Replicative Senescence in the Immune System: Impact of the Hayflick Limit on T-Cell Function in the Elderly

Abstract

Gerontologists, lured by the prospect of understandingthe cellular events that underlie the gross features ofhuman aging, are focusing increasingly on replicative(orcellular) senescence. The term “replicative senescence”describes the irreversible state of growth arrest experi-enced by all mitotically competent cells of human originfollowing a fairly predictable number of cell divisions inculture. First identified in human fetal fibroblasts byHayflick, replicative senescence, or the so-called Hay-flick limit, results from an intrinsic natural barrier tounlimited cell division exhibited by all normal somaticcells.The characteristics of replicative senescencehavebeenexplored in a variety of cell types (reviewed in Smithand Smith 1996; see also Be´rube´ et al. 1998 [in thisissue]), but only recently has this model been applied tothe immune system. Ironically, the Hayflick limit maybe particularly deleterious for immune cells, since theability to undergo rapid clonal expansion is absolutelyessential to their function. The decline of T-cell immunefunction during aging suggests that T cells might be anideal system in which to explore the potential role ofreplicative senescence during in vivo aging. Well-char-acterized cell surface markers, signal transduction path-ways, and functional traits further enhance the potentialutility of T cells as a model system, both to elucidatethe process of replicative senescence itself and to assessits physiological consequences.This review will summarize the results of research onT-cell replicative senescence in cell culture and will dem-onstrate that cells from elderly people have undergonechanges in vivo that are similar to those observed in thecell culture model. I will argue that T-cell replicativesenescence contributes to increased morbidity and mor-tality during aging and that the proportion of replica-