Metabolomics of Aging

衰老代谢组学

• 批准号: 8744299
• 负责人: Sun Hee Yim
• 金额: $ 16.22万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744299
• 关键词: Address; Affect; Age; Age-Months; Aging; Aging-Related Process; Animal Model; Animals; Area; Basic Science; Biological; Biological Process; Body Fluids; Brain; Caloric Restriction; Cell Culture System; Cell Line; Cells; Chemicals; Clinical; Clinical Research; Collaborations; Complex; Data; Development; Disease; Embryo; Environment; Environmental Risk Factor; Fibroblasts; Gene Expression Profile; Genes; Genetic; Genome; Genomics; Goals; Human; Institutes; Kidney; Life; Liver; Longevity; Lung; Mammals; Maps; Marker Discovery; Metabolic; Metabolic Pathway; Methods; Mole Rats; Molecular; Molecular Biology; Mus; Muscle; Organism; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Post-Translational Protein Processing; Process; Property; Proteome; Proteomics; Quality of life; Reporter; Research; Rodent; Rodent Model; Sampling; Sensitivity and Specificity; Serum; Sirolimus; Stress; System; Techniques; Technology; Testing; Tissues; Transcriptional Regulation; Urine; Whole Organism; Yeasts; age group; age related; animal tissue; candidate marker; computerized tools; environmental change; human disease; improved; in vivo; interest; loss of function; metabolomics; mouse model; public health relevance; response; signature molecule; small molecule; tool; transcriptomics

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.

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学过程。众所周知，较大的动物寿命更长，并且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“需要治疗的疾病”，但它是影响每个人的最普遍的疾病相关状态，并且大多数人类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像了解衰老一样重要。长寿是一个复杂过程的结果，遗传和环境因素都有影响。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，代谢物谱分析被用来研究代谢通量的动态变化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，以响应生理和环境变化。我们的研究兴趣是了解衰老过程中代谢物的动态，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“细胞损伤累积”的概念，表征其身份，并了解其潜在机制。虽然与年龄相关的损伤累积的概念并不新鲜，但该领域以前的进展受到技术的限制。所需要的是在表征细胞成分方面足够深入的方法，从而检测多种损伤形式。该技术的灵敏度和特异性的进步使得从最少量的组织中分析超过15，000种化合物的变化成为可能。先进的技术、代谢产物谱的灵敏度以及与布罗德研究所代谢产物谱主任Clary Clish博士的合作，将使我们能够测试以前无法解决的问题。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。我们将测试以下假设：存在作为年龄的函数而变化的代谢物，它们可以通过高级代谢物分析方法检测和分析，并且它们与年龄相关疾病的发展和已知延长寿命的治疗相关。为了解决这些问题，我们将在以寿命差异为特征的啮齿动物模型中表征代谢物，确定衰老的候选标志物，确定其基本特性，并在长寿动物模型中表征它们。