This Clinical Investigator Award application by Dr. Ronenn Roubenoff seeks to continue the study of human body composition he began under an NRSA Fellowship (DK08443). In acute illness, cancer, and starvation, loss of lean body mass (LBM) is a major determinant of survival, and loss of more that 40% of LBM is fatal. Loss of LBM is also one of the hallmarks of normal aging. The current research has shown that rheumatoid arthritis (RA), a common disease and a useful model of chronic inflammation, is associated with loss of a mean of 17% of LBM, despite apparently adequate dietary energy and protein intake. RA patients have elevated resting metabolic rates and decreased physical activity even when the disease is well-controlled. In addition, people with RA have a cytokine production profile that supports catabolism; a 7-fold increase in interleukin-1 (IL-1) and 3-fold increase in tumor necrosis factor (TNF) production by unstimulated peripheral blood mononuclear cells, and decreased cytokine production under stimulated conditions. TNF production correlates inversely with LBM, while no correlation is seen with IL-1. However, the normal independence of secretion of IL-1 and TNF seen in health is lost in RA, and IL-1 and TNF production become highly correlated. Given the known synergy between IL-1 and TNF in vivo, a cytokine milieu favoring catabolism may lead to loss of LBM in chronic inflammation. The accelerated loss of LBM in RA, coupled with the five- fold increase in mortality in this group, also raises the question of whether RA may serve as a model of pathologic or """"""""accelerated"""""""" aging, at least with regard to these parameters. This proposal further examines the hypotheses that 1) the known synergy between TNF and IL-1 creates a cytokine milieu that favors catabolism and leads to loss of LBM (now extending the observations to the mRNA level and include the cytokine antagonists IL-1 receptor antagonist and TNF binding protein); 2) that changes in hormone status may also exist in RA that influence LBM in a complex interplay between cytokines and endocrine hormones (growth hormone, insulin-like growth factor-1 androgens, cortisol, insulin); 3) that the link between these regulatory mechanisms and the outcome of loss of LBM is an alteration of nitrogen and energy metabolism (measured using 13C-leucine infusion); 4) that this metabolism can be altered by the physiologic stimulus of an exercise plus diet intervention; and 5) that exercise and diet can also alter the abnormal cytokine production seen in RA. Ten subjects with RA, 10 young controls, and 10 elderly controls will be recruited for these studies before and after a 12-week intervention. The close cooperation between the Human Nutrition Research Center at Tufts, with its expertise in body composition, diet, exercise and nutritional metabolism, and Tufts University School of Medicine, with expertise in cytokine and endocrine research, will combine to create the most favorable research environment for the candidate.
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