Metabolomics of Aging

描述(申请人提供)：衰老是从酵母到人类的一个普遍和基本的生物过程。众所周知，体型较大的动物寿命更长，衰老过程与代谢率之间存在关联。尽管美国联邦药品监督管理局并未将衰老定义为一种需要治疗的疾病，但它是影响每个人的最普遍的疾病相关状态，人类的大多数疾病都可以归类为老年病。在这方面，很少有生物医学目标像了解衰老那样重要。长寿是复杂过程的结果，遗传因素和环境因素都有影响。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力学以及遗传和环境因素之间的相互作用。代谢物图谱提供了对众多内源性小分子及其相互作用的定量分析，以响应生理和环境的变化。我们的研究兴趣在于了解衰老过程中代谢产物的动态变化，特别是分子损伤的积累。这项拟议的研究将使用代谢物图谱来测试衰老过程中“细胞损伤积累”的概念，确定它们的特征，并了解其潜在的机制。尽管与年龄相关的损害累积的概念并不新鲜，但这一领域以前的进展受到技术的限制。我们需要的是足够深入的方法来表征细胞成分，从而检测出大量的损伤形式。这项技术在灵敏度和特异度方面的进步使分析来自最少量组织的15,000多种化合物的变化成为可能。先进的技术、代谢物图谱的敏感性以及与布罗德研究所代谢物图谱主任Clary Clish博士的合作，将使我们能够测试以前无法解决的问题。利用这一快速发展的方法，我们建议推进衰老代谢组学领域的研究。我们将测试这些假设，即存在随年龄变化的代谢物，它们可以通过先进的代谢物图谱方法进行检测和分析，并且它们与年龄相关疾病的发展和已知的延长寿命的治疗方法相关。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，确定衰老的候选标记物，确定其基本性质，并在长寿动物模型中对其进行表征。

DESCRIPTION (provided by applicant): 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 coul 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.