Alcohol, Aging and Stress

by National Institute of Health

The body responds to stress through a hormone system called the hypothalamic-pituitaryadrenal (HPA) axis. Stimulation of this system results in the secretion of stress hormones (glucocorticoids). Chronic excessive glucocorticoid secretion can have adverse health effects, such as Cushing's syndrome. Alcohol intoxication activates the HPA axis and results in elevated glucocorticoid levels. Ironically, elevated levels of these stress hormones may contribute to alcohol's pleasurable effects. With chronic alcohol consumption, however, tolerance may develop to alcohol's HPA axis-activating effects. Chronic alcohol consumption, as well as chronic glucocorticoid exposure, can result in premature and/or exaggerated aging. Furthermore, the aging process affects a person's sensitivity to alcohol and HPA axis function. Thus, a three-way interaction exists among alcohol consumption, HPA axis activity, and the aging process. The aging process may impair the HPA axis' ability to adapt to chronic alcohol exposure. Furthermore, HPA axis activation may contribute to the premature or exaggerated aging associated with chronic alcohol consumption.

The fact that alcohol intoxication can relieve anxiety is well known. Paradoxically, those same intoxicating levels of alcohol also can induce excessive secretion of an important class of stress hormones, the glucocorticoids. Yet chronic alcohol exposure can trigger a tolerance to alcohol's effects on the body's stress response. For example, research has shown that healthy young rats can develop tolerance to alcohol's stimulatory effects on glucocorticoid secretion - that is, the animals respond to chronic alcohol use by producing smaller increases in glucocorticoid levels. This same effect also appears to occur in humans. Research also indicates, however, that aged rats are much less able than younger rats1 to develop such tolerance. Nonetheless, researchers do not know whether older humans likewise have a decreased ability to develop a tolerance to alcohol's effects on stress hormones. Investigators do know, however, that chronic exposure in humans to both elevated glucocorticoid levels and alcohol produces symptoms resembling premature or exaggerated aging.

This article examines the little-known, three-way relationship that exists among alcohol use and abuse, glucocorticoid secretion, and the aging process. In particular, the article considers evidence that the glucocorticoid- based stress response system, as regulated by the hypothalamic-pituitary- adrenal (HPA) axis, plays a key role in the physiological and psychological responses to alcohol. The article also examines whether the stress hormone system contributes to age-related changes in a person's response to alcohol (a reduced ability to develop tolerance to alcohol's effects) and to alcohol-related changes in the aging process (nerve cell degeneration in some brain areas). By highlighting the overlap between these relationships, this article may spur further research on this important and complex topic.

Alcohol's Effects on HPA Axis Function
in Young and Middle-Aged Individuals

Alcohol-Induced Stimulation of the HPA Axis

Extensive documentation exists indicating that alcohol consumption reduces anxiety while it simultaneously activates the stress hormones through the HPA axis. In humans and other animals, the magnitude and duration of the glucocorticoid response depend on the amount of alcohol consumed. In response to alcohol, the levels of cortisol - the chief glucocorticoid hormone in humans - can be substantial and even surpass the levels typically seen in response to various stressful circumstances. Interestingly, blood alcohol concentrations (BACs) below 0.1 percent appear to have little effect on HPA axis activation. Furthermore, the 0.1 percent level has been (and in some States continues to be) considered a threshold for alcoholrelated impairment and intoxication.

In addition to BACs, the extent to which alcohol leads to HPA axis activation appears to depend on genetic factors. Such a genetic influence is evident in people who have inherited a defective form of a particular gene that is involved in alcohol metabolism. Inheritance of this defective gene, which is especially prevalent among people of Asian descent, disallows the body to metabolize alcohol normally.2 People with the defective gene show significantly elevated blood cortisol levels, even at BACs below 0.1 percent. Other studies have found a greater HPA axis response to relatively low alcohol doses in people without family histories of alcoholism. This finding further supports the potential influence of genetic factors on the relationship between alcohol consumption and HPA activity.

The specific mechanism by which alcohol leads to HPA axis activation and elevated cortisol levels has not been conclusively established. One possibility is that alcohol disinhibits the HPA axis. In general, alcohol depresses nervous system activity. If some alcohol-sensitive nerve cells (neurons), in turn, exert inhibitory effects on the HPA axis, then the net effect of alcohol exposure would be HPA axis activation. A second possibility is that the HPA axis may be activated in response to certain stimulus properties of alcohol as part of a more coordinated, "whole body" stress response. Thus, a certain "body wisdom" may recognize alcohol intoxication as stressful despite the concurrent reduced sense of anxiety.

Tolerance to Alcohol's Stimulatory Effects on the HPA Axis

People who repeatedly expose themselves to alcohol or other drugs develop, over time, tolerance to certain effects - in other words, these people experience lesser effects with the same dose or require higher doses to achieve the same effect. For example, tolerance develops to alcohol-related sedation, motor incoordination, and memory impairment. Similarly, studies have shown that animals can develop tolerance to alcohol's HPA axis-activating effects. For example, rats exposed to high alcohol doses daily for several weeks had an increase in the levels of corticosterone - the chief glucocorticoid hormone in animals - on day 14 that was only about one-half the increase observed on day 1. This tolerance development could not be explained by a change over time in their bodies' ability to absorb or metabolize alcohol (development of metabolic tolerance), because the BACs achieved on day 14 were as high as those achieved on day 1 with the same alcohol dose.

However, researchers have not thoroughly studied the extent to which tolerance to alcohol's stimulatory effects on the HPA axis develops in humans. In one study, alcohol administration to five alcoholics did not induce a significant increase in cortisol levels in the blood, even though the subjects' BACs surpassed 0.1 percent. Conversely, alcohol administration produced a substantial increase in cortisol levels in three of five purportedly nonalcoholic men in the study, suggesting that the alcoholics developed at least some degree of tolerance. (Interestingly, the two nonalcoholic men who did not show a significant cortisol response to alcohol on further questioning revealed an extensive history of recent alcohol use.)

Although some tolerance to alcohol's effects on cortisol secretion may develop, it appears to be limited. For example, a study conducted in a controlled hospital setting found that men with a record of heavy and frequent alcohol use exhibited substantially elevated cortisol levels during an alcohol "binge". Furthermore, examination of seven different studies reveals that 6 to 40 percent of chronic alcohol users exhibited some of the symptoms of excessive cortisol production observed in Cushing's syndrome. Thus, at least in some people, chronic alcohol use apparently can lead to chronically elevated cortisol levels with all the associated symptoms, a condition that sometimes has been called "pseudo-Cushing's syndrome."

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.