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）是增加寿命并延迟动物年龄相关症状发作的最可靠方法。在当前的资金期间，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。果蝇果蝇果蝇中的印地基因突变大大延长了寿命。 Indy是Krebs循环中间体的二羧酸酯转运蛋白，主要在中间代谢中重要的组织中发现。已经提出了降低的Indy活性的寿命延长效应是导致遗传CR的形式，这是在此资金期间进行的生化，分子和遗传研究支持的假设。 indy长蝇的基因组转录反应的确定表明，在代谢问题中起作用的基因下调是暂时性下降的是线粒体氧化磷酸化（OP）络合物I和III的瞬时降低。我们表明，在Indy Flies中，OP I和III复合物具有较低的酶活性，产生了较少的活性氧（ROS），并导致较低的氧化损伤。但是，在Indy Flies中的ATP产生与对照相似，这可以通过在Indy Flies中发现的线粒体密度升高来解释。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寿命途径之间的其他联系，并构成了我们假设的基础，即OP复合物中的瞬时变化介导了Indy突变体中的寿命。同时，我们已经表明，RPD3组蛋白脱乙酰基酶的下调，或DSIR2组蛋白脱乙酰基酶的过表达在遗传上或通过与CR相似的机制延长果蝇中的果蝇中的DSIR2活性，从而延长果蝇中的寿命。这使我们有机会确定线粒体生理学的类似变化是否是遗传CR的三种飞行模型中延长途径的一部分。在本提案的目标1中，我们将确定Indy，RPD3和SiR2基因或CR的遗传操作是否通过下调每个寿命延伸条件下OP I和III组件的水平和活动来影响寿命。在AIM 2中，我们将确定降低复杂I和III的成分水平是否对苍蝇生理和寿命有影响。在AIM 3中，我们将检查OP I和III组件与已建立的INDY/RPD3/SIR2寿命途径之间的遗传相互作用。在AIM 4中，我们将通过评估INDY/RPD3/SIR2寿命途径中的线粒体生理和生物发生，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中的作用，应力反应和寿命是众所周知的，我们提出的实验将将当前知识扩展到OP成分在CR途径中的新作用，并有可能为治疗干预提供基础。公共卫生相关性：热量限制已成为保护有机体免受脊椎动物和无脊椎动物物种衰老的有害影响的最有效方法。该项目将通过热量限制研究水果果蝇（果蝇果蝇果蝇）的寿命延长的分子机制。它将揭示热量减少的摄入量如何影响新陈代谢和寿命，并为开发新疗法的疗法提供基础，以治疗人类与年龄相关疾病的治疗。