Alcohol, Aging and Stress

Premature or Exaggerated Aging With Chronic Glucocorticoid Exposure
by National Institute of Health

(Page 4 of 5)

People generally believe that a "hard life" (one fraught with difficulties, including repeated exposure to stressful situations) can lead to premature aging. Chronic stress-induced HPA axis overactivity may mediate such a process, a belief that is supported by research findings. For example, a study that examined post-mortem brains of vervet monkeys housed in a primate center detected extensive hippocampal damage in the brains of a subset of monkeys. These monkeys showed signs of chronic stress (gastric ulcers and bite scars) typically experienced by animals of low rank in the strict hierarchy found in this species. The hippocampus is vitally important for memory formation and, interestingly, has a high concentration of glucocorticoid receptors. Perhaps, as a result of the high glucocorticoid receptor levels, the growth and survival of many hippocampal neurons appear to depend on glucocorticoids. Some neurons, however, require the presence of only low glucocorticoid levels for survival and may be damaged by high glucocorticoid levels. Thus, chronic high glucocorticoid exposure may cause the death of some hippocampal neurons and increase the susceptibility of other neurons to damage or death from other toxic insults, such as lack of oxygen (hypoxia).

During an organism's lifetime, the effects of glucocorticoid exposure on brain cells may accumulate and contribute to neurodegeneration. This hypothesis has been supported by studies in middle-aged rats whose adrenal glands were removed to prevent glucocorticoid production and who received lower-than-normal cortisol doses to replace the missing corticosterone. This treatment minimized the extent of hippocampal nerve cell loss that usually occurs with old age, although the treatment did not prevent an agerelated cognitive decline in the animals.

However, another study that assessed individual variations in the ability of aged rats to navigate a maze (a task that depends on hippocampal function) found a relationship between nerve cell degeneration and cognitive performance. Some aged rats performed significantly worse than did younger rats, whereas the performance of other aged rats did not differ from that of the younger ones. When the investigators examined the brains of the cognitively impaired aged rats, the animals exhibited significant nerve cell loss in the hippocampus compared with that of both the unimpaired aged rats and the younger rats.

To determine whether differences in glucocorticoid levels contributed to the group differences in performance and hippocampal degeneration, researchers screened the rats prior to death for their HPA axis response to acute stress. The analyses found that the corticosterone levels of the cognitively impaired aged rats took longer to return to basal levels after the end of the stressful event compared with younger or unimpaired aged rats. This observation is consistent with the belief that animals exposed to greater levels of glucocorticoids (as a result of HPA overactivity, such as prolonged corticosterone secretion in response to stress) exhibit signs of advanced aging in the brain, particularly in the hippocampus. It is important to point out, however, that the hippocampus also exerts a crucial inhibitory control over the HPA axis. Accordingly, age-related degeneration of the hippocampus could precede, rather than follow, HPA axis overactivity.

The hypothesis that chronic HPA axis overactivity may lead to hippocampal degeneration in humans has gained support from recent MRI studies indicating that people with depression (many of whom have elevated basal cortisol levels during depressive episodes) and patients with Cushing's syndrome have, on average, reduced hippocampal volumes. In addition, the extent of hippocampal degeneration is correlated with the duration of depression or, in the case of Cushing's syndrome, the severity of cortisol overproduction. Other studies, in which older nonhuman primates were exposed to chronic high cortisol levels, did not produce any detectable hippocampal degeneration. Thus, high glucocorticoid levels alone may only increase the vulnerability of nerve cells to the harmful influences of additional factors. Such factors, associated with stress or pathological conditions, include low oxygen levels and elevated levels of potentially toxic molecules (free oxygen radicals and glutamate).

Alcohol, the HPA Axis, and Aging - Research Implications

Few studies have examined the threeway interaction of alcohol, the HPA axis, and aging. As outlined in the sidebar "Chronic Alcohol Consumption and Aging", aging likely alters the organism's physiological and psychological responses to alcohol. Moreover, chronic alcohol abuse appears to exacerbate the aging process. The HPA axis and the aging body's changing responses to glucocorticoids may serve as an important mediator of these processes. The existing evidence supporting this hypothesis is summarized in the following sections.

Age-Related Impaired Adaptation of the HPA Axis to Chronic Alcohol Exposure

One potential interaction among age, the HPA axis, and alcohol concerns alcohol's stimulatory effect on the HPA axis, which research has suggested may be greater in old than in young or middle-aged people. To investigate this hypothesis, researchers have examined the changes in corticosterone levels in response to 14 daily alcohol treatments in both aged and younger rats. In that study, both groups of animals displayed equivalent increases in corticosterone levels in response to alcohol on the first day of treatment, suggesting that in rats, no age-related difference exists in the initial response of the HPA axis to alcohol. In contrast, the ability of the HPA axis to adapt to repeated alcohol exposure differed greatly between the aged and the younger rats. Whereas young rats developed extensive tolerance in their corticosterone response to alcohol (showed smaller alcohol-induced increases in corticosterone levels) after 7 days of alcohol exposure, aged rats exhibited substantially less tolerance development. As a result, on days 7 and 14, the corticosterone levels in response to alcohol were significantly greater in the aged rats than in the younger ones. Such an agerelated impairment in tolerance development to alcohol also has been observed in rats that had to perform a previously learned task while under the influence of alcohol.

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.