Metabolomics of Aging

项目摘要 衰老是从酵母菌到人类的一个普遍而基本的生物过程。众所周知，体型较大的动物 寿命更长，衰老过程和代谢率之间存在关联。即使 衰老并没有被美国联邦药品管理局定义为一种需要治疗的疾病，它是最 影响每个人的与疾病相关的流行状态，人类的大多数疾病可能是 被归类为老年病。在这方面，很少有生物医学目标像 对衰老的理解。长寿是复杂过程的结果，这两种基因都有贡献 以及环境因素。基因组学、转录学和蛋白质组学研究工具已被应用于 了解衰老和与年龄相关的疾病。最近，代谢物图谱被用来研究 代谢流的动态以及遗传和环境因素之间的相互作用。代谢物图谱 提供对众多内源性小分子及其相互作用的定量分析 生理和环境的变化。我们的研究兴趣是了解 老化过程中的代谢物，尤其是分子损伤的积累。建议数 这项研究将使用代谢物图谱来测试在 老化，确定他们的身份，并了解潜在的机制。虽然这一概念 与年龄相关的损害积累并不新鲜，这一领域以前的进展受到以下因素的限制 技术我们需要的是足够深入地表征细胞成分的方法， 从而检测到大量的损坏形式。这项技术的灵敏度和特异度的进步使其 有可能分析来自最少量组织的15,000多种化合物的变化。进阶 技术、代谢物图谱的敏感性以及与代谢物总监Clary Clish博士的合作 布罗德研究所的分析，将使我们能够测试以前无法解决的问题。vbl.使用 这种快速发展的方法，我们建议推进代谢组学领域的衰老。我们将接受考验 假设存在随年龄变化的代谢物，它们可以被检测到，并 通过先进的代谢物分析方法进行分析，它们与年龄的发展相关- 已知可延长寿命的相关疾病和治疗方法。为了解决这些问题，我们将描述 以寿命差异为特征的啮齿动物模型中的代谢物，识别衰老的候选标记物， 确定它们的基本性质，并在长寿动物模型中描述它们的特征。

Project Summary Aging is a universal and fundamental biological process from yeast to humans. It is known that larger animals live longer and that there is an association between the aging process and the metabolic rate. Even though aging is not defined as a "condition to be treated" by the US Federal Drug Administration, it is the most prevalent disease-related state that affects every human being, and the majority of human diseases can be classified as the diseases of aging. In this regard, there are few biomedical goals as important as the understanding of aging. Longevity is a consequence of complex processes with contributions from both genetic and environmental factors. Genomic, transcriptomic, and proteomic research tools have been applied to understand aging and age-related diseases. Recently, metabolite profiling has been employed to investigate the dynamics of metabolic flux and interaction between genetic and environmental factors. Metabolite profiling offers the quantitative analysis of numerous endogenous small molecules and their interactions in response to physiological and environmental changes. Our research interests are in understanding dynamics of metabolites during the aging process, especially accumulation of molecular damage. The proposed study will employ metabolite profiling to test the concepts of 'cellular damage accumulation' during aging, characterize their identity, and understand the underlying mechanisms. Although the concept of age-associated damage accumulation is not new, previous advances in this area have been limited by technology. What were needed are methods that go to sufficient depth in characterizing cellular components, whereby detecting numerous damage forms. Advances in sensitivity and specificity of this technology made it possible to analyze changes in more than 15,000 compounds from minimal amounts of tissues. Advanced technology, sensitivity of metabolite profiles and collaboration with Dr. Clary Clish, Director of Metabolite Profiling at the Broad Institute, will allow us to test questions which could not be addressed previously. Using this rapidly developing approach, we propose to advance the area of metabolomics of aging. We will be test the hypotheses that there are metabolites that change as a function of age, that they can be detected and analyzed by advanced metabolite profiling methods, and that they correlate with the development of age- related disease and treatments known to extend lifespan. To address these questions, we will characterize metabolites in rodent models characterized by differences in lifespan, identify candidate markers of aging, determine their basic properties, and characterize them in long-lived animal models.