ALTERED RHYTHMS IN AGING--MECHANISMS AND RESTORATION OF FUNCTION

在金黄地鼠中，有明显的年龄相关变化 束缚和自由奔跑条件下昼夜节律的表达 条件，以及生物钟系统对 各种光和非光刺激。在此期间进行的研究 前一批款期在以下三个方面提出了重要意见 关于这种与年龄相关的改变的发展，他们的 纠正策略的潜在机制和可能的方法。 拟议的研究将以这些发现为基础，以1)确定 年与年龄相关的各种变化的发展年表 生物钟系统，2)确定生理机制 昼夜节律时钟系统中与年龄相关的潜在变化和3)测试 特定对策逆转或减弱疾病的效果 衰老对昼夜节律性的影响。特别是，各种 关于5-羟色胺和神经肽的作用的假说将得到检验。 Y，以及松果腺及其激素褪黑激素的影响， 在昼夜节律系统中与年龄相关的变化。涉及的对策 用褪黑激素治疗或改变光的强度- 暗周期将被用来检验与年龄相关的变化的假设 在昼夜节律系统中可以衰减、延迟或逆转。贯穿始终 建议的研究，衰老对五种基因表达的影响 不同的节奏(即，车轮运行行为，总的运动活动， 饮酒行为、体温和循环中的褪黑素水平)，以及 关于昼夜节律起搏器相移的能力 光的或非光的刺激，将在仓鼠身上确定。它是 预计对年龄的生理基础的阐明- 昼夜节律功能的相关变化，以及其基础机制 各种纠正策略的有效性，将带来新的见解 关于昼夜节律性的调节和组织及其 与环境刺激的相互作用。这些研究也有望 导致治疗、预防或延迟的新的临床方法 老年人的昼夜节律和睡眠紊乱。

In the golden hamster, there are pronounced age-related changes in the expression of circadian rhythm under both entrained and free-running conditions, as well as in the response of the circadian clock system to a variety of photic and non-photic stimuli. Studies performed during the previous grant period have provided important observations in three areas pertaining to the development of such age-related alterations, their underlying mechanisms and possible approaches for corrective strategies. The proposed studies will build on these findings to 1) determine the chronology of the development of various age-related changes in the circadian clock system, 2) to determine the physiological mechanisms underlying age-related changes in the circadian clock system and 3) to test the efficacy of specific countermeasures to reverse or attenuate the effects of aging on circadian rhythmicity. In particular, various hypotheses will be tested regarding the role of serotonin and neuropeptide Y, as well as the influence of the pineal gland and its hormone melatonin, in age-related changes in the circadian system. Countermeasures involving treatment with melatonin or altering the strength of the entraining light- dark cycle will be employed to test the hypothesis that age-related changes in the circadian system can be attenuated, delayed or reversed. Throughout the proposed studies, the effects of aging on the expression of five different rhythms (i.e., wheel-running behavior, total locomotor activity, drinking behavior, body temperature and circulating melatonin levels), and on the ability of the circadian pacemaker to be phase shifted by either photic or non-photic stimuli, will be determined in hamsters. It is anticipated that the elucidation of the physiological basis for age- related changes in circadian function, and of the mechanisms which underlie the efficacy of various corrective strategies, will lead to new insights into the regulation and organization of circadian rhythmicity and of its interaction with environmental stimuli. These studies are also expected to lead to new clinical approaches for treating, preventing or delaying disturbances of circadian rhythms and sleep in older human populations.