A characteristic feature of aging is a progressive impairment in the ability to maintain homeostasis in the face of environmental challenges. Heat shock proteins (Hsps) consist of a family of proteins that modulate stresses to the body. Hsps are ubiquitous, highly conserved proteins that have been found in the cells of all organisms studied thus far, including plants, bacteria, yeast, flies, and vertebrates. They are part of a multigene family that has been divided into 6 subfamilies based on molecular size, ranging from 8 to 150 kD (Jaattela 1999). Some are expressed constitutively, whereas others are induced by various types of metabolic or environmental stresses such as heat, ischemia, heavy metal ions, ethanol, nicotine, viral agents, surgical stress, and reactive oxygen species. Hsps are expressed in response to a mild stress which allows the cells to adapt to gradual changes in their environment and survive otherwise lethal conditions (Welch 1992; Whitley et al., 1999). Transcription of Hsp genes requires the activation and translocation to the nucleus of heat shock transcription factors (Hsfs), which recognize sequence elements (heat shock elements — HSEs) located within the Hsp gene promoters. The HSE consists of a series of pentameric units (5'-nGAAn-3') (Santoro 2000). Inactive Hsfs exist as monomers bound to Hsp70 and other chaperones. Once activated, they trimerize into an active form that is capable of binding to the promoter site of the stress protein gene and initiating transcription and translation (Whitley et al., 1999).
The expression of various types of Hsp protein and mRNA levels in response to heat stress has been shown to decrease with age in a variety of species from flies to rats. Old fruit flies were found to have a loss of resistance to oxidative stress induced by heat shock. This loss correlated with an increase in protein damage and a decrease in protection from the heat shock proteins (Fleming et al., 1992). The expression of protein and mRNA levels in members of the Hsp70 family in response to heat shock was found to be decreased with age in rat neurons (Pardue et al., 1992), hepatocytes (Rogue et al., 1993; Wu et al., 1993), and myocardium (Locke et al., 1996). Based on measurements of Hsp70 mRNA stability and transcription in rat hepatocytes, it was demonstrated that the age-related decline in Hsp70 expression was a result of a decline in Hsp70 transcription. Interestingly, this age-related decrease in Hsp70 expression was reversible with caloric restriction. Caloric restriction is the only experimental manipulation known to retard aging and increase survival in mammals (Heydari et al., 1993). In addition, this decline in Hsp70 transcription correlated with a decrease in the binding of Hsf1 to the heat shock element. This decreased binding activity was not due to reduced levels of Hsf1. In fact, Hsf1 levels were actually higher in hepatocytes from old rats, apparently due to a decrease in the degradation of Hsf1 since Hsf1 mRNA levels do not change and the synthesis of Hsf1 decreases with age (Heydari et al., 2000). Similarly, hearts from aged rats exposed to heat stress demonstrated a reduction in Hsf1 activation, Hsp72 mRNA, and Hsp72 protein content, though myocardial Hsf1 protein content was similar between age groups (Locke et al., 1996). Thus, it appears that during aging, the levels of Hsf1 remain constant, but the ability of this transcription factor to bind DNA is decreased in aged animals.
An age-related decline in Hsp72 expression was also seen in organ-cultured samples of normal human skin. Although the time course of Hsp72 expression was similar in both young and aged groups, a lower level of induction was achieved in the aged group (Muramatsu et al., 1996). A similar decline in Hsp47 expression is seen in aged mouse and human fibroblasts exposed to heat stress.
Hsp47 is a collagen-specific chaperone which participates in the processing and secretion of procollagen in the ER. This decline was regulated by transcriptional mechanisms and was characterized by a greater retention of procollagen molecules in the ER lumen of cells from old subjects (Miyaishi et al., 1995). Similarly, cultures of primary human peripheral lymphocytes exposed to heat stress revealed an age-related attenuation in the expression of many heat shock proteins, including Hsp70, Hsp90, Hsp60 (Rao et al., 1999). Murine and human fibroblasts also showed a decline in heat shock protein expression with age upon heat treatment (Miyaishi et al., 1995).
Given the central role of Hsps in cellular homeostasis, it seems likely that an impaired ability to produce Hsps in aging cells in response to stress could contribute to the increased incidence of infections and general morbidity and mortality that is seen in the elderly when exposed to stress.
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