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奏性 在特定时间有规律地出现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几种与衰老相关的疾病中发挥重要作用 疾病，并可能对寿命有重大影响。此外，还有 越来越多的人支持神经内分泌老化可能是由 氧化损伤，源于细胞抗氧化剂的进行性过载 容量。这项拟议的研究将使用雄性恒河猴来检查 限制卡路里摄入可防止衰老相关退化的机制 关键的神经内分泌昼夜节律，包括DHEAS，皮质醇，褪黑素 和睾丸激素。我们将进行实验，以检查与衰老相关的 随意喂养和年龄匹配的昼夜节律功能障碍的进展 体内限制卡路里的动物。这将涉及到重复的连续血液 通过设置的导管旋转系绳收集，以及伴随的 体温记录和体动描记。此外，身体的变化 成分和脑形态将使用DEXA进行非侵入性评估 和核磁共振成像。最终，这些动物的大脑将是 验尸以检验卡路里限制保护 老化的灵长类下丘脑免受氧化损伤。使用电子 显微镜下，我们将检查下丘脑关键核团的突触 参与调节昼夜节律神经内分泌功能及其在原位的应用 杂交组织化学以评估基因表达的变化。我们会 也使用免疫组织化学来检查特定轴突投射的丢失 以及与之相关的胶质细胞增多症。我们希望能显示出卡路里 限制有助于保护下丘脑核免受氧化损伤， 更重要的是，它有助于维持神经的完整性 连接视交叉上核(中枢生物钟)的通路 至室旁核(肾上腺的下丘脑调节器) 轴)。更深入地了解老年人的老龄化相关变化 灵长类动物神经内分泌昼夜节律及其保护作用 热量限制应该有助于阐明人类衰老的机制和 帮助开发针对多种疾病的有效治疗方法 在老年人身上。

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.