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

项目概要 衰老是影响所有生物体的随时间衰退的过程。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衰退和 人类疾病。线虫是研究衰老和许多基因的优秀模型系统 已确定可以延缓衰老的干预措施。例如，减少胰岛素/IGF1 或去除 生殖干细胞可显着延长雌雄同体的寿命。 寿命方面的性别差异在整个动物界都存在，包括人类。甚至 尽管线虫是一个成熟的衰老模型系统，但男性的寿命在很大程度上被忽视了，因为 用于雌雄同体的经典单一性别群体衰老实验大大缩短了男性的寿命。 单身雄性离开琼脂培养皿寻找伴侣，用雄性进行经典的衰老实验 技术上有困难。我们建议使用液体 96 孔衰老测定来测试男性对突变的反应 以及已知可以延长雌雄同体寿命的干预措施，以确定性别特异性差异 线虫的寿命调节，并描述这些差异如何以及在何处发生。到目前为止，我们发现 至少一种干预措施，即生殖系消融，会引起性别特异性反应：与 雌雄同体，雄性寿命在种系丧失后不会发生显着变化。确实，性别特定 据报道，雌雄同体寿命的许多重要下游调节因子存在差异 规定。例如，激素和胰岛素信号传导，以及蛔苷，产生的小分子 通过蠕虫，显示出性别特异性的特征。然而，这些信号尚未经过研究 对寿命的影响。在本提案中，我们的目标是首先根据已知的情况对男性寿命进行分类 改变雌雄同体寿命的干预措施，例如胰岛素信号、TOR 信号的突变， AMPK 信号传导、线粒体呼吸链成分和饮食等干预措施 限制和添加特定蛔苷。在我们的第二个目标中，我们将研究分子 观察到的性别差异背后的机制。例如，对于种系消融，我们将 研究生殖细胞干细胞损失后发生（或未发生）的代谢变化 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，在目标 3 中，我们将确定 使用特定组织中具有性反转的菌株来研究寿命中的性别特异性差异。此类研究将 帮助我们了解以特定性别方式影响生物体寿命的特定过程。 1