Circadian Clocks and Aging

昼夜节律时钟和衰老

• 批准号: 9064732
• 负责人: Jadwiga M Giebultowicz
• 金额: $ 25.32万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064732
• 关键词: Activity Cycles; Address; Affect; Age; Aging; Aging-Related Process; Anabolism; Animal Model; Behavior; Behavioral; Biological; Biology; Brain; Cells; Circadian Rhythms; Complex; Data; Disease; Drosophila melanogaster; Equilibrium; Gene Expression; Genes; Genetic; Genetic Enhancement; Glutathione; Head; Health; Homeostasis; Human; Impairment; Individual; Lead; Life; Link; Longevity; Mammals; Mediating; Molecular; Motor; Mutation; Nature; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Observational Study; Organ; Organism; Outcome; Oxidation-Reduction; Pacemakers; Pathology; Pathway interactions; Peripheral; Physiological; Physiological Processes; Play; Premature aging syndrome; Regulation; Rejuvenation; Reporting; Research; Rest; Role; Sleep; Societies; Symptoms; System; Testing; Tissues; Transgenic Organisms; Work; age effect; age related; anti aging; circadian pacemaker; clinically relevant; cognitive function; cryptochrome; fly; functional decline; gene therapy; healthy aging; improved; in vivo; insight; intervention effect; mutant; novel; overexpression; pleiotropism; prevent; research study

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.

描述（由申请人提供）：人类生理和认知功能中与衰老相关的衰退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，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枢起搏器和大多数身体器官中的外周振荡器组成，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中的每日振荡。在人类中进行的多项观察性研究将生物钟的破坏与加速衰老症状（如神经退行性疾病）联系起来，但其潜在机制尚不清楚。我们最近报道了一个时钟基因的突变导致模式生物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，昼夜节律机制在衰老果蝇的外周时钟中衰退。我们的初步数据表明，特定的遗传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，促进健康寿命。我们将作为三个实验室之间的合作团队来测试这一假设，这些实验室具有互补的专业知识，专注于三个目标：1）确定不同组织中与年龄相关的时钟基因表达衰减的分子原因; 2）测试时钟基因振荡的改善是否可以避免衰老苍蝇的功能衰退并延长健康寿命和寿命;和3）确定由外周时钟控制的通路，介导衰老苍蝇的健康寿命益处。我们的研究结果应该产生关键信息之间的功能联系强大的外周生物钟和老化率。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在人类衰老过程中保持最佳健康的新方法。