Molecular Genetics of Caloric Restriction in Aging Flies

衰老果蝇热量限制的分子遗传学

• 批准号: 7738622
• 负责人: BLANKA ROGINA
• 金额: $ 31.12万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738622
• 关键词: Adult; Affect; Age; Aging; Animals; Biochemical; Biogenesis; Caloric Restriction; Citric Acid Cycle; Complex; Data; Development; Disease; Down-Regulation; Drosophila genus; Drosophila melanogaster; Electron Microscopy; Electron Transport Complex III; Energy Intake; Energy Supply; Fertility; Foundations; Funding; Genes; Genetic; Genetic Models; Genomics; Glucose; Glycogen; Histone Deacetylase; Histones; Homeostasis; Homologous Gene; Human; Invertebrates; Knowledge; Life; Link; Lipids; Longevity; Longevity Pathway; Mammals; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolism; Metformin; Microarray Analysis; Mitochondria; Molecular; Molecular Genetics; Morphology; Mutation; Organism; Oxidative Phosphorylation; Paraquat; Pathway interactions; Pharmaceutical Preparations; Phosphorus; Phylogenetic Analysis; Physiological; Physiology; Play; Positioning Attribute; Production; RNA Interference; Reactive Oxygen Species; Resistance; Respiration; Resveratrol; Role; Symptoms; Testing; Therapeutic Intervention; Tissues; Yeasts; age effect; age related; base; biological adaptation to stress; complex IV; density; dicarboxylate-binding protein; energy balance; enzyme activity; feeding; fly; gene function; genetic manipulation; interest; lipid metabolism; loss of function mutation; mortality; mutant; novel; overexpression; oxidative damage; public health relevance; research study; response; trend

DESCRIPTION (provided by applicant): Caloric restriction (CR) is the surest way of increasing life span and delaying the onset of age-related symptoms in animals. During the current funding period, we made significant contributions to our understanding of the effects of age and caloric intake on physiology and longevity of adult Drosophila. Mutation in the Indy gene in the fruit fly, Drosophila melanogaster, dramatically extends life span. INDY is a dicarboxylate transporter of Krebs cycle intermediates primarily found in the tissues important for intermediary metabolism. The life extending effect of reduced Indy activity has been proposed to result in a form of genetic CR, a hypothesis supported by biochemical, molecular and genetic studies carried out during this funding period. Determination of the genomic transcriptional responses of Indy long-lived flies reveal down-regulation of genes that function in metabolism-particularly noteworthy is a transient decrease in the expression of components of the mitochondrial oxidative phosphorylation (OP) complexes I and III. We showed that in Indy flies OP I and III complex have lower enzyme activity, produced less reactive oxygen species (ROS), and caused lower oxidative damage. However, production of ATP in Indy flies is similar to the control, a result that could be explained by increased mitochondrial density found in Indy flies. Considering the crucial role of mitochondria in energy production and cellular homeostasis, our preliminary data provide additional links between metabolic and longevity pathways and form the basis for our hypothesis that transient change in the OP complexes mediate longevity in Indy mutant flies. In parallel, we have shown that down-regulation of the rpd3 histone deacetylase, or overexpression of dSir2 histone deacetylase genetically, or increasing dSir2 activity by feeding flies resveratrol, extends life span in Drosophila by a mechanism similar to CR. This give us an opportunity to determine if similar changes in mitochondrial physiology are part of the pathway underlying life span extension in three fly models of genetic CR. In aim 1 of this proposal, we will determine if genetic manipulations of Indy, rpd3, and Sir2 genes, or CR, effect longevity by downregulation of the levels and activity of the OP I and III components in each life span extending condition. In aim 2, we will determine if decreasing the levels of components of complex I and III have effects on fly physiology and longevity. In aim 3, we will examine genetic interactions between OP I and III components and the established Indy/rpd3/Sir2 longevity pathway. In aim 4, we will further elucidate the role mitochondria play in CR life span extension by assessing the mitochondrial physiology and biogenesis in the Indy/rpd3/Sir2 longevity pathway. Since the role of mitochondria in energy homeostasis, stress response and longevity is well known, our proposed experiments will extend current knowledge to the novel role of the OP components in the CR pathway and potentially provide a basis for therapeutic intervention. PUBLIC HEALTH RELEVANCE: Caloric restriction has emerged as the most efficient way to protect the organism against deleterious effects of aging in both vertebrate and invertebrate species. This project will study the molecular mechanism underlying life span extension in fruit flies, Drosophila melanogaster, by caloric restriction. It will reveal how reduced caloric intake affects metabolism and life span, and provide the foundation for the development of new therapies for the treatments of age-associated diseases in humans.

描述（由申请人提供）：热量限制（CR）是延长动物寿命和延缓年龄相关症状发生的最可靠方法。在当前资助期间，我们为了解年龄和热量摄入对成年果蝇生理和寿命的影响做出了重大贡献。果蝇（Drosophila melanogaster）中 Indy 基因的突变可显着延长寿命。 INDY 是三羧酸循环中间体的二羧酸转运蛋白，主要存在于对中间代谢重要的组织中。有人提出，Indy 活动减少的寿命延长效应会导致某种形式的遗传 CR，这一假设得到了本资助期间进行的生化、分子和遗传学研究的支持。对 Indy 长寿果蝇基因组转录反应的测定揭示了代谢功能基因的下调，尤其值得注意的是线粒体氧化磷酸化 (OP) 复合物 I 和 III 成分表达的短暂减少。我们发现印第果蝇中 OP I 和 III 复合物具有较低的酶活性，产生较少的活性氧 (ROS)，并造成较低的氧化损伤。然而，印第果蝇中 ATP 的产生与对照相似，这一结果可以通过印第果蝇中发现的线粒体密度增加来解释。考虑到线粒体在能量产生和细胞稳态中的关键作用，我们的初步数据提供了代谢和长寿途径之间的额外联系，并为我们的假设奠定了基础，即 OP 复合物的瞬时变化介导了 Indy 突变果蝇的长寿。与此同时，我们还发现，在果蝇中，rpd3 组蛋白脱乙酰酶的下调，或 dSir2 组蛋白脱乙酰酶的基因过度表达，或通过给果蝇喂食白藜芦醇来增加 dSir2 活性，可以通过类似于 CR 的机制延长果蝇的寿命。这使我们有机会确定线粒体生理学的类似变化是否是三种遗传 CR 果蝇模型中延长寿命的途径的一部分。在本提案的目标 1 中，我们将确定 Indy、rpd3 和 Sir2 基因（或 CR）的基因操作是否通过下调每种寿命延长条件下 OP I 和 III 成分的水平和活性来影响寿命。在目标 2 中，我们将确定降低复合物 I 和 III 成分的水平是否会对果蝇生理和寿命产生影响。在目标 3 中，我们将检查 OP I 和 III 成分之间的遗传相互作用以及已建立的 Indy/rpd3/Sir2 长寿途径。在目标 4 中，我们将通过评估 Indy/rpd3/Sir2 长寿途径中的线粒体生理学和生物发生，进一步阐明线粒体在 CR 寿命延长中的作用。由于线粒体在能量稳态、应激反应和长寿中的作用众所周知，我们提出的实验将把现有的知识扩展到 OP 成分在 CR 途径中的新作用，并可能为治疗干预提供基础。公共健康相关性：热量限制已成为保护脊椎动物和无脊椎动物物种免受衰老有害影响的最有效方法。该项目将研究通过热量限制延长果蝇寿命的分子机制。它将揭示减少热量摄入如何影响新陈代谢和寿命，并为开发治疗人类年龄相关疾病的新疗法奠定基础。