Flavin-containing monooxygenases in endogenous metabolism and aging

项目摘要/摘要 饮食摄取/新陈代谢与长期健康和疾病之间的联系首次被证实是近一年来 一百年前。饮食限制(DR)，定义为减少卡路里摄入量，而不是营养不良，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既相对未经测试，也很难在人类身上实施，因此领先 科学家更好地定义DR改善健康的机制，以努力模仿其益处 在没有真正的博士的情况下，这个项目专注于一种外源代谢酶家族，黄素- 含有DR下游诱导的单加氧酶，或FMO，最近有报道称 对提高线虫的健康、抗逆性和寿命来说是必要的和充分的。 有趣的是，以前的报告也显示了在DR和DR的作用下，哺乳动物系统中FMO同源物的诱导 其他已知的可以延长寿命的条件。不幸的是，这些油井影响的机制(S)- 保守的FMO蛋白对健康和长寿的影响在很大程度上是未知的，因为它们在I期中起主要作用 异种生物解毒与观察到的对健康和长寿的影响没有明显的联系。这个项目将 以最近发表的初步数据为基础，这些数据支持FMO酶在调节 内源性代谢。利用最近开发的工具，包括一种新的线虫食物来源 更好地测量它们的新陈代谢和基于代谢组学的技术，以使用氧同位素并识别 对于加氧酶的底物，这个项目将确定FMO活性的机制和影响 简单的线虫，秀丽线虫。初步数据清楚地建立了一碳代谢 (OCM)作为FMO-2影响的关键中间代谢网络，改善健康和延长寿命。 本项目产生的数据将为以下方面提供证据：1)FMO-2的关键内源性靶点(S)是什么 是什么以及它们如何连接到OCM；2)FMO-2的表达和活性如何改变OCM通量以及如何 这可以通过外源代谢物复制，以及3)OCM下游和 它们如何在理解压力反应和寿命的相互交织的本质中发挥作用。为了确保 这个项目的成功，所有的化验都将由线虫生物学和衰老方面的专家合作进行 与新陈代谢组学和数据分析方面的专家合作。生成的数据将为 FMO酶的代谢影响，然后可以在哺乳动物系统中进一步研究。此外, 由于所关注的通路对多种与年龄相关的疾病很重要，它们可能导致 无论是否利用FMO活动的机制来改善健康的方法(S)。

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.