Aging is associated with a decline in immunological vigor which can contribute to the development of age-associated diseases. We have shown that macrophages from old mice and humans synthesize more prostaglandin (PG)E2 (which has a suppressive effect on T cell-mediated immunity) than young mice and humans. Furthermore, vitamin E (E) supplementation decreases PGE2 production and enhances interleukin (IL)-2 production, lymphocyte proliferation (LP), and the delayed-type hypersensitivity skin test in aged mice and humans. We have also shown that in addition to the cyclooxygenase (COX) product (PGE2), production of 5-lipoxygenase (LO) products [leukotriene (LT)B4 and LTC4)] increase with age. However, only in vitro inhibition of PGE2 enhances LP in old mice. Thus, we have concluded that, of the arachidonic acid metabolites, the age associated increase in PGE2 contributes to the decline of T cell-mediated function with age. The molecular basis for increased production of PGE2 and the exact nature of the immuno-stimulatory effect of E or its biological significance in the aged has not been determined. It is proposed that: the age-associated increase in PGE, production is due to an increase in the level and/or activity of COX and that E supplementation decreases PGE2 production in macrophage from old mice by decreasing COX level and/or activity. This will be tested by comparing the activity, mRNA and protein level for constitutive and mitogen-induced COX in macrophage from young and old mice as well as from old mice fed 30 or 500 ppm E. It is further proposed that the increase in macrophage production of PGE, contributes to the age-associated decline in IL-2 production and LP and that E enhances IL-2 production and LP in old mice by decreasing macrophage-mediated suppression (mainly production of PGE2). This will be tested by coculturing macrophage and splenic T cells from young and old mice fed 30 ppm E or old mice fed 30 and 500 ppm E in the presence or absence of specific inhibitors and metabolites and measuring LP, PGE2, H202 IL-2 and IL-4 production. The biological significance of the immuno-stimulatory effect of E will be determined by investigating the effect of E supplementation on influenza virus infection. Through these studies we will determine: I) the molecular basis for the age-associated increase in PGE2 production and its decrease by E, 2) the contribution of PGE2 to the age-associated decrease in mitogenic response, and 3) the mechanism and the biological significance of the immunostimulatory effect of E in aged mice. This information should in turn help in designing practical dietary interventions to reverse and/or delay the age-associated decline of the immune response.
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