ATTENUATED STRESS RESPONSES IN YOUNG AND OLD HUMAN-LYMPHOCYTES

Aging generally is understood to be a period defined by altered respon ses to physiological stress. At the molecular level, several stress re sponses involving specific gene expression have been revealed, and the rmal stress has been tightly linked to induction of the heat shock gen e family (D.A. Jurivich. In E. Bittar (ed.), Principles of Medical Bio logy, Vol. 4, JAI press, San Diego, 1996, pp. 411-462). Perturbations in heat shock gene transcription consistently have been noted in senes cent cells from all species examined thus far. Because heat shock prot eins serve several vital functions in the immune system, changes in th e thermal stress response could potentially contribute to immunosenesc ence. Inadequate promoter priming by the transactivator of heat shock genes, heat shock factor 1 (HSF1), is thought to account for age-depen dent diminution in expression of these genes, although the exact mecha nism for this loss is not clearly understood. We have found that human lymphocytes exhibit an age-dependent loss in HSF1-DNA binding, althou gh a range of binding has been observed in both young and old donor ce lls. This report characterizes a subset of young and old human donor l ymphocytes that are non-responders to thermal stress defined by the ab sence of HSF1-DNA binding after a 42 degrees C heat shock. Whole cell extracts from these donor cells have the capacity to inhibit HSF1-DNA binding when mixed with pre-activated HSF1 from HeLa cells. This inhib itory activity is lost upon heat denaturation and does not appear to b e protease mediated. Serial passage of lymphoblasts recapitulates loss of heat inducible HSF1-DNA observed in old donor lymphocytes, thus su ggesting that loss of replicative potential and aging lead to altered stress responses. Uncoupling of the thermal response and its potential relevance to apoptosis and aging are discussed. (C) 1997 Elsevier Sci ence Ireland Ltd.