Genetic analysis of lifespan by insulin-like signaling

通过胰岛素样信号传导对寿命进行遗传分析

• 批准号: 7132246
• 负责人: Catherine A Wolkow
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7132246
• 关键词: Caenorhabditis elegans; RNA interference; biological signal transduction; cell component structure /function; developmental genetics; gene environment interaction; gene mutation; genetic regulation; genetic screening; genetically modified animals; helminth genetics; insulin receptor; longevity; mitochondria

Lifespan in the nematode, Caenorhabditis elegans, is determined by genetic pathways and by environmental conditions. One of the most dramatic genetic effects on longevity is observed in animals with mutations inactivating the nematode's insulin-like signaling pathway. In particular, defects in the DAF-2/insulin-like pathway can triple the adult lifespan. Previous studies showed that DAF-2/insulin signaling affects lifespan non-cell autonomously from different cells in the body. Using a transgenic approach, we have found that cells throughout the nervous system have the capability of promoting normal lifespan through the DAF-2/insulin pathway. This finding suggests that a DAF-2/insulin signaling produces a diffusible signal that coordinates aging in the body. We are currently conducting genetic screens, using RNA-interference, to identify genes involved in the production and reception of this diffusible signal. A second focus of this work is to study how DAF-2/insulin signaling affects metabolism in C. elegans. In humans, insulin is an important controller of metabolism and health, as cellular insulin resistance is a hallmark of type II diabetes. Therefore, we are working to identify how the DAF-2 pathway interacts with known metabolic control pathways, including the TOR kinase pathway that senses nutrient availability. These studies may reveal ways to modify cellular insulin sensitivity. In addition, we are characterizing how mitochondrial function is altered in animals with defective DAF-2/insulin signaling. Ultimately, we hope to understand the metabolic changes that promote long lifespan in daf-2 pathway mutants.

线虫的寿命由遗传途径和环境条件决定。对寿命最显著的遗传效应之一是在动物中观察到的，这些动物的突变使线虫的胰岛素样信号通路失活。特别是，β 2/胰岛素样途径的缺陷可以使成年人的寿命延长三倍。以前的研究表明，β 2/胰岛素信号传导影响寿命非细胞自主从不同的细胞在体内。使用转基因方法，我们发现整个神经系统的细胞具有通过β 2/胰岛素途径促进正常寿命的能力。这一发现表明，β 2/胰岛素信号传导产生了一种可扩散的信号，协调体内的衰老。我们目前正在进行基因筛选，使用RNA干扰，以确定参与生产和接收这种可扩散信号的基因。 这项工作的第二个重点是研究β 2/胰岛素信号传导如何影响C.优美的在人类中，胰岛素是代谢和健康的重要控制器，因为细胞胰岛素抵抗是II型糖尿病的标志。因此，我们正在努力确定β 2途径如何与已知的代谢控制途径相互作用，包括感知营养可用性的TOR激酶途径。这些研究可能揭示改变细胞胰岛素敏感性的方法。此外，我们正在研究线粒体功能如何在有缺陷的β 2/胰岛素信号传导的动物中改变。最终，我们希望了解促进daf-2通路突变体长寿的代谢变化。