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，物理，增生剂和组织的功能下降有关 稳态导致在生物体上确定。识别理论策略 预防或推迟与年龄有关的下降已成为生物医学科学研究的紧迫目标。衰老有 与一系列配置的蜂窝过程和标记为标志的分子途径相关。 但是，标志之间的关系尚未明确定义。互动的确定 在标志中，将为识别新型热目标的更现实机会开放 减速有机老化。我们将确定衰老两个标志之间的轨迹和关系 - 使用我们的加速或减速模型，放松受管的营养感应和线粒体功能障碍 老化。 卡路里限制（CR）延迟了与年龄相关的变化的发作，降低了衰老率，并扩展了 多种物种的寿命。我们的初步数据表明，将苍蝇从高热量转移到低热量 饮食立即降低苍蝇死亡率，影响新陈代谢并扩展生存。相反，从 低饮食至高饮食会加速衰老。对可用营养素的动态代谢适应反映在 组织特异性转录组，提供了一个极好的模型，可以发现标志的快速变化 衰老开始解剖他们的关系。我们的项目旨在确定养分之间的相互作用 苍蝇中的感测和线粒体功能，其中衰老速率通过转移而降低或加速 进行不同的饮食。我们将使用一种集成的实验和遗传方法，其中包括对变化的分析 在代谢，转录组，代谢组，线粒体功能和苍蝇健康的物理标记中。 我们提出以下具体目的：确定衰老率快速变化对失调的影响 通过使用涉及新陈代谢研究的综合方法，并确定营养 移位蝇的不同组织中的转录组和靶向代谢组学谱（AIM 1）。确定效果 线粒体功能障碍的老化率变化（AIM 2）。确定两个标志之间的互动 通过使用上皮分析使用我们的加速和减速衰老模型（AIM 3）。我们提出的 研究将促进我们对分子和物理机制的基本知识 在衰老的标志中，确定其层次结构如何影响有机衰老。衰老的标志是 高度保守的物种，表明我们的发现可以转化为哺乳动物生物。