A metabolomic model of aging in the common marmoset

描述(申请人提供)：研究人员通过研究短寿命的动物模型，包括线虫、果蝇和老鼠，在加深我们对衰老的理解方面取得了巨大的成功。然而，对于这些模型能否很好地解释人类的衰老现象，我们的知识存在一个根本性的缺口。这里提出的这项工作的长期目标是开发一种相对短暂的灵长类动物--常见的绒猴(Callithrix Jacchus)，作为更好地了解人类和非人类灵长类动物衰老生物学的强大模型。这项应用的目的是研究复杂的代谢途径如何随着年龄的变化而变化，并确定这些变化是如何导致寿命和虚弱的。这项工作的中心假设是，共同调节的代谢模块的破坏将随着年龄的增长而进展，并将预测与年龄相关的功能障碍和生存。此外，饮食限制是一种公认的延缓各种物种衰老的干预措施，它将防止或延缓这些代谢关系和途径的退化。这项拟议研究的基本原理是，一旦我们确定了与绒猴衰老有关的代谢模块，我们将处于有利地位，进一步将绒猴发展为杰出的衰老模型，重要的是，我们将研究决定个体内和个体之间衰老速度差异的最接近的分子因素。中心假设将通过追求三个具体目标来验证：1)对NEPRC普通绒猴群体进行纵向研究，以确定与寿命和衰老功能指标相关的代谢谱；2)验证和管理绒猴代谢组学衰老数据库；以及3)检查热量限制(CR)对绒猴代谢谱和年龄相关功能障碍的影响。这里提出的工作具有创新性，因为它为衰老研究开发了一种新的动物模型，并开发了一种新的网络方法来研究遗传变量人群中的衰老机制。此外，为该项目创建的跨学科研究小组特别适合将这里提出的工作付诸实施。这里提出的工作意义重大，因为它将为更广泛的研究界提供一个比现有的更长寿命的模型系统更容易处理的灵长类衰老模型，并将引入一套强大的、概念新颖且易于实现的网络分析工具来研究自然人口老龄化的潜在机制。归根结底，这一知识有可能增加对导致个体内部、个体之间和人类群体中不同性状衰老速度差异的机制的理解。 公共卫生相关性：该项目旨在开发一种寿命相对较短的灵长类动物--常见的绒猴，作为一种新的模型，以更好地了解人类和灵长类动物衰老的生物学。这项研究将使用详细的化学和基于计算机的分析来分析身体的调节和功能如何随着年龄的变化而变化。所获得的知识有可能解释个体内衰老特征差异的原因，也可能解释人类种群中个体之间衰老的差异。

DESCRIPTION (provided by applicant): Researchers have had enormous success in furthering our understanding of aging through the study of short- lived animal models, including nematode worms, fruit flies, and mice. However, there is a fundamental gap in our knowledge of how well these models can explain aging phenomena in humans. The long-term goal of the work proposed here is to develop a relatively short-lived primate, the common marmoset (Callithrix jacchus), as a powerful model to better understand the biology of aging in humans and non-human primates. The objective of this application is to examine how complex metabolic pathways change with age in marmosets, and to determine how these alterations contribute to longevity and frailty. The central hypothesis of this work is that disruption of co-regulated metabolic modules will progress with aging and will predict age-associated dysfunction and survival. Moreover, dietary restriction, a well-established intervention to delay aging in a variety of species, will prevent or delay degradation of these metabolic relationships and pathways. The rationale for the proposed research is that once we identify metabolic modules that are associated with aging in marmosets, we will be well-positioned to further develop the marmoset as an outstanding aging model and, importantly, to study the proximate molecular factors that determine variation in rates of aging both within and among individuals. The central hypothesis will be tested by pursuing three specific aims: 1) to perform a longitudinal study on the NEPRC common marmoset colony to identify metabolic profiles associated with longevity and functional measures of aging; 2) to validate and curate a marmoset metabolomics aging database; and 3) to examine effects of caloric restriction (CR) on metabolic profiles and age-associated dysfunction in marmosets. The work proposed here is innovative, because it develops a novel animal model for aging research, and a novel network approach to study mechanisms of aging in genetically variable populations. Moreover, the interdisciplinary research team created for this project is particularly well suited to bring the work proposed here to fruition. The work proposed here is significant because it will provide the broader research community with a primate model of aging that is more tractable than the existing, longer-lived model systems, and it will introduce a powerful, conceptually novel and easily implemented set of network analysis tools to study the underlying mechanisms of aging in natural populations. Ultimately, this knowledge has the potential to increase understanding of the mechanisms that cause variation in rates of aging among traits within individuals, and among individuals, in human populations. PUBLIC HEALTH RELEVANCE: This project is to develop a relatively short-lived primate, the common marmoset, as a new model to better understand the biology of aging in humans and primates. The study will use detailed chemical and computer- based analyses to analyze how the regulation and function of the body changes with age. The acquired knowledge has the potential to explain causes of variation in traits of aging within individuals and also differences in aging among individuals in human populations.