Alcohol, the HPA Axis, and Aging

by National Institute of Health

(Page 5 of 5)

Researchers have not yet determined the reason for impaired tolerance development in aged rats. Current investigations focus on the mechanisms that underlie tolerance development to alcohol in general. One potential mechanism involves an increased ability of the liver to break down (metabolize) and remove alcohol from the body after repeated alcohol exposure (metabolic tolerance). As a result, BACs resulting from a certain alcohol dose (and, by extension, alcohol's effects on the body) would be lower after chronic alcohol consumption than after a onetime drinking episode. Although animal studies have shown that chronic, highalcohol exposure increases the levels or functions of certain alcohol-metabolizing liver enzymes, this mechanism does not appear to be a major contributing factor to alcohol tolerance. Similarly, no differences in BACs existed between the aged and younger rats on any of the test days in the study by Spencer and McEwen.

Consequently, tolerance development to alcohol must result primarily from an overall decrease in the organism's response to a given amount of alcohol after repeated alcohol consumption (functional tolerance). As indicated in the study by Spencer and McEwen, this functional tolerance appears to develop more slowly in aged rats than in younger ones, providing some important clues to the aging process in general and to adaptation mechanisms to alcohol in particular. Researchers have examined several factors that may contribute to functional tolerance development, including direct changes in the cells' response to alcohol, as well as changes in various systems that may help the body compensate for alcohol's effects. Some of those physiological adaptations to repeated alcohol exposure involve "unconscious" learned responses that offset some of alcohol's effects. For example, the body can "learn" to increase body temperature in response to alcohol-related stimuli to offset alcoholinduced decreases in body temperature (alcohol's hypothermic effects). Such complex mechanisms are especially vulnerable to the effects of aging and therefore are probably responsible for impaired alcohol tolerance development in older individuals. In addition, agerelated changes at the cellular level may contribute to the body's decreased ability to adapt to repeated alcohol exposure.

The impaired tolerance of the stress hormone response of aged rats to repeated alcohol exposure is reminiscent of the impaired habituation of the response of aged rats to repeated stress. Consequently, future studies must establish whether impaired alcohol tolerance reflects an age-related process specific to repeated alcohol exposure or to a consequence of aging that affects stress adaptation in general. Other investigations of the three-way interaction of alcohol, HPA activity, and aging should explore the possibility that greater cortisol responses to repeated alcohol exposure lead to an increase in alcohol's rewarding effects in older people. Such an enhancement in alcohol's rewarding effects could help explain the surprisingly high number of people who develop alcohol use disorders for the first time late in life.

Chronic HPA Activation, Chronic Alcohol Exposure, and Premature or Exaggerated Aging

To date, researchers have not investigated alcohol's acute and chronic effects on HPA activity in elderly humans. However, many of the symptoms associated with excessive cortisol production in patients with Cushing's syndrome (diabetes, muscle weakness, osteoporosis, atherosclerosis, hypertension, memory impairment, wasting away of brain tissue, sleep disturbances, and compromised immunity) also commonly occur in elderly people, especially among those who abuse alcohol. This overlap of the symptoms of aging and of chronic cortisol overexposure suggests that alcohol-induced excessive cortisol secretion is, at least in part, responsible for the premature or exaggerated aging seen in many alcoholics.

As described earlier, the chronic elevation of glucocorticoid levels may contribute to nerve cell degeneration in the hippocampus. Neuroimaging studies of the brains of living alcoholics, however, found significant reductions in the sizes of other brain areas in addition to the anterior hippocampus. Although the hippocampus is structurally related to the cortex, glucocorticoids do not appear to have a degenerative effect on the cortex in general. Researchers must therefore determine whether elevated cortisol levels contribute to a general alcohol-induced neurodegeneration or account only for hippocampal degeneration. Even a selective cortisol-mediated alcohol effect on the hippocampus is of serious concern because of the central role of that brain region in memory processes.

Conclusions and Treatment Implications

The findings reviewed in this article suggest that numerous interactions exist among chronic alcohol consumption, HPA activity, and the aging process. For example, alcohol-related overactivity of the HPA axis and the resulting elevated cortisol levels may contribute to premature or exaggerated aging in many people with a long history of alcohol abuse. In addition, elderly people may be more susceptible than younger people to a stress-induced pattern of drinking, because alcohol elicits greater cortisol responses that may enhance alcohol's rewarding properties. Finally, elevated cortisol responses in older people may intensify the pathophysiology associated with alcohol abuse, even in people who develop alcohol use disorders late in life.

Based on these observations, some researchers have speculated that therapeutic approaches to inhibit cortisol secretion and/or cortisol's effects might be useful as a potential adjunct to alcoholism treatment. Because cortisol is such an important hormone that normally helps regulate many physiological processes in the body, medications that completely suppress its production or activity would not likely be a viable treatment for chronic alcoholics. Nevertheless, as researchers gain a better understanding of the regulation of the HPA axis, they may discover treatments to effectively modulate HPA axis activity and minimize the development of HPA axis overactivity. Such treatments may be useful in reducing the pathophysiology associated with chronic alcohol abuse and may reduce alcohol's rewarding effects, which contribute to its addictive nature.

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.