Progressive anorexia and cachexia are common in elderly individuals and are major factors contributing to premature death and disability. The cytokine IL-1B is acknowledged to be involved in normal aging, but its role in this complex has been largely ignored because in the absence of infectious or autoimmune disease, plasma IL-1B does not correlate with anorexia and cachexia of aging. Most research concerning IL-1B has centered on its peripheral effects, but the investigator contends that any search for the true cause of anorexia and cachexia of aging should include the role of IL-1B in the brain. New data obtained in the investigator's laboratory show that IL-1B is 100- to 500-fold more effective for inducing weight loss and depressing motivation for food when administered into a lateral ventricle of the brain (icv) compared to in the periphery. Moreover, he has now shown that aged rodents lose substantially more body weight than mature adults following icv injection of recombinant IL-1B. The broad working hypothesis is that the anorexia and cachexia of aging are caused directly by IL-1B within the CNS. The proposed experiments will be conducted in mice because of the availability of recombinant murine cytokines, specific receptor antagonists, and ICE knockouts. They will assess the motivation of mice to eat as an in vivo readout for icv administration of recombinant murine IL-1B, as well as other features of cachexia including plasma urea nitrogen, serum triglycerides, weight loss and body composition. In their first objective, they will compare the anorectic and cachectic properties of IL-1B-injected icv in mature adult and aged mice. The PI will test the most critically important possibilities for CNS-controlled anorexia and cachexia, including effects of constant icv infusion of IL-1B and potential synergism between IL-1B and TNFa. For the hypothesis to be correct, salient features of the brain cytokine network must differ between aged and adult mice. Therefore, in the second objective he will employ cellular and molecular strategies to characterize ICE, IL-1B, and type I and type II IL-1 receptors in the brain of aged mice. Finally, in objective 3 the PI will explore alternative approaches for alleviating anorexia and cachexia caused by IL-1B in the CNS. Specifically, he will determine which IL-1 receptor isoform is responsible for inducing anorexia and cachexia in vivo and will test the new idea that ICE knockouts are refractory to the metabolic effects of inflammatory stimuli in the brain.
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