Circadian Clocks and Aging

描述(申请人提供)：人类生理和认知功能的年龄相关性下降是社会非常关注的问题，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，昼夜节律系统对于在衰老过程中保持健康很重要。昼夜节律系统由调节行为的中央起搏器和大多数身体器官中的外围振荡器组成，这些振荡器协调基因表达、小代谢物和组织特有的生理过程中的日常波动。在人类身上进行的多项观察性研究将生物钟的紊乱与加速衰老的症状联系在一起，例如神经退行性疾病，但其潜在机制尚不清楚。我们最近报道，在模式生物黑腹果蝇中，时钟基因的一个突变会导致过早衰老和神经元动态平衡受损。我们还确定，由于时钟基因表达减少，在衰老果蝇的外周时钟中，昼夜节律机制衰退。我们的初步数据表明，特定的基因干预可以改善衰老有机体的分子和行为节律。我们假设，增加昼夜节律时钟的强度可能会延缓衰老，促进健康。我们将作为三个具有互补专业知识的实验室之间的协作团队来测试这一假说，重点放在三个目标上：1)确定不同组织中时钟基因表达随年龄增长而衰退的分子原因；2)测试时钟基因振荡的改善是否可以避免衰老果蝇的功能衰退，延长健康寿命和寿命；以及3)确定由外围时钟控制的通路，从而调节衰老果蝇的健康寿命。我们的研究结果应该能提供有关强大的外周生物钟和衰老速度之间的功能联系的关键信息。从这项活体研究中获得的见解可能具有临床意义，因为它揭示了通过增强昼夜节律系统在人类衰老期间保持最佳健康的新方法。

DESCRIPTION (provided by applicant): 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 biological mechanisms that support healthy aging and longevity. Recent evidence suggests that the circadian system is important for maintaining health during aging. The circadian system comprises of a central pacemaker regulating behavior and peripheral oscillators in most body organs that coordinate daily oscillations in gene expression, small metabolites, and tissue-specific physiological processes. Multiple observational studies in humans linked disruption of circadian clocks with accelerated aging symptoms, such as neurodegenerative diseases, but the underlying mechanisms are not understood. We recently reported that a mutation in one of the clock genes leads to premature aging and impaired neuronal homeostasis in the model organism Drosophila melanogaster. We also determined that the circadian mechanism decays in peripheral clocks of aging flies due to reduced expression of clock genes. Our preliminary data suggest that specific genetic interventions can improve molecular and behavioral rhythms in the aging organism. We hypothesize that increasing the strength of circadian peripheral clocks may retard aging and promote health span. We will test this hypothesis as a collaborative team between three labs with complementary expertise focusing on three aims: 1) Identify molecular causes of age- related decay of clock gene expression in different tissues; 2) Test whether improvement in clock genes oscillations avert functional decay in aging flies and extend health span and lifespan; and 3) Identify pathways controlled by peripheral clocks that mediate health span benefits in aging flies. Our results should yield critical information regarding functional links between strong peripheral circadian clocks and aging rate. Insights obtained from this in vivo research may have clinical relevance by uncovering novel ways to maintain optimal health during aging in humans by enhancement of the circadian systems.