress response, fat metabolism, and insulin resistance in aging. Specific aims are: 1) to determine the association between subjective daily life experiences and the cortisol response curve to an acute psychophysical challenge in healthy and non-obese men and women 65 years of age and older; 2) to determine the effect of cortisol hyper-responsiveness on several functional indicators of lipolysis and insulin resistance in this same older sample; and 3) to determine the degree to which the relation between cortisol hyper-responsiveness and insulin resistance is modulated by growth hormone (GH) response to the psychophysical challenge and by levels of IL-6 and visceral adiposity in older age. We plan to use a recently-published hybrid method - the Day Reconstruction Method (DRM) - for gathering quantitative information about affective responses to daily life experiences that may be contributors to or consequences of a HPA hyper-responsiveness in aging and will use a novel psychophysical challenge with tasks that mimic common real life environmental situations, such as those encountered when driving an automobile. The automated psychophysical test (APT) is a computerized series of timed performance measures of simple reaction time, choice reaction, visual tracking, static and dynamic acuity, and information processing. In addition, we will use state-of-the-art methods for the quantification of visceral adiposity (CT scan) and the indicators of lipolysis and insulin resistance (the hyperinsulinemic-euglycemic clamp with tracer infusions for determination of hepatic glucose production and peripheral lipolysis) in order to determine the health and functional consequences associated with a negative response to common daily challenges.