Aging and lymphocyte function: a model for testing gerontologic hypotheses of aging in man

Advanced age in humans and experimental animal models has been consistently associated with declines in the in vivo and in vitro responsiveness of T lymphocytes. The declines in vitro responses cannot be explained by decrease in numbers of differentiated T cells or by age-associated changes in the proportion of CD4+ 'helper' to CD8+ 'cytotoxic/suppressor' T cells. However, recent studies have demonstrated a decline with age in numbers of what appear to be antigenically 'naive' or 'virgin' T cells, accompanied by a proportionate increase in 'memory' T cells which mediate anemnestic or recall responses to previously encountered antigens. The findings lead to the hypothesis that thymic involution leads to decline in input of newly differentiated 'naive' T cells, while T cell number in peripheral tissues is maintained by accumulation of longer lived 'memory' T cells due to lifetime antigen exposure. So far, limited data suggest that increasing average biological age of the memory T cells which accumulate with age is largely responsible for declines in vitro activation responses of human peripheral blood T cells and that a subset of these memory T cells becomes refractory to activation stimuli as a consequence of in vivo cellular aging. Approaches to testing this hypothesis are presented and the implications of these findings for use of memory T cells as a model for investigating the mechanisms of in vivo cellular aging, are discussed.