Attenuated stress responses in young and old human lymphocytes.
Aging generally is understood to be a period defined by altered responses to physiological stress. At the molecular level, several stress responses involving specific gene expression have been revealed, and thermal stress has been tightly linked to induction of the heat shock gene family (D.A. Jurivich. In E. Bittar (ed.), Principles of Medical Biology, Vol. 4, JAI press, San Diego, 1996, pp. 411-462). Perturbations in heat shock gene transcription consistently have been noted in senescent cells from all species examined thus far. Because heat shock proteins serve several vital functions in the immune system, changes in the thermal stress response could potentially contribute to immunosenescence. Inadequate promoter priming by the transactivator or heat shock genes, heat shock factor 1 (HSF1), is thought to account for age-dependent diminution in expression of these genes, although the exact mechanism for this loss is not clearly understood. We have found that human lymphocytes exhibit an age-dependent loss in HSF1-DNA binding, although a range of binding has been observed in both young and old donor cells. This report characterizes a subset of young and old human donor lymphocytes that are non-responders to thermal stress defined by the absence 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 inhibitory activity is lost upon heat denaturation and does not appear to be protease mediated. Serial passage of lymphoblasts recapitulates loss of heat inducible HSF1-DNA observed in old donor lymphocytes, thus suggesting 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.
Jurivich
D A
DA
Department of Veterans Affairs, Northwestern University Medical School, Chicago, IL 60611, USA. jurivich@uic.edu
Qiu
L
L
Welk
J F
JF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002457:Cell Extracts; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D006361:Heating; D006801:Humans; D008875:Middle Aged; D011480:Protease Inhibitors; D014157:Transcription Factors
D002457:Cell Extracts; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D011480:Protease Inhibitors; D014157:Transcription Factors; D004247:DNA