Heat Shock Stress
Nonlethal heat stress induces a characteristic set of proteins in cells that are called heat shock proteins. This stress response is ancient and highly conserved throughout living organisms. Many types of stress in addition to mildly elevated temperature can induce heat shock proteins. Heat shock proteins act as molecular chaperones by helping cells to repair or remove damaged proteins and by participating in the intracellular transport of newly synthesized proteins. Therefore, they are important regulators of cellular adaptation to stress. An important function of heat shock proteins in relation to aging is their ability to confer resistance or tolerance to future insults. The mechanisms for protection against future stresses are poorly understood but may involve the ability of heat shock proteins to promote cell survival by interfering with a cell death program that leads to cell suicide. The synthesis of heat shock proteins is also linked to neuroendocrine responses to stress. For example, elevated glucocorticoid secretion can induce specific heat shock proteins in different cells as a beneficial effect of the stress response. Their role in protein degeneration and the stress response is highlighted by their accumulation in plaques and tangles, the brain deposits associated with Alzheimer’s disease pathology.
In the 1990s, researchers in the field of aging, including Richardson, Nikki Holbrook, and Marcelle Morrison-Bogorad, thought that the decreased ability of aged individuals to maintain homeostasis in the face of insults could be due to inadequate cellular responses to stress like the heat shock protein response. They found that the induction of heat shock proteins in response to stress decreases with age. Richardson’s group found that the induction of heat shock protein 70 by heat stress in liver cells cultured from old rats was reduced by 50 percent compared with young rats. Furthermore, the decrease in heat shock protein 70 induction occurred at the transcriptional level of regulation and was dependent on reduced binding of a transcription factor to the promoter of the heat shock protein 70 gene. Holbrook’s group at the National Institute of Aging used transplantation studies to determine whether the deficit in heat shock protein 70 response in blood vessels was due to the age of the tissue or to the environment. Transplantation of old vessels to a young host restored their response, and transplantation of young vessels to an old host resulted in a reduced response. In the case of blood vessels, heat exposure produced less of an increase in blood pressure in old rats than in young rats, which resulted in less heat shock protein 70 induction. In other circumstances, hormonal or metabolic changes that occur during aging could result in aged cells receiving less of a stimulus to induce the response. Age-related changes could also reduce the effectiveness of the heat shock proteins. For example, genotoxic stress can damage heat shock proteins in the cells of aged individuals due to mutated DNA, errors in translation of mRNA into protein, or reduced repair, and also diminish their role in stress tolerance. Therefore, the environment is a factor that should be considered in interpreting age-related differences in the response of cells to stress.
Richardson and Holbrook proposed in a 1996 review that the widespread reduction in stress-induced heat shock protein 70 expression in aged organisms indicates the importance of this response in both cellular and organismal aging. Consistent with this hypothesis is the ability of caloric restriction to restore the stress-induced heat shock response during aging. Furthermore, mutants that increase life span in nematodes also overexpress heat shock proteins in response to stress, and overexpression of heat shock protein 70 sometimes results in increased life span in fruit flies. Basal levels of heat shock protein 70 are usually not different between young and old individuals, but other members of the heat shock protein family do increase during aging in mice, fruit flies, and nematodes. Age-related increases in basal heat shock protein expression may be a response to accumulated damage and oxidative stress. Therefore, as proposed by Gordon Lithgow and Tom Kirkwood in 1996, heat shock proteins that function as molecular chaperones may regulate organismal aging.