Laurie Barclay, MD

August 14, 2006

August 14, 2006 — Reactions to stress affect brain aging via hormonal effects, according to 2 invited presentations at the 114th annual convention of the American Psychological Association (APA) in New Orleans, Louisiana.

"By stress, I mean what we call 'allostatic load,' or the cumulative effect of stress and lifestyle — that is, what we eat, drink, if we smoke, how well we sleep, whether we are physically active — these are determined in part by our life experiences, which include stress and being anxious and worried, under much tension in a job or at home, etc," presenter Bruce S. McEwen, PhD, told Medscape.

"Effects that we know about include impairment of memory, shrinkage of the hippocampus, impaired glucose utilization," he added. "We cannot yet pinpoint specific effects of chronic stress, measured by life events, but we do know that some people age more quickly than others in terms of brain function." Dr. McEwen is the Alfred E. Mirsky Professor and head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at The Rockefeller University in New York City.

Based on animal models and some human data, the adrenal stress hormone cortisol appears to play an important role in mediating the effects of stress on the brain. The hippocampus, a vital brain region for episodic, spatial, and contextual memory, has many cortisol receptors, which makes it especially vulnerable to stress hormones.

Although acute stress seems to enhance immune function and improve memory, chronic stress has the opposite effect and may even lead to disorders that become more prevalent with aging, such as depression, diabetes, and cognitive impairment. Dr. McEwen notes that diabetes and obesity are risk factors for cognitive decline and for Alzheimer's disease, as well as for depression, and that comorbidity of diabetes and dementia may first be manifest as geriatric depression.

"Depressive illness over a long time [years] leads to shrinkage of the hippocampus," Dr. McEwen said. "The overall lack of physical activity and the epidemic of obesity and diabetes are matters of concern, then, for brain health."

To address these concerns, some physicians turn to pharmaceutical agents, including antidepressants, anxiolytics, beta-blockers, antidiabetic medications, antioxidants, and anti-inflammatory drugs.

"They are very useful, but each of them has side effects and, in the case of antidepressants, they are not effective for everyone," Dr. McEwen said. "Lifestyle change is preferable but hard to achieve, yet regular exercise, social support, and finding meaning and purpose in life have benefits that include better mental and physical health and hopefully less reliance on pharmaceutical agents. Programs by government and private agencies that encourage these positive actions can only but help."

A case in point is the Experience Corps, a program for older volunteers designed for both generativity and health promotion, in which older volunteers were placed in public elementary schools in roles designed to meet needs of the schools while increasing the social, physical, and cognitive activity of the volunteers. In a pilot study ( J Urban Health: Bull NY Acad Med. 2004;81(1):64-78) by Linda P. Fried, from Johns Hopkins School of Public Health in Baltimore, Maryland, and colleagues, elderly Experience Corps participants declined significantly less, compared with control subjects, in physical activity, strength, walking speed, cognitive activity, and social supports.

The second presentation, by Elissa S. Epel, PhD, an assistant professor of psychiatry at the
University of California, San Francisco, also summarized the effects of stress on brain aging and brain function, emphasizing hippocampal vulnerability and hormonal effects.

"The brain may be the most sensitive indicator of chronic stress," Dr. Epel told Medscape. "A person who has been overexposed to cortisol, due to chronic treatment with high doses of prednisone or excessive duration of experiencing chronic stress, will likely have an atrophied hippocampus. Functionally, this person will likely show deficits in certain types of memory."

Disrupted circadian rhythms may also reflect brain aging, according to Dr. Epel. Although the brain "clock" efficiently regulates diurnal rhythms of hormonal levels in youth, the aged brain is less efficient in regulating hormonal cycles.

"The low levels of anabolic hormones or dysregulated levels of cortisol that we often see in the blood of the elderly is likely a reflection of this aged clock losing its sense of timing, in that it now sends the hormone-releasing signals to the body in a more dysregulated way," Dr. Epel explains. "Aging alone alters most hormonal signals from the brain, leading to lower levels of anabolic hormones, [but] stress can also alter these brain signals, thus speeding up the age-related decline in anabolic hormones. In this way, chronic stress may alter the rate of hormonal aging."

With aging, decreased levels of anabolic hormones lead to other age-related changes, such as decreased bone mass, and shifting body composition toward greater fat mass and lower muscle mass. At the cellular level, the shift in hormonal balance may affect the cellular aging system, leading to decreased telomerase and shortened telomeres. Telomeric sequences shorten with each DNA replication, and when at least some of the telomeres reach a critically short length, the cell becomes senescent and stops dividing, which may cause or contribute to some age-related diseases. Individuals under constant stress, such as caregivers for patients with chronic illness, or those with obesity and/or diabetes, are more likely to have decreased telomere length and telomerase activity regulating cell division.

Despite these effects of age-related declines in anabolic hormones, Dr. Epel cautioned against replacement therapy with growth hormone (GH) or dehydroepiandrosterone (DHEA).

"Although most anabolic hormones change dramatically with age, simply replacing these hormones is in most cases not indicated," Dr. Epel said. "Hormone replacement, such as for GH, can never fully mimic the body's natural pattern of secretion each day. There is little to no evidence that...hormone replacement leads to greater longevity; in fact, there is risk in taking anabolic hormones."

In the future, Dr. Epel suggested that there may be a useful index of hormonal aging, such as the
cortisol/DHEA ratio, that predicts disease risk and could be easily modifiable. Unfortunately, she believes that there is too little research currently validating such an index.

"While [GH or DHEA] might decrease atrophy and aging of bodily tissues, they clearly increase the risk of certain types of cancer," Dr. Epel said. "On a positive note, there is a tremendously important role of lifestyle, including stress management, for maintaining a healthy hormonal balance. Sufficient sleep and an active lifestyle have potent effects on hormonal balance, increasing GH factors, whereas insufficient sleep and excessive stress can increase cortisol."

Older people are exposed to more chronic stressors, but theydo not necessarily experience greater daily stress, according to Dr. Epel. Adaptive coping strategies successfully used by the elderly include finding meaning in life events, strengthening meaningful social ties, and spiritual or religious beliefs. Even in younger individuals, these strategies tend to be linked to more adaptive profiles of hypothalamic-pituiutary axis function (either diurnal rhythm or reactivity) after facing a major stressor.

"Many of the neuroendocrine changes that occur with aging are not inevitable, as demonstrated by healthy centenarians," Dr. Epel concluded.

Dr. McEwen is a member of the MacArthur Foundation research network on socioeconomic status and is funded by grants from the National Institutes of Health. He is also a coauthor, with Elizabeth Norton Lasley, of the book The End of Stress as We Know It (Joseph Henry Press, 2002). Dr. Epel's research is supported by grants from the National Institute on Mental Health.

APA 2006 Annual Convention: Session 2115 - Invited Address: Annual Neal Miller Lecture, presented August 11, 2006; session 3065 - Invited Address, presented August 12, 2006.


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