RESPONSIVENESS OF THE AGING CIRCADIAN CLOCK TO LIGHT

老化生物钟对光的反应

• 批准号: 7376832
• 负责人: SUSAN J BENLOUCIF
• 金额: $ 17.87万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376832
• 关键词: RESPONSIVENESS; AGING; CIRCADIAN; CLOCK; LIGHT

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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。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。近 50% 的老年人口报告有慢性睡眠障碍。该年龄段常见的现象是睡眠阶段提前，并伴有睡眠维持性失眠和早醒。这会缩短总睡眠时间并导致白天疲劳和表现受损。睡眠提前与昼夜节律核心体温（CBT）节律时间提前相关，表明生物钟时间提前。相位超前的原因尚不清楚。然而，我们实验室的初步数据表明，老年受试者在 CBT 最低限度之前暴露于光后不会出现相位延迟，而 CBT 最低限度的时间会导致年轻受试者出现最大延迟。 该提案的第一个目标是更好地理解时钟对光响应能力与年龄相关的变化背后的机制。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。近 50% 的老年人口报告有慢性睡眠障碍。该年龄段常见的现象是睡眠阶段提前，并伴有睡眠维持性失眠和早醒。这会缩短总睡眠时间并导致白天疲劳和表现受损。睡眠提前与昼夜节律核心体温（CBT）节律时间提前相关，表明生物钟时间提前。相位超前的原因尚不清楚。然而，我们实验室的初步数据表明，老年受试者在 CBT 最低限度之前暴露于光后不会出现相位延迟，而 CBT 最低限度的时间会导致年轻受试者出现最大延迟。 该提案的第一个目标是更好地理解时钟对光响应能力与年龄相关的变化背后的机制。第一个具体目标将检验生物钟随着年龄的增长而对光的反应减弱的假设。该假设将通过比较年轻人和老年人在三个不同时间（或阶段）暴露于光后相对于最低温度的褪黑激素、促甲状腺激素（TSH）和 CBT 节律的相移幅度来检验。第二个具体目标将测试光的相位响应曲线随着年龄而改变的假设。该假设将通过绘制相对于褪黑激素、TSH 和 CBT 初始相位的相移方向和大小来测试，以生成对光的相位响应曲线。将在年轻人和老年人中比较相位标记相移的方向和幅度，以确定年龄是否影响时钟对光的相位依赖响应。 该提案的第二个目标是评估是否可以通过增加光照强度或通过钙通道拮抗剂尼莫地平的药物治疗来补偿衰老生物钟对光反应性的与年龄相关的变化（具体目标 3）。 拟议的实验将提供大量数据，以便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。