Calorie Restriction and Hallmarks of Aging in Drosophila

果蝇的热量限制和衰老标志

• 批准号: 10901041
• 负责人: BLANKA ROGINA
• 金额: $ 41.52万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901041
• 关键词: Abdomen; Acceleration; Address; Affect; Age; Age of Onset; Aging; Biochemical Pathway; Biogenesis; Caloric Restriction; Calories; Cell physiology; Chest; Complex; Data; Deceleration; Deterioration; Development; Diet; Disease; Drosophila genus; Event; Female; Foundations; Genes; Goals; Head; Health; Homeostasis; Hour; Human; Individual; Insulin; Intervention; Invertebrates; Knowledge; Life; Link; Longevity; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Nutrient; Nutrient availability; Organism; Pathway interactions; Physiological; Process; Production; Research; Science; Signal Transduction; Somatomedins; Therapeutic; Time; Tissues; Transcription Coactivator; Translating; Visualization; Work; age effect; age related; design; detection of nutrient; fly; functional decline; genetic approach; healthspan; improved; male; member; metabolic abnormality assessment; metabolome; metabolomics; mitochondrial dysfunction; mortality; new therapeutic target; novel therapeutics; prevent; survivorship; therapeutic target; transcriptome; transcriptomics; whole genome

Project Summary Aging is associated with functional decline in metabolic, physiological, proliferative, and tissue homeostasis leading to deterioration on the organismal level. The identification of therapeutic strategies that prevent or postpone age-related decline has become an urgent goal of biomedical science research. Aging has been linked with an array of conserved cellular processes and molecular pathways marked as hallmarks. However, relationship between the hallmarks has not been clearly defined. Determination of the interaction among hallmarks would open more realistic opportunity for identification of novel therapeutic targets to decelerate organismal aging. We will determine trajectories and relationships between two hallmarks of aging – deregulated nutrient sensing and mitochondrial dysfunction – by using our model of accelerated or decelerated aging. Calorie restriction (CR) delays the onset of age-related changes, decreases the rate of aging, and extends the life span in a variety of species. Our preliminary data show that shifting flies from a high-calorie to a low-calorie diet immediately decreases fly mortality, affects metabolism, and extends survivorship. In contrast, shifting from a low diet to a high diet accelerates aging. Dynamic metabolic adaptations to available nutrients are reflected in the tissue-specific transcriptome, which provides an excellent model to uncover rapid changes in the hallmarks of aging to start dissecting their relationship. Our project is designed to determine interactions between nutrient sensing and mitochondrial function in flies, in which the rate of aging is reduced or accelerated by shifting flies to different diets. We will use an integrated experimental and genetic approach that includes analysis of changes in metabolism, transcriptome, metabolome, mitochondrial function, and physiological markers of fly health. We propose the following specific aims: Determine effects of rapid change in aging rate on deregulated nutrient sensing by using an integrated approach involving the study of metabolism, and determination of the transcriptomic and targeted metabolomics profile in different tissues of shifted flies (Aim 1). Determine effects of change in the aging rate on mitochondrial dysfunction (Aim 2). Determine interactions between the two hallmarks by using our model of accelerated and decelerated aging by performing epistatic analysis (Aim 3). Our proposed study will advance our basic knowledge on the molecular and physiological mechanisms underlying interactions among hallmarks of aging and determine how their hierarchy affects organismal aging. Hallmarks of aging are highly conserved across species, suggesting that our findings could be translated to mammalian organisms.

项目摘要 衰老与代谢、生理、增殖和组织的功能下降有关。 体内平衡导致生物体水平的恶化。确定治疗策略， 预防或延缓与年龄相关的衰退已成为生物医学科学研究的迫切目标。老龄化 与一系列保守的细胞过程和标记为标志的分子途径有关。 然而，标志之间的关系尚未明确界定。相互作用的测定 将为识别新的治疗靶点提供更现实的机会， 延缓机体衰老。我们将确定衰老的两个标志之间的轨迹和关系- 营养感应失调和线粒体功能障碍-通过使用我们的加速或减速模型 衰老 热量限制（CR）延迟了与年龄相关的变化的发生，降低了衰老的速度，并延长了 生命周期的变化。我们的初步数据显示，将苍蝇从高热量转换为低热量 饮食立即降低苍蝇死亡率，影响新陈代谢，并延长生存期。相反，从 从低饮食到高饮食会加速衰老。对有效养分的动态代谢适应反映在 组织特异性转录组，它提供了一个很好的模型来揭示标志物的快速变化， 开始剖析他们的关系我们的项目旨在确定营养物质 果蝇的感觉和线粒体功能，其中衰老速度因果蝇的转移而降低或加速 不同的饮食。我们将使用一个综合的实验和遗传的方法，包括分析的变化 在代谢，转录组，代谢组，线粒体功能，苍蝇健康的生理标志物。 我们提出了以下具体目标：确定老龄化速度的快速变化对放松管制的影响 通过使用综合方法进行营养感测，包括研究代谢和确定 转录组学和靶向代谢组学谱在不同组织的转换苍蝇（目的1）。确定影响 线粒体功能障碍的衰老率变化（目的2）。确定两个标志之间的相互作用 通过使用我们的加速和减速老化模型进行上位分析（目的3）。我们提出的 这项研究将推进我们对相互作用的分子和生理机制的基本知识 并确定它们的层次结构如何影响有机体的衰老。衰老的标志是 在物种间高度保守，这表明我们的发现可以转化为哺乳动物生物。