Metabolomics of Aging

描述（由申请人提供）：衰老是从酵母到人类的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。尽管美国联邦药物管理局没有将衰老定义为“需要治疗的病症”，但它是影响每个人的最普遍的与疾病相关的状态，人类的大多数疾病都可以归类为衰老疾病。在这方面，很少有生物医学目标比理解衰老更重要。长寿是遗传和环境因素共同作用的复杂过程的结果。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相关的疾病。近年来，代谢物谱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在生理和环境变化响应中的相互作用的定量分析。我们的研究兴趣是了解衰老过程中代谢物的动力学，特别是分子损伤的积累。拟议的研究将采用代谢物分析来测试衰老过程中“细胞损伤积累”的概念，表征它们的特性，并了解其潜在机制。尽管与年龄相关的损伤积累的概念并不新鲜，但该领域先前的进展受到技术的限制。我们所需要的是能够深入表征细胞成分的方法，从而检测出多种损伤形式。该技术在灵敏度和特异性方面的进步，使其能够从最少量的组织中分析超过15,000种化合物的变化。先进的技术，代谢物谱的敏感性，以及与Broad研究所代谢物谱主任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。我们将测试以下假设：代谢物随着年龄的变化而变化，它们可以通过先进的代谢物分析方法进行检测和分析，它们与年龄相关疾病的发展和已知延长寿命的治疗有关。为了解决这些问题，我们将在具有寿命差异的啮齿动物模型中表征代谢物，确定候选衰老标志物，确定其基本特性，并在长寿动物模型中表征它们。

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.