Sex-specific regulation of lifespan and metabolism in C. elegans

线虫寿命和代谢的性别特异性调节

• 批准号: 10442410
• 负责人: Veerle Rottiers
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442410
• 关键词: Ablation; Acids; Address; Affect; Agar; Age; Aging; Animal Model; Animals; Behavior; Behavioral; Biological Assay; Biological Models; Caenorhabditis elegans; Catalogs; Data; Disease; Eating; Enzymes; Excision; Family; Food; Gender; Genes; Hermaphroditism; High Pressure Liquid Chromatography; Histones; Hormonal; Human; IGF1 gene; Insulin; Intervention; Intestines; Lead; Light; Lipids; Liquid substance; Literature; Longevity; Measures; Metabolic; Metabolism; MicroRNAs; Mitochondria; Molecular; Mutation; NMR Spectroscopy; Nature; Nervous system structure; Nuclear Hormone Receptors; Organism; Output; Paper; Partner in relationship; Pathway interactions; Phenotype; Prevention; Prevention strategy; Process; Protein Biosynthesis; Regulation; Reporting; Research; Respiratory Chain; Series; Sex Differences; Signal Pathway; Signal Transduction; Societies; Subcutaneous Tissue; Testing; Time; Tissues; age related; dietary restriction; experimental study; germline stem cells; hormonal signals; insulin signaling; male; mitochondrial dysfunction; mutant; neglect; prevent; programs; proteostasis; response; sex; sex determination; small molecule; stem cells; tool; transcription factor; transcriptome sequencing

Project summary Aging is the process of decline over time that affects all organisms. Understanding the mechanisms behind the aging process in model systems could ultimately lead to the prevention of age-related decline and disease in humans. C. elegans is an excellent model system to study aging and many genes and interventions have been identified that delay aging. For instance, reduction of insulin/IGF1 or removal of the germline stem cells robustly increases hermaphrodite lifespan. Sex specific differences in longevity are seen throughout the animal kingdom, including in humans. Even though C. elegans is an established aging model system, male lifespan has been largely neglected, since classic single sex group aging experiments used for hermaphrodites dramatically shorten male lifespan. Single males leave the agar dishes in search of mates making classic aging experiments with males technically difficult. Using a liquid 96-well aging assay, we propose to test how males respond to mutations and interventions that are known to extend hermaphrodite lifespan to identify sex-specific differences in lifespan regulation in C. elegans and characterize how and where these differences occur. So far, we found at least one intervention, ablation of the germline, elicits a sex specific response: in contrast to hermaphrodites, male lifespan does not change significantly upon germline loss. Indeed, sex specific differences are reported for many of the important downstream regulators of hermaphrodite lifespan regulation. For instance, hormone and insulin signaling, as well as ascarosides, small molecules produced by the worms, show sex-specific profiles. However, these signals have not been studied in regard to the effect on lifespan. In this proposal, we aim to first catalog the male lifespan in response to known hermaphrodite lifespan changing interventions such as mutations in insulin signaling, TOR signaling, AMPK signaling, and mitochondrial respiratory chain components and interventions such as dietary restriction and addition of specific ascarosides. In our second aim, we will investigate the molecular mechanisms behind the observed sex-specific differences. For example, for germline ablation, we will investigate the metabolic changes that occur (or fail to occur) upon germ cell stem cell loss in hermaphrodites and males using NMR spectroscopy and HPLC-MS to identify the signal from the germline stem cells that regulates longevity. Finally, in Aim 3, we will determine the nature and tissue localization of the sex-specific differences in lifespan using strains with sex reversal in specific tissues. Such research will help us understand specific processes affect the lifespan of organisms in a sex specific manner. 1

项目摘要 衰老是随着时间的流逝而下降的过程，会影响所有生物体。了解背后的机制 模型系统中的衰老过程最终可能导致预防与年龄相关的下降和 人类疾病。秀丽隐杆线虫是研究衰老和许多基因的出色模型系统， 已经确定了干预措施延迟衰老。例如，减少胰岛素/IGF1或去除 种系干细胞强烈增加雌雄同体的寿命。 在整个动物界，包括人类，都可以看到性别特定的寿命差异。甚至 尽管秀丽隐杆线虫是一种已建立的衰老模型系统，但男性的寿命已被大大忽视，因为 用于雌雄同体的经典单性别衰老实验大幅缩短了男性寿命。 单身男性离开琼脂菜，寻找与男性进行经典衰老实验的伴侣 在技​​术上困难。使用液体96孔老化测定法，我们建议测试男性对突变的反应 以及已知延长雌雄同体寿命的干预措施以识别性别特定的差异 秀丽隐杆线虫中的寿命调节，并表征了这些差异的发生方式和何处。到目前为止，我们发现 至少一种干预措施，消融种系，引起性别反应：相反 雌雄同体的雌雄同体随着种系损失而不会发生显着变化。确实，性别特定 报告了许多重要的雌雄同体寿命的重要下游调节剂的差异 规定。例如，激素和胰岛素信号传导以及垃圾抛物剂，产生的小分子 通过蠕虫，显示针对性别的特征。但是，这些信号尚未研究 对寿命的影响。在此提案中，我们的目标是首先针对已知的男性寿命分类 雌雄同体的寿命改变干预措施，例如胰岛素信号传导中的突变，TOR信号传导， AMPK信号传导以及线粒体呼吸链成分和饮食等干预措施 限制和添加特定的垃圾酰化。在我们的第二个目标中，我们将研究分子 观察到的性别特异性差异背后的机制。例如，对于种系消融，我们将 研究在生殖细胞干细胞损失时发生的代谢变化（或不发生） 使用NMR光谱和HPLC-MS识别来自种系的信号的雌雄同体和雄性 调节寿命的干细胞。最后，在AIM 3中，我们将确定 使用特定组织中的性逆转菌株在寿命上的性别特异性差异。这样的研究将会 帮助我们了解特定的特定方式影响生物的寿命。 1