Circadian Clocks and Aging

昼夜节律时钟和衰老

基本信息

批准号：
8707933
负责人：
Jadwiga M Giebultowicz
金额：
$ 24.35万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8707933
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 prevent research study

项目摘要

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非常重要。昼夜节律系统由大多数身体器官中调节行为的中央起搏器和外周振荡器组成，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。对人类的多项观察性研究表明，生物钟的破坏与神经退行性疾病等加速衰老症状有关，但其潜在机制尚不清楚。我们最近报道，其中一个时钟基因的突变导致模型生物果蝇过早衰老和神经元稳态受损。我们还确定，由于时钟基因表达的减少，衰老果蝇的外周时钟的昼夜节律机制会衰退。我们的初步数据表明，特定的遗传干预可以改善衰老有机体的分子和行为节律。我们假设，增强外周生物钟的强度可能会延缓衰老并延长健康寿命。我们将作为三个具有互补专业知识的实验室之间的合作团队来测试这一假设，重点关注三个目标：1）确定不同组织中时钟基因表达与年龄相关的衰退的分子原因； 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并延长健康寿命和寿命； 3）确定由外周时钟控制的通路，调节衰老果蝇的健康跨度益处。我们的结果应该提供有关强大的外周生物钟和衰老率之间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在人类衰老过程中保持最佳健康的新方法。