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，通过研究短的，我们对衰老的理解 活的动物模型，包括线虫、果蝇和老鼠。然而，在以下方面存在着根本的差距 我们对这些模型能够很好地解释人类衰老现象的了解。中国的长期目标是 这里提出的工作是培育一种相对短暂的灵长类动物，普通的绒猴(Callithrix Jacchus)， 作为一个强大的模型，更好地理解人类和非人类灵长类动物的衰老生物学。这个 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， 并确定这些变化如何有助于长寿和虚弱。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老年人衰老的干预措施 物种的多样性，将防止或延缓这些代谢关系和途径的退化。这个 这项拟议研究的基本原理是，一旦我们确定了与衰老相关的代谢模块 在绒猴方面，我们将处于有利地位，进一步将绒猴发展为杰出的老化模式， 重要的是，研究决定衰老速度变化的最接近的分子因素 在个人之间。中心假设将通过追求三个具体目标来检验：1)执行 对NEPRC常见绒猴群体的纵向研究以确定与其相关的代谢谱 寿命和衰老的功能指标；2)验证和策划恒河猴代谢组学的衰老 数据库；以及3)检查卡路里限制(CR)对代谢特征和年龄的影响 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，以及一种研究遗传变量衰老机制的新网络方法 人口。此外，为该项目创建的跨学科研究团队特别适合于 让这里提出的工作取得成果。这里提出的工作意义重大，因为它将提供 更广泛的研究社区，拥有比现有的、更长寿的灵长类衰老模型更容易处理的 系统模型，它将引入一组功能强大、概念新颖且易于实现的网络 研究自然人口老龄化的潜在机制的分析工具。归根结底，这种知识 有可能增加对导致老年人衰老速度差异的机制的理解 在人类群体中，个体内部、个体之间的特征。

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.