Exploring links between circadian clocks and aging.

探索生物钟与衰老之间的联系。

• 批准号: 8030253
• 负责人: Jadwiga M Giebultowicz
• 金额: $ 14.55万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8030253
• 关键词: Address; Affect; Age; Aging; Animal Model; Behavior; Biological; Biological Markers; Circadian Rhythms; Clock protein; Data; Defect; Drosophila genus; Drosophila melanogaster; Gene Expression; Genes; Goals; Health; Homeostasis; Human; Individual; Knowledge; Laboratories; Lead; Life; Limb structure; Link; Longevity; Malignant Neoplasms; Mammals; Metabolism; Modeling; Molecular; Nature; Neurodegenerative Disorders; Organism; Outcome; Pathology; Pathway interactions; Phosphorylation; Physiological; Physiology; Play; Premature aging syndrome; Property; Research; Research Proposals; Role; Societies; System; Testing; Transgenic Organisms; Western Blotting; Work; age related; aged; anti aging; circadian pacemaker; cognitive function; fly; gene therapy; genetic manipulation; healthy aging; improved; innovation; insight; novel; premature; repaired; research study; stressor

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.

描述(申请人提供)：探索生物钟和衰老之间的联系摘要：与年龄有关的人类生理和认知功能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，生物(生物钟)对于在衰老过程中保持健康很重要。生物钟是一种内源性分子调节器，它将基因表达水平、生理功能和行为的日常变化与外部昼夜周期协调起来。哺乳动物生物钟的紊乱会加速衰老，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紊乱也会导致过早衰老和寿命下降。这项提议的目的是检验这样一种假设，即昼夜节律网络的放松与果蝇的衰老有因果关系。我们计划通过两个目标来研究昼夜节律系统与衰老的关系：a)我们将试图通过转基因操作来增加衰退时钟基因的表达，并确定这些处理是否能够增强老年果蝇PER和TIM昼夜节律振荡的幅度。这将使我们能够识别导致昼夜节律网络与年龄相关的衰退的分子缺陷，并帮助我们尝试通过遗传干预来逆转这种衰退。b)测试在衰老过程中，高幅度的昼夜节律振荡是否支持长寿和健康。我们的研究结果应该会提供有关强大的生物钟和长寿之间联系的关键信息。果蝇是解决这些联系的一个很好的模型，因为它的寿命短(~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将昼夜节律振荡与健康和长寿联系起来的机制。这一探索性研究提案的结果可能指出，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。 公共卫生相关性：与年龄相关的人类各种生命功能的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，生物(生物钟)在衰老期间维持健康方面发挥着重要作用。这项拟议的研究将揭示导致生物钟机制与年龄相关的衰退的分子机制。在模型生物体上进行的这项工作所获得的见解可能会导致通过提高老年个体的生物钟幅度来延长人类寿命的新方法。