Exploring links between circadian clocks and aging.

探索生物钟与衰老之间的联系。

• 批准号: 8225201
• 负责人: Jadwiga M Giebultowicz
• 金额: $ 20.8万
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8225201
• 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; public health relevance; 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（由申请人提供）：探索生物钟与衰老之间的联系 摘要：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衰老和衰老的生物学机制。长寿。最近的证据表明，生物钟（昼夜节律）对于在衰老过程中保持健康非常重要。昼夜节律钟是内源性分子调节剂，可协调基因表达水平、生理功能和行为与外部昼夜周期的日常变化。哺乳动物生物钟的破坏会导致加速衰老和增加与年龄相关的疾病，例如癌症和神经退行性疾病。我们实验室的数据表明，模式生物果蝇的生物钟被破坏也会导致过早衰老和寿命缩短。该提案的目的是检验昼夜节律网络失调与果蝇衰老存在因果关系的假设。我们计划通过关注两个目标来研究昼夜节律系统与衰老之间的关系：a）我们将尝试通过转基因操作来增加下降的时钟基因的表达，并确定这些治疗是否可以增强每个和时间昼夜节律振荡的幅度老苍蝇。这将使我们能够识别导致与年龄相关的昼夜节律网络衰退的分子缺陷，并帮助我们尝试通过基因干预来扭转这种衰退 b) 测试高振幅的昼夜节律振荡是否支持衰老过程中的长寿和健康。我们的结果应该提供有关强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绝佳模型，因为它的寿命短（约 60 天），并且果蝇和人类之间生物钟基因和衰老机制的保护。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昼夜节律系统的节律振荡与健康和长寿之间的联系机制。这项探索性研究提案的结果可能会指出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。 公共卫生相关性：人类各种生命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，生物钟（昼夜节律）在衰老过程中维持健康方面发挥着重要作用。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。从对模型生物体进行的这项工作中获得的见解可能会导致通过增强衰老个体的生物钟幅度来延长人类寿命的新方法。

项目成果

Circadian regulation of glutathione levels and biosynthesis in Drosophila melanogaster.

果蝇谷胱甘肽水平和生物合成的昼夜节律调节。

• 发表时间: 2012
• 影响因子: 3.7
• 作者: Beaver, Laura M;Klichko, Vladimir I;Chow, Eileen S;Kotwica;Williamson, Marisa;Orr, William C;Radyuk, Svetlana N;Giebultowicz, Jadwiga M
• 通讯作者: Giebultowicz, Jadwiga M