Flavin-containing monooxygenases in endogenous metabolism and aging

项目总结/摘要 饮食摄入/代谢与长期健康和疾病之间的联系首次建立近20年。 世纪前。饮食限制（DR），定义为热量摄入减少而不营养不良，仍然是 最有效和可重复的干预措施，以改善多个物种的健康和寿命。 不幸的是，长期DR相对未经测试，并且很难在人类中实施， 科学家们更好地定义DR改善健康的机制，以模拟其益处 该项目的重点是一个家庭的异生素代谢酶，黄素- 含有在DR下游诱导的单加氧酶或FMOs，最近报道 这两个都是必要的和足够的，以增加线虫C的健康，抗应激能力和寿命。优雅 有趣的是，先前的报道也显示了在哺乳动物系统中，在DR下FMO同源物的诱导， 其他已知能延长寿命的条件。不幸的是，这些影响的机制- 保守的FMO蛋白对健康和长寿的作用在很大程度上是未知的，因为它们在I期的主要作用是 异生物质解毒与观察到的对健康和寿命的影响没有明确的联系。该项目将 基于最近发表的初步数据，支持FMO酶在调节 内源代谢利用最近开发的工具，包括线虫的新食物来源， 更好地测量他们的新陈代谢和代谢组学为基础的技术，使用氧同位素， 该项目将确定FMO活性的机制和影响， 简单的线虫，秀丽隐杆线虫。初步数据清楚地确立了一碳代谢 (OCM)作为受FMO-2影响的关键中间代谢网络，以改善健康和延长寿命。 本项目产生的数据将提供以下证据：1）FMO-2的关键内源性靶点 以及它们如何与OCM连接，2）OCM通量如何被FMO-2表达和活性修饰，以及它们如何与OCM连接。 这可能通过外源性代谢物复制，以及3）OCM的下游机制是什么， 它们如何帮助我们理解压力反应和长寿之间的相互交织。确保 该项目的成功，所有的分析将由线虫生物学和老化方面的专家合作进行 代谢组学分析和数据分析的专家。由此产生的数据将为 FMO酶的代谢影响，然后可以在哺乳动物系统中进一步询问。此外，本发明还提供了一种方法， 由于关注的途径对多种年龄相关疾病很重要，它们可能导致 在利用或不利用FMO活性机制的情况下改善健康的方法。

Project Summary/Abstract The link between dietary intake/metabolism and long-term health and disease was first established nearly a century ago. Dietary restriction (DR), defined as a decrease in caloric intake without malnutrition, remains the most potent and reproducible intervention to improve health and longevity across multiple species. Unfortunately, long-term DR is both relatively untested and very difficult to implement in humans, leading scientists to better define the mechanisms through which DR improves health in an effort to mimic the benefits in the absence of true DR. This project focuses on a family of xenobiotic metabolizing enzymes, flavin- containing monooxygenases, or FMOs, that are induced downstream of DR and were recently reported to be both necessary and sufficient to increase health, stress resistance, and longevity in the nematode C. elegans. Interestingly, previous reports also show induction of FMO homologs in mammalian systems under DR and other conditions known to increase longevity. Unfortunately, the mechanism(s) for the effects of these well- conserved FMO proteins on health and longevity are largely unknown, as their primary role in phase I xenobiotic detoxification is not clearly linked to the observed effects on health and longevity. This project will build upon recently published and preliminary data that support a role for FMO enzymes in regulating endogenous metabolism. Utilizing recently developed tools, including a novel food source for nematodes to better measure their metabolism and a metabolomics based technique to use oxygen isotopes and identify substrates of oxygenases, this project will identify the mechanisms and implications for FMO activity within the simple nematode, Caenorhabditis elegans. The preliminary data clearly establish one-carbon metabolism (OCM) as the key intermediate metabolic network affected by FMO-2 to improve health and increase longevity. The data produced by this project will provide evidence as to 1) what the key endogenous target(s) of FMO-2 are and how they connect to OCM, 2) how OCM flux is modified by FMO-2 expression and activity and how this may be replicated through exogenous metabolites, and 3) what mechanisms are downstream of OCM and how they play into understanding the intertwined nature of stress response and longevity. To ensure the success of this project, all assays will be performed by experts in nematode biology and aging in collaboration with experts in metabolomics profiling and data analysis. The resulting data will provide a model for the metabolic impact of FMO enzymes that can then be further interrogated in mammalian systems. In addition, since the pathways focused on are important for multiple age-associated diseases, they may lead to approaches that improve health with or without exploiting the mechanism(s) of FMO activity.