A metabolomic model of aging in the common marmoset

摘要： 研究人员已经取得了巨大的成功，通过研究短- 活体动物模型，包括蠕虫、果蝇和小鼠。然而，在这方面存在着根本性的差距。 我们对这些模型如何解释人类衰老现象的了解。的长期目标 这里提出的工作是开发一种寿命相对较短的灵长类动物，普通的绒猴（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衰老的生物学。的 本申请的目的是研究绒猴中复杂的代谢途径如何随年龄变化， 并确定这些改变如何导致长寿和虚弱。这项工作的核心假设是 共同调节的代谢模块的破坏将随着衰老而进展，并将预测与年龄相关的 功能障碍和生存。此外，饮食限制，一个成熟的干预措施，以延缓衰老， 不同物种的代谢产物将阻止或延迟这些代谢关系和途径的降解。的 这项研究的基本原理是，一旦我们确定了与衰老有关的代谢模块， 在绒猴中，我们将处于有利地位，以进一步发展绒猴作为一个杰出的老化模型， 重要的是，研究决定衰老速度变化的最接近的分子因素， 在个体之间。中心假设将通过追求三个具体目标来检验：1）执行一个 NEPRC普通绒猴群的纵向研究，以确定与 寿命和衰老的功能措施; 2）验证和策划一个绒猴代谢组学衰老 数据库; 3）检查热量限制（CR）对代谢谱和年龄相关性的影响 绒猴的功能障碍这里提出的工作是创新的，因为它开发了一种新的动物模型， 衰老研究，以及一种新的网络方法来研究遗传变量中的衰老机制， 人口数量。此外，为该项目创建的跨学科研究团队特别适合于 使在此提出的工作取得成果。这里提出的工作是重要的，因为它将提供 更广泛的研究社区与灵长类动物的老化模型，更容易处理比现有的，更长寿的 模型系统，它将介绍一个功能强大，概念新颖，易于实现的网络集 分析工具来研究自然人群中衰老的潜在机制。最终，这些知识 有可能增加对导致衰老率变化的机制的理解， 在个体内部，个体之间，在人群中。

Abstract: 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.