Dysregulation of cytokine production with aging

Aging represents a clinical situation in which there is a decline in many physiological functions. The focus of this work centers around changes within the immune system. Fidelity of the immune system is known to depend upon the proper functioning of a subtle and well-balanced network of cytokines that control the survival, proliferation, and differentiation of lymphocytes and other lymphoid cells. T cells, B cells, and macrophage cell populations from aged individuals have been shown to demonstrate alterations in the inducibility and production of certain cytokine species. The work contained within this dissertation demonstrates a dysregulation in the production of interleukin (IL-10) by B cells and IL-12 by macrophages in aged mice. These cytokines, based on their pleiotropic activities, might be contributing significantly to the aging phenotype. Furthermore, experiments contained within these chapters provide evidence, for the first time, that macrophages appear to be the cell type primarily responsible for the dysregulation of cytokines observed in aging. A common denominator between the species of macrophage cytokines observed to be dysregulated with aging is their inducibility by the transcription factor nuclear factor (NF)-kB. Evidence is provided within Chapter 4 of this thesis that there are elevations in active nuclear NF-kB in splenocytes obtained from aged animals. This observation suggests that there is some common factor responsible for the dysregulation of cytokines in aging and the subsequent effect their presence has on various physiological functions. It has been established that elevations in reactive oxygen intermediates (ROIs) and lipid peroxides occur with aging. This dissertation demonstrates in Chapter 4 that antioxidant treatment of aged animals markedly reduces nuclear NF-kB activity, lowers lipid peroxidation, and eliminates the abnormal production of interleukin-6 and other aberrantly expressed molecules commonly observed in these animals. This observation provides evidence, for the first time, for a molecular explanation of the presence of dysregulated cytokines in old age.