AGING AND CIRCADIAN RHYTHMS

哺乳动物昼夜节律系统中的第一个（也是唯一一个）单基因突变 最近在金仓鼠身上发现了这种突变， 生物钟的周期（自由下的内源性周期） 运行条件从正常的24小时减少到约20小时）， 时钟对光的相移效应的响应， 活动诱导刺激。 这些对生物钟的影响是 与突变体寿命减少50%有关 仓鼠 拟议研究的总体目标是 确定1）tau突变仓鼠的寿命缩短是否是由于 遗传或环境因素，2）如果年龄相关的变化， 生物钟系统在tau突变动物中出现在较早的年龄，3） tau蛋白突变对年龄相关变化的时间有什么影响， 生物钟系统，以及4）如果寿命在tau中减少， 因为突变对生物钟的影响， 本身 为了达到这些目标，运动活动的昼夜节律 将被用作生物钟状态的标记节奏 位于视交叉上核（SCN）， 哺乳动物的行为和生理节律。 在一系列的 实验中，雄性和雌性野生型和tau突变仓鼠将被 暴露于恒定光（LL）或光暗（LD）循环中， 两个昼夜节律范围（即20或24小时LD周期），以确定 突变动物的寿命缩短是由于一种内在的遗传 对寿命或突变体的生物钟功能丧失的影响 动物通常被带入标准的24小时光照周期。 中 第二个系列的实验，年龄对1）期间的影响， 2）活动节律与夹带的相位关系 光暗循环，3）在相移之后的再夹带速率， 光暗周期; 4）生物钟对光的反应 脉冲或各种活动诱导刺激将被确定， 野生型和tau突变仓鼠。 这些研究的结果将 确定昼夜节律系统中的突变是否对 生物钟系统中与年龄相关的正常变化，以及 这种变化是否发生在突变仓鼠的早期， 在时间上与动物寿命的缩短相对应。 中 第三个系列的实验，破坏昼夜节律的影响， 将在SCN中建立寿命时钟，以确定 如果生物钟本身的变化是导致寿命缩短的原因 变异动物的基因 最后一系列实验涉及 来自野生型和突变体的胎儿SCN组织的移植 将对相同或不同基因型的动物进行仓鼠 为了确定移植的SCN组织在恢复中的作用， 老年仓鼠的昼夜节律功能 考虑到生物钟在人体内所起的中心作用， 调节不同的生物系统，年龄相关的变化， 生物钟可能会对人类的健康产生重大影响。 有机体 已经发现了各种昼夜节律异常， 老年人，包括那些患有阿尔茨海默病的人， 睡眠-觉醒周期的紊乱。 关于昼夜节律突变 影响与年龄相关的生物钟变化， 突变引起的干扰影响衰老本身，可能提供新的 关于年龄相关的潜在生理基础的信息 昼夜节律系统内的功能障碍以及生物钟功能的改变 可能会导致衰老。

The first (and only) single gene mutation in a mammalian circadian system has recently been discovered in the golden hamster, this mutation alters the period of the circadian clock (the endogenous period under free- running conditions is reduced from the normal 24 hrs to about 20 hrs) and the response of the clock to the phase shifting effects of light and activity-inducing stimuli. These effects on the circadian clock are associated with ,.about a 50% decrease in the lifespan of the mutant hamsters. The overall objectives of the proposed studies are to determine 1) if decreased longevity in tau mutant hamsters is due to genetic or environmental factors, 2) if age-related changes in the circadian clock system occur at an earlier age in tau mutant animals, 3) what effect the tau mutation has on the timing of age-related changes in the circadian clock system, and 4) if longevity is reduced in the tau mutant animal because of the mutation's effects on the circadian clock itself. To reach these objectives, the circadian rhythm of locomotor activity will be used as a marker rhythm for the state of the circadian clock located in the suprachiasmatic nucleus (SCN) that underlies most behavioral and physiological rhythms in mammals. In one series of experiments, male and female wild-type and tau mutant hamsters will be exposed to either constant light (LL) or light-dark (LD) cycles in the two circadian ranges (i.e. 20 or 24-hr LD cycles) to determine if the decreased lifespan in the mutant animals is due to an intrinsic genetic effect on longevity or to the inability of the circadian clock of mutant animals to entrain normally to the standard 24-hr light cycle. In a second series of experiments, the effects of age on 1) the period of the clock, 2) the phase relationship of the activity rhythm to entraining light-dark cycles, 3) the rate of reentrainment following phase shifts in the light-dark cycle, and 4) the response of the circadian clock to light pulses or to a variety of activity-inducing stimuli will be determined in wild-type and tau mutant hamsters. The results of these studies will establish whether a mutation in the circadian system has an effect on normal age-related changes in the circadian clock system, as well as whether such changes occur at an earlier age in the mutant hamsters that corresponds in time with the decreased lifespan of the animals. In a third series of experiments, the effects of destruction of the circadian clock in the SCN on longevity will be established in order to determine if changes in the clock itself are responsible for the reduced lifespan of the mutant animals. A final series of experiments involving the transplantation of fetal SCN tissue from both wild-type and mutant hamsters to animals of the same or different genotype will be carried out to determine the role of transplanted SCN tissue in the restoration of circadian function in old hamsters. In view of the central role played by the circadian clock in the regulation of diverse biological systems, age-related changes in the clock can be expected to have a major impact on the health of the organism. A variety of circadian abnormalities have been found in elderly humans, including those suffering from Alzheimer's disease and disturbances of the sleep-wake cycle. Studies on how circadian mutations affect age-related changes in the circadian clock and whether circadian disturbances induced by mutations affect aging itself, may provide new information on the underlying physiological bases for age-related dysfunction within the circadian system and how altered clock function may contribute to the aging process.