Exploring links between circadian clocks and aging.

摘要：人类生理和认知功能与年龄相关的衰退受到社会的高度关注，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（昼夜节律）时钟对于在衰老过程中保持健康很重要。生物钟是内源性分子调节剂，协调基因表达水平、生理功能和行为与外部昼夜周期的日常变化。哺乳动物生物钟的紊乱会导致衰老加速，并增加与年龄相关的疾病，如癌症和神经退行性疾病。我们实验室的数据表明，模式生物黑腹果蝇生物钟的破坏也会导致过早衰老和寿命受损。这一提议的目的是验证一个假设，即解除昼夜节律网络与果蝇衰老有因果关系。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增加衰退时钟基因的表达，并确定这些处理是否可以增强老年果蝇的per和tim昼夜节律振荡的振幅。这将使我们能够识别导致与年龄相关的昼夜节律网络衰减的分子缺陷，并帮助我们尝试通过遗传干预来逆转这种衰减。b)测试高振幅的昼夜节律振荡是否支持衰老期间的长寿和健康。我们的研究结果应该为强生物钟和长寿之间的联系提供关键信息。果蝇是解决这些联系的一个很好的模型，因为它的寿命短（约60天），并且在果蝇和人类之间保存时钟基因和衰老机制。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。这项探索性研究计划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。

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.