Metabolomics of Aging

项目摘要 衰老是从酵母到人类的普遍和基本的生物学过程。众所周知，大型动物 寿命更长，并且衰老过程和代谢率之间存在关联。即使 美国联邦药物管理局并没有将衰老定义为“需要治疗的疾病”， 流行疾病相关的状态，影响到每一个人，大多数人类疾病可以是 被归类为衰老性疾病。在这方面，很少有生物医学目标像 理解衰老。长寿是一个复杂过程的结果，遗传因素和 和环境因素。基因组学、转录组学和蛋白质组学研究工具已被应用于 了解衰老和与年龄有关的疾病。最近，代谢物谱分析已被用于研究 代谢通量的动态以及遗传和环境因素之间的相互作用。代谢物分析 提供了许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 衰老过程中代谢产物的积累，尤其是分子损伤。拟议 研究将采用代谢物分析来测试“细胞损伤累积”的概念， 老化，表征他们的身份，并了解潜在的机制。的概念虽然 与年龄相关的损伤累积并不是新的，以前在这一领域的进展受到以下因素的限制： 技术.我们需要的是在表征细胞成分方面足够深入的方法， 从而检测多种损坏形式。该技术的灵敏度和特异性的进步使其 可以从最少量的组织中分析超过15，000种化合物的变化。先进 技术、代谢产物谱的灵敏度以及与代谢产物总监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。使用 这种快速发展的方法，我们建议推进衰老代谢组学领域。我们将受到考验 假设存在随着年龄而变化的代谢物，它们可以被检测到， 通过先进的代谢物分析方法进行分析，并且它们与年龄的发展相关， 相关疾病和治疗已知延长寿命。为了解决这些问题，我们将描述 代谢物在以寿命差异为特征的啮齿动物模型中，鉴定衰老的候选标志物， 确定它们的基本特性，并在长寿动物模型中对其进行表征。

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.