Expression of heat shock protein 70 is altered by age and diet at the level of transcription.

Abstract

Because heat shock proteins have been shown to play a critical role in protecting cells from hyperthermia and other types of physiological stresses, it was of interest to determine what effect age and caloric restriction have on the ability of cells to regulate the expression of heat shock protein 70 (hsp70), the most prominent and most evolutionarily conserved of the heat shock proteins. Caloric restriction is the only experimental manipulation known to retard aging and increase survival of mammals. The ability of hepatocytes isolated from young/adult (4-to 7-month-old) and old (22-to 28-month-old) male Fischer F344 rats fed ad libitum or a caloric restriction diet (60% of the content of the ad libitum diet) to express hsp70 was determined after a mild heat shock (42.5°C for 30 min). We found that the induction of hsp70 synthesis and mRNA levels by heat shock was 40 to 50S% lower in hepatocytes isolated from old rats than in hepatocytes isolated from young rats. Using in situ hybridization, we found that essentially all hepatocytes from the young/adult and old rats expressed hsp70 in response to heat shock; therefore, the age-related decrease in the induction of hsp70 expression was not due to an age-related accumulation of cells that do not respond to heat shock. Measurements of hsp70 mRNA stability and hsp70 transcription demonstrated that the age-related decline in hsp70 expression arose from a decline in hsp70 transcription. Interestingly, the age-related decline in the induction of hsp70 expression was reversed by caloric restriction; e.g., the induction of hsp70 synthesis, mRNA levels, and nuclear transcription were significantly higher in hepatocytes isolated from old rats fed the caloric restricted diet than in hepatocytes isolated from old rats fed ad libitum. The levels of the heat shock transcription factor in nuclear extracts isolated from heat-shocked hepatocytes were measured in a gel shift assay. Binding of the heat shock transcription factor to the heat shock element decreased with age and was significantly higher in hepatocyte extracts isolated from old rats fed the caloric restriction diet than in those from old rats fed ad libitum. Thus, our study demonstrates that the ability of hepatocytes to respond to hyperthermia and express hsp70 decreases significantly with age and that this decrease occurs at the transcriptional level. In addition, caloric restriction, which retards aging, reversed the age-related decline in the induction of hsp70 transcription in hepatocytes.Organisms ranging from bacteria to humans and plants respond to hyperthermia by synthesizing a group of proteins known as heat shock proteins (hsps). Because the synthesis of hsps is induced not only by hyperthermia but also by a variety of other stresses (ethanol, amino acid analogs, heavy metal4, free radicals, etc.), hsps also have been referred to as stress-induced proteins (26). The number of hsps varies from organism to organism and even between cell types in an organism (9). However, all organisms (e.g., archaebacteria and...

Heat shock transcription factor activation and Hsp72 accumulation in aged skeletal muscle

“…The novel feature of this study is that after heat shock, both fast and slow skeletal muscles from aged animals demonstrated similar HSF activation and Hsp72 accumulation as the same muscles from adult animals. These results may appear to contrast with those of previous studies (Liu et al 1989;Choi et al 1990;Fargnoli et al 1990;Blake et al 1991;Heydari et al 1993;Nitta et al 1994;Kregal et al 1995), but a number of factors may explain these apparent differences. First, most studies that have examined the heat shock response and aging have used cultured cells or cells removed from aged animal tissues (Liu et al 1989;Choi et al 1990;Fargnoli et al 1990;Heydari et al 1993), but the in vivo heat shock response has been reported to lack the coordinated control that is characteristic of cultured cell populations (Blake et al 1990;Locke and Tanguay 1996a).…”

“…Cells and tissues from aged animals have been reported to exhibit decreased Hsp induction and expression after heat shock (Liu et al 1989;Choi et al 1990;Fargnoli et al 1990;Blake et al 1991;Heydari et al 1993;Nitta et al 1994;Kregal et al 1995;Locke and Tanguay 1996b). The diminished ability to induce Hsps in aged cells and tissues appears to result from decreased HSF activation (Heydari et al 1993;Locke et al 1996).…”

“…Induction of Hsps has been shown to confer protection to cells and tissues from both young and adult animals, but cells and tissues from aged animals have demonstrated a diminished hsp induction and thus a diminished protection (Blake et al 1991;Heydari et al 1993;Nitta et al 1994, Locke andTanguay 1996b). For example, when both adult and aged animals were heat stressed and allowed to recover, the hearts from the aged animals demonstrated reduced HSF activation, decreased Hsp72 expression, and lack of myocardial protection (Locke and Tanguay 1996b).…”

Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: Relevance to Alzheimer's disease

“…Aging usually lowers the expression of antioxidant enzymes and stress protein expression. This loss can be modulated through interventions with diet or exercise [58,62,118]. One effect of the combined treatment EA was a significant increase in the expression of inducible heme oxygenase (HO-1) also known as HSP32.…”

Induction after Administering Paraquat of Heme Oxygenase-1 and Heat Shock Protein 70 in the Liver of Senescence-accelerated Mice

“…Heydari et al have shown that the half-life of mRNA for HSP70 was longer in hepatocytes isolated from old rats than that of HSP70 mRNA in hepatocytes isolated from young adult rats. 15 ) Thus, it seems likely that HSP70 is degraded more slowly with increasing age.…”