Calorie Restriction and Hallmarks of Aging in Drosophila

项目摘要 衰老与代谢、生理、增殖和组织的功能衰退有关 动态平衡导致生物体水平的恶化。确定治疗策略， 预防或延缓衰老已成为生物医学科学研究的迫切目标。年龄增长有 与一系列保守的细胞过程和标记为特征的分子通路联系在一起。 然而，这些标志之间的关系还没有得到明确的定义。相互作用的确定 这些特征将为确定新的治疗靶点提供更现实的机会 延缓生物体衰老。我们将确定衰老的两个特征之间的轨迹和关系- 放松营养感知和线粒体功能障碍--通过使用我们的加速或减速模型 衰老。 卡路里限制(CR)延缓了与年龄相关的变化的发生，减缓了衰老的速度，并延长了 在不同物种中的寿命。我们的初步数据显示，将果蝇从高卡路里转变为低卡路里 饮食会立即降低苍蝇的死亡率，影响新陈代谢，延长生存时间。相比之下，从 低饮食与高饮食会加速衰老。对可用营养素的动态代谢适应反映在 组织特异性转录组，它提供了一个很好的模型来揭示特征的快速变化 开始剖析他们之间的关系。我们的项目旨在确定营养物质之间的相互作用 苍蝇的感觉和线粒体功能，通过改变苍蝇来减缓或加速衰老速度 不同的饮食习惯。我们将使用集成的实验和遗传学方法，其中包括分析变化 在代谢、转录组、代谢组、线粒体功能和苍蝇健康的生理标记物方面。 我们提出了以下具体目标：确定老龄化速度快速变化对放松管制的影响 使用一种综合的方法进行营养传感，包括研究新陈代谢和测定 转移果蝇不同组织中转录和靶向代谢组学图谱(目标1)。确定以下因素的影响 线粒体功能障碍的增龄率变化(目标2)。确定这两个特征之间的相互作用 通过使用我们的加速和减速老化模型进行上位性分析(目标3)。我们的建议 研究将促进我们对相互作用潜在的分子和生理机制的基本知识 在衰老的特征中，并确定它们的等级如何影响生物衰老。衰老的特征是 在不同物种中高度保守，这表明我们的发现可以转化为哺乳动物的生物。

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.