Development Project 2

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d. SPECIFIC AIMS: Body composition and fat distribution, and the redistribution of fat with aging, are related to disability through increased risk of age-related diseases and impaired physical function. Non-invasive imaging of fat depots by computed tomography (CT) shows that the amount of fat in abnormal or ectopic locations, such as surrounding the visceral organs and within muscle, has adverse consequences on health and function. Beyond fat volume, our preliminary data indicate that adipose tissue density (as determined by CT signal attenuation) predicts mobility limitation and mortality, independent of total adiposity or fat location (see section f). However, unlike in skeletal muscle where CT attenuation is known to be indicative of greater triglyceride infiltration, virtually nothing is known regarding the nature and biologic basis of variation in CT attenuation in adipose tissue, providing us with an opportunity to explore this area using a reverse translational approach. We propose that higher fat density (e.g., higher CT attenuation) is due to a greater infiltration of inflammatory cells, which results in greater production of inflammatory mediators and, perhaps, reduced physical function. It is well known that fat depots are heterogenous in that they differ in metabolic function, as well as biochemical and cellular composition. There is location-specific variability in the number of stromal cells, preadipocytes, and inflammatory cells such as macrophages in fat. Much evidence suggests these depot-specific characteristics may contribute to age-related health problems; yet, the pathophysiological mechanisms by which different fat depots affect chronic disease and disability are not fully understood. Although it is possible to study molecular and metabolic characteristics of subcutaneous fat in humans, for obvious reasons, it is not feasible to invasively study deep subcutaneous, visceral, pericardial, or intra-muscular fat depots in humans. Thus, a reliable and valid animal model, with relevant application to changes in adiposity and associated health conditions with human aging, is needed to elucidate physiological and molecular differences between adipose tissue depots, factors underlying changes in fat distribution with age, and how these depot differences and fat distribution changes contribute to disabling chronic disease and declines in physical function with age. The overall goal of this Development Project is to incorporate and expand the use of the nonhuman primate resources at WFUSM for the study of human aging, especially for the study of regional adipose tissue characteristics and their link to aging-related health conditions. This will be done by testing specific hypotheses, both retrospectively (using stored specimens and bioimaging scans) and prospectively (using a longitudinal study), in cynomolgus monkeys as outlined below. The proposed studies will improve our understanding of the biologic basis of differential fat CT attenuation using this well-characterized nonhuman primate model of fat distribution and age-related disease, and will allow us to determine the nature and composition of adipose tissue at the histologic and molecular level as a complement to the imaging studies. Performing the in vitro and the imaging assessments of adipose tissue in tandem with inflammatory disease biomarkers and functional capacity will provide the necessary "proof-of-concept" data for establishing this animal as a research model with similarities to human aging for future use by OAIC investigators.