A metabolomic model of aging in the common marmoset

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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.