The Heat Shock Response. Stress Proteins and Aging in Mammals

The most extensively studied response to acute stressors is the expression of HSPs. HSPs are the products of a family of highly conserved genes, found from bacteria to mammalian cells, that are rapidly transcribed and translated in cells and tissues exposed to a variety of stressors. Recent studies have provided evidence that in the intact animal even a behavioral or psychological stress can elicit the response.

HSP genes are regulated by heat shock transcription factors (HSF), which are themselves sensitive to a variety of stressors. The HSPs facilitate the disassembly and disposal of damaged proteins and the folding, transport, and insertion of newly synthesized proteins into cellular organelles. Thus, they facilitate the removal of damaged structures as well as their replacement.

There is very good evidence that the expression of HSP genes is sufficient to increase resistance to thermal stress (thermotolerance) in many circumstances. Across different species, distinct HSP families are important in thermal tolerance. HSP-104 is responsible for tolerance to several environmental stressors in the yeast S. cerevisiae, and inducible HSP-70 confers thermotolerance in Drosophila embryos and in a range of cultured mammalian cells. The addition of antibodies to HSP-70 compromises survival after thermal stress in fibroblasts.

Stress Proteins and Aging in Mammals. There is good evidence that stress proteins (e.g., HSPs and antioxidants) directly influence aging. It is also likely that the converse is true - aging seems to influence the extent to which stress proteins are synthesized in response to a variety of stressors. The expression of HSP-70 has been studied in inbred strains of animals at different ages and also in cells cultured to senescence. These studies show that there is a striking reduction in the magnitude of the induced response with both age and senescence.

Considerable specificity has been observed for responses to different stressors. For example, the physical restraint of an animal induces HSP-70 expression selectively in the adrenal cortex and in the media of blood vessels. These responses are dependent on the activation of the hypothalamic- pituitary-adrenal (HPA) axis and the sympathetic nervous system, respectively. Old rats show a reduced HSP-70 response at both sites.

Other work has shown a reduced HSP-70 response in the myocardium of old rats associated with reduced protection from ischemia in the Langendorff isolated-heart model. Interestingly, an HSP response may be selective for the nature of the stressor. For example, the hepatic HSP-70 response of old rats to passive heat stress is attenuated, whereas that to exertional heat stress is not.

HSPs are also important in the cellular actions of glucocorticoids, the archetypical stress hormones. High-affinity intracellular binding of glucocorticoids (e.g., estrogens and gestagens) requires that their receptors to be present as a heteromeric complex containing a HSP-90 dimer; other proteins such as HSP-70, p59/HSP-56, and p23 may also be present, although HSP-70 appears to be involved in the assembly of the complex rather than a component of it. This complex also serves to prevent the receptor from homodimerization and binding to chromatin and possibly serves to inhibit its degradation.