Age-related alterations in the activation of heat shock transcription factor 1 in rat hepatocytes

The induction of hsp70 transcription by heat shock is significantly reduced in hepatocytes isolated from old rats compared to hepatocytes isolated from young! adult rats, and the decline in hsp70 transcription is correlated with a decrease in the induction of heat shock transcription factor 1 (HSF1) binding to the heat shock element. However, the decreased HSF1 binding activity to DNA is not due to reduced levels of HSF1 that are available for activation by heat shock. In fact, the levels of HSF1 are two- to threefold higher in hepatocytes from old rats, and the age-related increase in the levels of HSF1 protein in hepatocytes appears to arise from a decrease in the degradation of the HSF1 because HSF1 mRNA levels do not change and the synthesis of HSF1 decreases approximately 50% with age. No evidence was found for an impairment in HSF1 oligomerization in hepatocytes from old rats, e.g., the level of HSF1 trimers, the nuclear translocation of HSF1, and the phosphorylation of HSF1 after heat shock are similar in hepatocytes isolated from young/adult and old rats. However, the thermostability of the DNA binding activity of HSF1 was significantly reduced with age in a cell-free system as well as in isolated hepatocytes. (C) 2000 Academic Press.