The actions of counterregulatory hormones that are released as part of the stress response are important in restoring the balance in physiological systems. Stress increases the release of physiological mediators from the autonomic nervous system and adrenal glands, including fast-acting catecholamines and slow-acting steroids (mainly glucocorticoids), that participate in the adaptive response. The signal to release stress mediators into the blood is first transmitted from a physical (e.g., heat) or psychological (e.g., predator odor) stress through the nervous and immune systems to the brain. These signals are integrated in the brain, where they are converted into defensive behaviors (reflex withdrawal of a limb or running away from a predator) and hormonal responses that are important for survival. For example, glucocorticoids mobilize energy (glucose) stored in the liver for use by muscle, and they inhibit processes (e.g., growth and reproduction) that are not necessary for adaptation. Glucocorticoids are essential for surviving severe stress, but their effects exerted throughout the body can be damaging if the stress is prolonged, and may eventually result in disease. There are controls in place to prevent excess secretion of glucocorticoids, called a negative feedback loop. After the stress-induced increase in glucocorticoids in the blood, these hormones turn down their own production by decreasing the synthesis of factors made in the hypothalamus of the brain and in the pituitary gland that promote their synthesis and secretion from the adrenal gland.
Age-related changes in the adrenal glands and nervous system contribute to a decreased ability of elderly individuals to adapt to stress. Since glucocorticoids regulate natural defense mechanisms (e.g., immunity and inflammation) with both permissive and suppressive actions to protect against stress, decreased sensitivity to glucocorticoids may increase vulnerability to stress. Excess production of glucocorticoids by the adrenal glands could also be a culprit, as proposed by Sapolsky in his glucocorticoid cascade hypothesis, since elevated levels of this steroid hormone do not always return to baseline as quickly in older individuals after stress. Therefore, catabolic effects of glucocorticoid excess may contribute to the development of conditions that are prevalent in elderly persons, including immune suppression and cancer, muscle atrophy, osteoporosis, diabetes, and memory decline. An association between reduced negative feedback regulation of the hypothalamic-pituitary-adrenal axis during aging, especially in the face of stress, disease, and other forms of challenge (exercise, driving test) supports this hypothesis. Based on studies supported by the John D. and Catherine T. MacArthur Foundation through its Research Networks on Successful Aging and on Socioeconomic Status and Health, the interplay of these same factors is also associated with cognitive decline (learning, memory, and language loss).
Since the findings of neuron loss by Philip Landfield in the late 1970s, much has been made of the harmful effects of glucocorticoids in the hippocampus, a part of the brain that is involved in learning and memory. Follow-on studies by Robert Sapolsky and Michael Meaney beginning in the middle 1980s, when they were doctoral students in Bruce McEwen’s laboratory at the Rockefeller University, suggested that chronic stress and excess production of glucocorticoids resulted in the death of hippocampal neurons during aging, thus contributing to age-related memory loss. However, memory impairment in old rats correlates better with loss of connections between neurons than with the loss of principal neurons in the hippocampus. Studies performed by McEwen’s group between 1995 and 2000 demonstrate that chronic stress induces synaptic loss and atrophy of the hippocampus similar to that which occurs during aging. The reversibility of these effects in rodents may help to explain how humans who are routinely treated with high doses of glucocorticoids for long periods do not seem to have extensive hippocampal damage and memory impairment. Beginning in 1987, researchers at McGill University in Canada conducted a longitudinal study sampling individuals over a three- to six-year period, and found that memory impairment occurred only in a sub-group of healthy elderly individuals with both a high and an increasing cortisol (glucocorticoid) level. The increasing inability of these individuals to decrease their hormone level over time is an indication of failure in the nervous and endocrine systems. Together with the MacArthur Foundation studies conducted by Teresa Seeman, this work highlights the importance of individual variability in response to stress. The good news is that some deleterious effects of stress may be reversible even in elderly persons. Since psychosocial factors are important in how an individual responds to stress, it may be possible, with effective stress management, to decrease excess glucocorticoid production in humans.
Glucocorticoid excess and chronic stress are unlikely to be the only factors that result in an inability to adapt to stress during aging. In a 1998 article published in the New England Journal of Medicine, McEwen suggests a revision in the approach to understanding the relationship between changes in the environment and biological responses to emphasize both beneficial and detrimental effects of stress mediators and, in particular, the costs of adaptation to stress. Short-term beneficial effects result in allostasis, which means the capacity to adapt or restore homeostasis through change, whereas long-term detrimental effects constitute an allostatic load (the cost of having to adapt to challenges and changes in the environment). By measuring allostatic load at earlier ages, it may be possible to identify risk factors (e.g., overactivity of the hypothalamic-pituitary-adrenal axis) that result in late onset diseases (e.g., Type II diabetes, dementia). Since cellular responses are of primary importance in adaptation to stress, it is necessary to determine how stress mediators regulate cellular responses to achieve allostasis during aging. Age-related changes in cellular constituents involved in these responses may result in an increased allostatic load, thus contributing to a reduced capacity of older organisms to adapt and restore homeostasis. Three major types of stress are discussed in the following sections in relation to cellular aging changes.