Effect of Aging and Caloric Restriction on Circadian Ph*

描述（申请人提供）：人体生理表现出强烈的节律性 在特定时间出现的峰值和最低点的成分， 天 越来越多的证据表明，昼夜节律的扰动 神经内分泌回路可能在一些与衰老有关的 疾病，并可能对寿命产生重大影响。 此外， 越来越多的人支持神经内分泌衰老可能是由 氧化损伤，源于细胞抗氧化剂的渐进性过载 容量 这项拟议中的研究将使用雄性恒河猴来检查 热量限制可以防止衰老相关恶化的机制 关键的神经内分泌昼夜节律，包括DHEAS，皮质醇，褪黑激素 和睾丸激素 我们将进行实验，研究与衰老有关的 自由进食和年龄匹配的动物中昼夜节律功能障碍的进展 限制卡路里的动物体内。 这将涉及重复的系列血液 通过导管-旋转-系绳装置收集，连同伴随的 体温记录和活动描记法 此外，身体的变化 将使用DEXA非侵入性地评估脑组织的组成和脑形态 和MRI。 最终，这些动物的大脑 检查尸体以检验热量限制保护 衰老的灵长类动物下丘脑免受氧化损伤 使用电子 通过显微镜，我们将检查下丘脑关键核团的突触学 参与调节昼夜神经内分泌功能和原位使用 杂交组织化学以评估基因表达的变化。 我们将 我还用免疫组织化学方法检测了特定轴突投射的缺失 以及相关的神经胶质增生。 我们希望证明热量 限制有助于保护下丘脑核免受氧化损伤， 更重要的是，它有助于保持神经系统的完整性， 连接视交叉上核（中央生物钟）的通路 室旁核（肾上腺的下丘脑调节器 轴）。 更深入地了解与衰老有关的变化， 灵长类动物的神经内分泌昼夜节律回路和 热量限制应该有助于阐明人类衰老的机制， 帮助开发针对多种疾病的有效疗法 在老年人中。

DESCRIPTION (provided by applicant): Human physiology shows strong rhythmic components with peaks and nadirs occurring regularly at specific times of the day. Accumulating evidence suggests that perturbation of the circadian neuroendocrine circuitry may play an important role in several aging-related disorders and may have a major influence on life span. Furthermore, there is growing support for the view that neuroendocrine aging may be caused by oxidative injury, stemming from a progressive overload of a cell's antioxidant capacity. The proposed research will use male rhesus monkeys to examine the mechanism by which caloric restriction can prevent aging-related deterioration of key neuroendocrine circadian rhythms, including DHEAS, cortisol, melatonin and testosterone. We will perform experiments to examine the aging-related progression of circadian dysfunction in ad libitum-fed and age-matched calorie-restricted animals in vivo. This will involve repeated serial blood collections via a catheter-swivel-tether set up, together with concomitant body temperature recordings and actography. In addition, changes in body composition and brain morphology will be assessed non-invasively using DEXA and MRI respectively. Ultimately, the brains of these animals will be examined postmortem to test the hypothesis that caloric restriction protects the aging primate hypothalamus from oxidative injury. Using electron microscopy, we will examine the synaptology of key hypothalamic nuclei involved in mediating circadian neuroendocrine function and use in situ hybridization histochemistry to assess changes in gene expression. We will also use immunohistochemistry to examine loss of specific axonal projections and the associated increase in gliosis. We expect to show that caloric restriction helps to protect hypothalamic nuclei from oxidative injury and, more importantly, that it helps to maintain the integrity of the neural pathway that links the suprachiasmatic nucleus (the central biological clock) to the paraventricular nucleus (the hypothalamic regulator of the adrenal axis). A deeper understanding of aging-related changes in central neuroendocrine circadian circuits of primates and the protective influence of caloric restriction should help to elucidate the mechanism of human aging and help with the development of effective therapies for a wide range of disorders in the elderly.