Circadian Clocks and Aging

描述（由申请人提供）：与年龄相关的人类生理和认知功能下降受到社会的高度关注，迫切需要确定支持健康老龄化和长寿的生物学机制。最近的证据表明，在衰老过程中，昼夜节律系统对维持健康很重要。昼夜节律系统包括调节行为的中央起搏器和大多数身体器官中的外周振荡器，这些外周振荡器协调基因表达、小代谢物和组织特异性生理过程的日常振荡。多项人类观察性研究将生物钟紊乱与加速衰老症状（如神经退行性疾病）联系起来，但其潜在机制尚不清楚。我们最近报道了一种时钟基因的突变导致模式生物黑腹果蝇的过早衰老和神经元稳态受损。我们还确定，由于时钟基因的表达减少，衰老果蝇的外周时钟的昼夜节律机制衰退。我们的初步数据表明，特定的基因干预可以改善衰老生物体的分子和行为节律。我们假设增加生物钟的强度可能会延缓衰老并促进健康。我们将通过三个实验室之间的合作团队来验证这一假设，并具有互补的专业知识，重点关注三个目标：1)确定不同组织中时钟基因表达年龄相关衰减的分子原因；2)测试时钟基因振荡的改善是否能避免衰老果蝇的功能衰退，延长健康寿命和寿命；3)确定由外周时钟控制的途径，介导衰老果蝇的健康益处。我们的研究结果应该提供关于强外围生物钟和衰老率之间的功能联系的关键信息。从这项体内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来维持人类衰老过程中最佳健康的新方法。

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.