Systematic Analysis of C elegans Longevity Determinants

线虫长寿决定因素的系统分析

• 批准号: 7260446
• 负责人: Siu Sylvia Lee
• 金额: $ 24.01万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7260446
• 关键词: Affect; Age; Aging; Aging-Related Process; Animals; Biological Assay; Caenorhabditis elegans; Caloric Restriction; Candidate Disease Gene; Cell physiology; Cells; Classification; Communication; Complex; Depth; Dissection; Energy Metabolism; Event; Future; Genes; Genetic; Genome; Genomics; Goals; Homologous Gene; Insulin; Intake; Interphase Cell; Intervention; Investigation; Life; Longevity; Mammals; Mediating; Membrane Potentials; Mitochondria; Molecular; Nervous system structure; Numbers; Nutrient; Oxidative Phosphorylation; Pathway interactions; Phylogeny; Physiological; Process; Production; Protein Overexpression; Proteins; RNA Interference; Regulatory Pathway; Reporter; Research Personnel; Respiration; Respiratory Chain; Role; Screening procedure; Signal Pathway; Signal Transduction; Site; Testing; Time; Tissues; Yeasts; age related; base; comparative; genetic technology; human disease; insight; insulin secretion; insulin signaling; late disease onset; longevity gene; mutant; novel; programs; research study

DESCRIPTION (provided by applicant): How organismal lifespan is determined is poorly understood. Previous investigations in C. elegans have identified novel mechanisms for longevity control that operate in evolutionarily diverse species. However, the analysis of C. elegans lifespan genes has been far from comprehensive. I have exploited recent advances in genomic and genetic technology to systematically identify new genes that affect C. elegans lifespan. My analyses point to mitochondrial oxidative phosphorylation as a major determinant of C. elegans lifespan and, additionally, identify over 100 new candidate longevity genes that previously have not been implicated in C. elegans lifespan. This proposal aims to develop each of these results. In C. elegans, mitochondria affect lifespan by acting in the same genetic pathway as caloric restriction, the only intervention known to extend lifespan from yeast to mammals. Thus, molecular dissection of how mitochondrial respiration affects lifespan may provide important insights into how nutrient usage and energy metabolism influence longevity across phylogeny. To understand the mechanism whereby mitochondrial respiration affects C. elegans longevity, I propose, in aim 1, to determine the cell(s)/tissue(s) in which mitochondria act to influence lifespan, and to investigate the physiological trigger that relates respiration to lifespan. In aim 2, I propose to elucidate the downstream signaling events that may mediate the longevity effect of mitochondrial respiration. As a first step to characterize the large number of additional new longevity genes I identified, I propose, in aim 3, to assign the candidate longevity genes to specific genetic pathways, and to examine how each candidate gene affects the onset and/or progression of aging features in C. elegans. Many of these new candidate longevity genes have mammalian homologs, and their molecular characterization will likely provide significant insights into the molecular underpinnings of organismal aging, and may have important implications for age-related human diseases.

描述（由申请人提供）：人们对如何确定生物体寿命知之甚少。先前对秀丽隐杆线虫的研究已经确定了在进化多样化的物种中发挥作用的新的长寿控制机制。然而，对秀丽隐杆线虫寿命基因的分析还远远不够全面。我利用基因组和遗传技术的最新进展来系统地识别影响线虫寿命的新基因。我的分析指出，线粒体氧化磷酸化是线虫寿命的主要决定因素，此外，还确定了 100 多个新的候选长寿基因，这些基因以前并未与线虫寿命有关。该提案旨在发展这些成果中的每一项。在秀丽隐杆线虫中，线粒体通过与热量限制相同的遗传途径影响寿命，热量限制是已知的唯一可以延长从酵母到哺乳动物寿命的干预措施。因此，对线粒体呼吸如何影响寿命的分子剖析可能为了解营养利用和能量代谢如何影响整个系统发育的寿命提供重要见解。为了了解线粒体呼吸影响线虫寿命的机制，我建议在目标 1 中确定线粒体影响寿命的细胞/组织，并研究将呼吸与寿命联系起来的生理触发因素。在目标 2 中，我建议阐明可能介导线粒体呼吸长寿效应的下游信号传导事件。作为表征我发现的大量额外新长寿基因的第一步，我建议在目标 3 中将候选长寿基因分配给特定的遗传途径，并检查每个候选基因如何影响线虫衰老特征的发生和/或进展。许多新的候选长寿基因具有哺乳动物同源物，它们的分子特征可能会为机体衰老的分子基础提供重要的见解，并可能对与年龄相关的人类疾病产生重要影响。