Exploring links between circadian clocks and aging.

描述（由申请人提供）：探索生物钟和衰老之间的联系摘要：与生物钟相关的人类生理和认知功能下降受到社会的极大关注，迫切需要确定支持健康衰老和长寿的生物学机制。最近的证据表明，生物钟（昼夜节律）对于在衰老过程中保持健康很重要。昼夜节律钟是一种内源性分子调节因子，它能使基因表达水平、生理功能和行为的每日变化与外部昼夜周期相协调。哺乳动物生物钟的破坏导致加速衰老和增加与年龄相关的病理，如癌症和神经退行性疾病。来自我们实验室的数据表明，模式生物果蝇（Drosophila melanogaster）的生物钟中断也会导致过早衰老和寿命缩短。该建议的目的是检验昼夜节律网络失调与果蝇衰老有因果关系的假设。我们计划通过关注两个目标来研究昼夜节律系统与衰老之间的关系：a）我们将尝试通过转基因操作来增加下降的时钟基因的表达，并确定这些处理是否可以增强老年果蝇的每时和每刻昼夜节律振荡的幅度。这将使我们能够识别导致昼夜节律网络的年龄相关衰退的分子缺陷，并帮助我们尝试通过遗传干预来逆转这种衰退B）测试昼夜节律振荡的高振幅是否支持衰老期间的长寿和健康。我们的研究结果应该提供关于强大的生物钟和长寿之间联系的关键信息。果蝇是一个很好的模型，以解决这些联系，由于其寿命短（~60天）和保护的时钟基因和衰老机制之间的苍蝇和人类。从这项创新的探索性研究中获得的见解将有助于更好地理解昼夜节律系统的节律振荡与健康和长寿之间的联系机制。这项探索性研究提案的结果可能会指出通过增强昼夜节律系统来维持人类衰老过程中最佳健康的新方法。 公共卫生相关性：与衰老相关的人类各种生命功能的下降引起了社会的极大关注，迫切需要确定支持健康衰老和长寿的生物学机制。最近的证据表明，生物钟（昼夜节律）在衰老过程中保持健康方面发挥着重要作用。这些研究将揭示导致生物钟机制老化的分子机制。从对模式生物进行的这项工作中获得的见解可能会导致通过增强衰老个体的生物钟幅度来增加人类寿命的新方法。

DESCRIPTION (provided by applicant): Exploring links between circadian clocks and aging Summary: Age-related decline in the physiological and cognitive functions in humans is of great concern to society and there is an urgent need to identify the biological mechanisms that support healthy aging and longevity. Recent evidence suggests that the biological (circadian) clocks are important for maintaining health during aging. Circadian clocks are endogenous molecular regulators that coordinate daily changes in the level of gene expression, physiological functions and behavior with external day/night cycles. Disruption of circadian clocks in mammals result in accelerated aging and increased age-related pathologies such as cancer and neurodegenerative diseases. Data from our laboratory demonstrated that disruption of circadian clock in the model organism Drosophila melanogaster also leads to premature aging and compromised longevity. The aim of this proposal is to test the hypothesis that deregulation of circadian network is causally linked to aging in Drosophila. We plan to investigate the relationship between circadian systems and aging by focusing on two aims: a) we will attempt to increase the expression of declining clock genes via transgenic manipulations, and determine whether these treatments can enhance the amplitude of per and tim circadian oscillations in old flies. This will allow us to identify the molecular defects that cause age-related decay of circadian network and help us attempt to reverse this decay by genetic interventions b) Test if high amplitude of circadian oscillations support longevity and health during aging. Our results should provide critical information regarding links between strong circadian clocks and longevity. The fruitfly Drosophila is an excellent model to address these links due to its short lifespan (~60 days) and conservation of clock genes and aging mechanisms between flies and humans. Insights obtained from this innovative exploratory research will lead to a better understanding of the mechanisms that link rhythmic oscillations of the circadian system with health and longevity. The outcomes of this exploratory research proposal may point to novel ways to maintain optimal health during aging in humans by enhancement of the circadian systems. PUBLIC HEALTH RELEVANCE: Age-related decline in various life functions in humans is of great concern for society, and there is an urgent need to identify the biological mechanisms that support healthy aging and longevity. Recent evidence suggests that the biological (circadian) clocks play important roles in maintaining health during aging. The proposed studies will uncover the molecular mechanisms that cause age related decay of the circadian clock mechanism. Insights obtained from this work performed on a model organism may lead to novel ways of increasing longevity in humans by enhancing the circadian clock amplitude in aging individuals.