The decline in the immune system which occurs with age has been attributed to a loss of function or malfunction of T-lymphocytes. Human lymphocytes from old subjects exhibit an impaired ability to respond to antigenic or mitogenic stimulation and undergo blast transformation and proliferation. This has led to the hypothesis that impaired T-cell function may account for the increased incidence of cancer, autoimmunity, diabetes and other disorders of aging. The proposed research is a continuation of studies in progress designed to examine carbohydrate metabolism of lymphocytes from young and old subjects when subjected to mitogen challenge. Blast transformation requires increased glycolytic activity, and intracellular levels of NAD increase markedly prior to transformation. Lymphocytes from old people show an impairment in both these respects. Senescent cells are also known to accumulate more labile, negatively charged """"""""abnormal"""""""" proteins during aging. We have shown for triosephosphate isomerase this is due to specific nonenzymatic deamidation which is the first step in the normal catabolism of the enzyme. These studies have led to the hypothesis that an alteration in protein catabolism of old cells allows these deamidated intermediates to accumulate. The studies will examine the adenylate charge, redox state and induction of glycolytic enzymes from a spectrum of age groups. Studies are also designed to determine the metabolic pathway(s) by which lymphocytes synthesize NAD and its function during blast transformation. Studies also are designed to determine if deamidations occur in other glycolytic enzymes and if altered protein catabolism accounts for the accumulation of the more negatively charged unstable isozymes and the inability of old cells to induce the glycolysis when exposed to mitogens. These investigations will provide a better understanding of the normal biochemical changes required for activation of the normal lymphocyte and should provide important clues to the molecular basis of the impaired immune responses which accompany aging.
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