A metabolomic model of aging in the common marmoset

描述（由申请人提供）：研究人员通过对包括线虫、果蝇和小鼠在内的短寿动物模型的研究，在进一步了解衰老方面取得了巨大的成功。然而，对于这些模型如何很好地解释人类的衰老现象，我们的知识存在根本性的差距。这项工作的长期目标是开发一种相对寿命较短的灵长类动物，即普通狨猴（Callithrix jacchus），作为一个强大的模型，以更好地了解人类和非人类灵长类动物的衰老生物学。本应用程序的目的是研究狨猴复杂的代谢途径如何随着年龄的增长而变化，并确定这些变化如何影响长寿和虚弱。这项工作的中心假设是，协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，一种在多种物种中公认的延缓衰老的干预措施，将阻止或延缓这些代谢关系和途径的降解。这项研究的基本原理是，一旦我们确定了与狨猴衰老相关的代谢模块，我们就能很好地将狨猴作为一种杰出的衰老模型进一步发展，更重要的是，研究决定个体内部和个体之间衰老速率变化的近似分子因素。中心假设将通过追求三个具体目标来验证：1)对NEPRC常见狨猴群体进行纵向研究，以确定与寿命和衰老功能测量相关的代谢谱；2)验证并建立绒猴代谢组学衰老数据库；3)研究热量限制（CR）对狨猴代谢特征和年龄相关功能障碍的影响。这项工作具有创新性，因为它为衰老研究提供了一种新的动物模型，并为研究遗传变异群体的衰老机制提供了一种新的网络方法。此外，为这个项目创建的跨学科研究团队特别适合将这里提出的工作付诸实践。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、更长寿的模型系统更容易处理的灵长类动物衰老模型，它将引入一套强大的、概念新颖的、易于实现的网络分析工具来研究自然种群中衰老的潜在机制。最终，这一知识有可能增加对导致个体内部特征之间以及人群中个体之间衰老率变化的机制的理解。

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.