An in vivo switch in T-cell subpopulations from those of naive to those of activated / memory subsets may offer some benefit to the aged by counteracting the overall deleterious effect of the aging process on the immune system. Although there is no question that immune responses are dampened by the aging process, the enhanced production of lymphokines by aged T cells in the presence of a decrease in proliferative responses to both mitogens and antigens (of the T-helper variety) is likely to be advantageous to the aged. The shift during the aging process from the naive subset to the activated/memory subset and the associated loss in the proliferative response of CD4+ T cells are accompanied by a decrease in intracellular calcium mobilization.51 It has been suggested that the primary cause of the dampening of immune function during the aging process is the inability of individual cells to undergo significant [Ca2+]i mobilization. Because the aging process also is associated with a marked increase in secretion of lymphokines involved in T helper cell function, however, it is questionable whether the loss of [Ca2+]i mobilization in either CD4+ or CD8+ T cells is as detrimental to immune function as originally hypothesized. Differences in the function of CD44hi cells isolated from young adult and aged mice, although perhaps only quantitative, suggest that there must be some underlying difference in the events involved in either the activation or regulation of lymphokine production by these two groups. The enhanced production of lymphokines from CD4+ T-cell subsets from aged mice cannot be explained by their enhanced production of the regulatory lymphokine IL-10; if IL-10 down regulation was playing a major role, the production of lymphokines such as IFN$gM would be even more pronounced in the aged. A more effective use of a particular population of APCs by the aged T cell could result in enhanced lymphokine signals in the absence of additional T-cell expansion. The loss of MHC restriction58 during the aging process or the more effective use of activated B cells such as APC in aged mice also may account for increased lymphokine production. Additional expansion may not be required in these activated/memory cells, which already may have undergone maximum expansion. There are marked differences in the pathways of both T-cell activation and T-cell tolerance in Th1 (IL-2-producing) and Th2 (IL-4-producing) T-cell clone studies in vitro.22 It has been clearly established in mice, for example, that cloned CD4+ helper cells of the Th2 type are characterized by a T helper pattern of lymphokine secretion and do not mobilize intracellular calcium.22 It is likely that different types of T cells exist in vivo as well as in vitro, and that one of these subpopulations is of the activated/memory type (CD44hi, IL-4-producing). If that interpretation of the available data is correct, then the aged animal is adequately equipped with memory CD4+ and CD8+ T cells that can be activated to release lymphokines required to drive T helper cell activity, but is likely to be deficient in precursor T cells directed against new antigens that were not encountered during early life. Such new antigens could be associated with new strains of influenza virus or a malignant neoplasm of recent onset. It appears likely that, as a result of repeated expansion of T cells to environmental antigens throughout life, there is an accumulation of memory cells to these antigens with adequate lymphokine potential and a concomitant loss of naive cells. This scenario, applicable in the normal aging process, may be influenced directly by other events during the aging process. Exposure to infections, tumors, or various drugs may cause further down-regulation of the immune system in the aged patient. Future studies of cytokine synthesis and release should provide deeper insights into these, as well as other, immunologic changes noted during aging. Those insights may well lead to new therapeutic approaches, including cytokine therapy or administration of cytokine inhibitors or antagonists for treatment of immunologic problems in the elderly.