RESPONSIVENESS OF THE AGING CIRCADIAN CLOCK TO LIGHT

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。我们的长期目标是了解老年人慢性睡眠障碍的基础，并开发有效的治疗方法。据报道，近50%的老年人口患有慢性睡眠障碍。在这个年龄段，常见的是睡眠阶段的提前，伴随着睡眠维持性失眠和清晨醒来。这会缩短总的睡眠时间，导致白天的疲劳和表现受损。睡眠的提前与昼夜核心体温(CBT)节律的计时提前有关，这表明生物钟的计时提前。同步推进的原因尚不清楚。然而，我们实验室的初步数据显示，在CBT最小值之前暴露于光线后，老年受试者没有相位延迟，这一时间在年轻受试者中导致最大延迟。这项提议的第一个目标是更好地理解这种与年龄相关的时钟对光的反应变化背后的机制。我们的长期目标是了解老年人慢性睡眠障碍的基础，并开发有效的治疗方法。据报道，近50%的老年人口患有慢性睡眠障碍。在这个年龄段，常见的是睡眠阶段的提前，伴随着睡眠维持性失眠和清晨醒来。这会缩短总的睡眠时间，导致白天的疲劳和表现受损。睡眠的提前与昼夜核心体温(CBT)节律的计时提前有关，这表明生物钟的计时提前。同步推进的原因尚不清楚。然而，我们实验室的初步数据显示，在CBT最小值之前暴露于光线后，老年受试者没有相位延迟，这一时间在年轻受试者中导致最大延迟。这项提议的第一个目标是更好地理解这种与年龄相关的时钟对光的反应变化背后的机制。第一个具体目标将检验这样一个假设，即随着年龄的增长，生物钟对光的反应变得不那么灵敏。这一假设将通过比较年轻人和老年人在三个不同的时间(或阶段)暴露在相对于最低温度的光后褪黑素、促甲状腺激素(TSH)和CBT的节律相移的幅度来检验。第二个具体目标将检验对光的相位响应曲线随年龄变化的假设。这一假设将通过绘制相对于褪黑激素、TSH和CBT初始阶段的相移的方向和大小来检验，以生成对光的相响应曲线。相标记的相移方向和大小将在年轻人和老年人中进行比较，以确定年龄是否影响时钟对光的相位相关反应。这项建议的第二个目标是评估是否有可能通过增加光暴露的强度或通过钙通道拮抗剂尼莫地平的药物治疗(特定目标3)来补偿老化的昼夜节律时钟对光的反应的年龄相关变化。拟议的实验将提供大量数据，更好地了解年龄对昼夜节律和睡眠的影响，并改进老年人昼夜节律和睡眠障碍的治疗方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our long-term goal is to understand the basis of, and develop effective therapies for, chronic sleep disturbances in older adults. Chronic sleep disturbance is reported by nearly 50% of the elderly population. Common in this age group is an advance in the phase of sleep, accompanied by sleep maintenance insomnia and early morning awakenings. This can shorten the total sleep time and lead to daytime fatigue and impaired performance. The advance in sleep is associated with an advance in the timing of the circadian core body temperature (CBT) rhythm, indicating an advance in the timing of the circadian clock. The cause of the advance in phase is not known. However, preliminary data from our laboratory show that elderly subjects do not phase delay following exposure to light before the CBT minimum, a time that induces maximal delays in young subjects. The first goal of this proposal is to better understand the mechanism underlying this age-related change in responsiveness of the clock to light. Our long-term goal is to understand the basis of, and develop effective therapies for, chronic sleep disturbances in older adults. Chronic sleep disturbance is reported by nearly 50% of the elderly population. Common in this age group is an advance in the phase of sleep, accompanied by sleep maintenance insomnia and early morning awakenings. This can shorten the total sleep time and lead to daytime fatigue and impaired performance. The advance in sleep is associated with an advance in the timing of the circadian core body temperature (CBT) rhythm, indicating an advance in the timing of the circadian clock. The cause of the advance in phase is not known. However, preliminary data from our laboratory show that elderly subjects do not phase delay following exposure to light before the CBT minimum, a time that induces maximal delays in young subjects. The first goal of this proposal is to better understand the mechanism underlying this age-related change in responsiveness of the clock to light. The first Specific Aim will test the hypothesis that the circadian clock becomes less responsive to light with age. This hypothesis will be tested by comparing the magnitude of phase shifts of rhythms of melatonin, thyrotropin (TSH), and CBT in young and older adults following exposure to light at three different times (or phases) relative to the temperature minimum. The second Specific Aim will test the hypothesis that the phase response curve to light is altered with age. This hypothesis will be tested by plotting the direction and magnitude of phase shifts relative to the initial phase of melatonin, TSH, and CBT to generate the phase response curves to light. The direction and magnitude of phase shifts of the phase markers will be compared in young and older adults to determine whether age affects the phase dependent response of the clock to light. The second goal of this proposal is to assess whether it is possible to compensate for age-related changes in the responsiveness of the aging circadian clock to light, by increasing the intensity of the light exposure or by pharmacological treatment with the calcium channel antagonist nimodipine (Specific Aim 3). The proposed experiments will provide a vast amount of data in which to better understand the effect of age on circadian rhythms and sleep, and lead to improved treatments for circadian rhythm and sleep disorders in older adults.