Increased systemic level of inflammatory cytokines leads to numerous age-related diseases. In senescent macrophages, elevated prostaglandin E2 (PGE2) production contributes to the suppression of T cell function with aging, which increases the susceptibility to infections. However, the regulation of these inflammatory cytokines and PGE2 with aging still remains unclear. We have verified that cyclooxygenase (COX)-2 expression and PGE2 production are higher in LPS-stimulated macrophages from old mice than that from young mice. Downregulation of RXR alpha, a nuclear receptor that can suppress NF-kappa B activity, mediates the elevation of COX2 expression and PGE2 production in senescent macrophages. We also have found less induction of ABCA1 and ABCG1 by RXR alpha agonist in senescent macrophages, which partially accounts for high risk of atherosclerosis in aged population. Systemic treatment with RXR alpha antagonist HX531 in young mice increases COX2, TNF-alpha, and IL-6 expression in splenocytes. Our study not only has outlined a mechanism of elevated NF-kappa B activity and PGE2 production in senescent macrophages, but also provides RXR alpha as a potential therapeutic target for treating the age-related diseases. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.