Nov. 30, 2004 Increasing scientific evidence suggests that prolonged psychological stress takes its toll on the body, but the exact mechanisms by which stress influences disease processes have remained elusive. Now, scientists report that psychological stress may exact its toll, at least in part, by affecting molecules believed to play a key role in cellular aging and, possibly, disease development.
In the study, published in the November 30 issue of Proceedings of the National Academy of Sciences, the UCSF-led team determined that chronic stress, and the perception of life stress, each had a significant impact on three biological factors -- the length of telomeres, the activity of telomerase, and levels of oxidative stress -- in immune system cells known as peripheral blood mononucleocytes, in healthy premenopausal women.
Telomeres are DNA-protein complexes that cap the ends of chromosomes and promote genetic stability. Each time a cell divides, a portion of telomeric DNA dwindles away, and after many rounds of cell division, so much telomeric DNA has diminished that the aged cell stops dividing. Thus, telomeres play a critical role in determining the number of times a cell divides, its health, and its life span. These factors, in turn, affect the health of the tissues that cells form. Telomerase is an enzyme that replenishes a portion of telomeres with each round of cell division, and protects telomeres. Oxidative stress, which causes DNA damage, has been shown to hasten the shortening of telomeres in cell culture.
The results of the study -- which involved 58 women, ages 20-50, all of whom were biological mothers either of a chronically ill child (39 women, so-called "caregivers") or a healthy child (19 women, or "controls") -- were dramatic.
As expected, most women who cared for a chronically ill child reported that they were more stressed than women in the control group, though, as a group, their biological markers were not different from those of the controls. However, in one of the study's key findings, the duration of caregiving -- after controlling for the age of the women -- proved critical: The more years of care giving, the shorter the length of the telomeres, the lower the telomerase activity, and the greater the oxidative stress.
Moreover, the perception of being stressed correlated in both the caregiver and control groups with the biological markers. In fact, in the most stunning result, the telomeres of women with the highest perceived psychological stress -- across both groups -- had undergone the equivalent of approximately 10 years of additional aging, compared with the women across both groups who had the lowest perception of being stressed. The highest-stress group also had significantly decreased telomerase activity and higher oxidative stress than the lowest-stress group.
"The results were striking," says co-author Elizabeth Blackburn, PhD, Morris Herzstein Professor of Biology and Physiology in the Department of Biochemistry and Biophysics at UCSF. "This is the first evidence that chronic psychological stress -- and how a person perceives stress -- may damp down telomerase and have a significant impact on the length of telomeres, suggesting that stress may modulate the rate of cellular aging."
The link from mind to body
"Numerous studies have solidly demonstrated a link between chronic psychological stress and indices of impaired health, including cardiovascular disease and weakened immune function," says lead author Elissa Epel, PhD, UCSF assistant professor of psychiatry. "The new findings suggest a cellular mechanism for how chronic stress may cause premature onset of disease. Anecdotal evidence and scientific evidence has have suggested that chronic stress can take years off your life; the implications of this study are that this is true at the cellular level. Chronic stress appears to have the potential to shorten the life of cells, at least immune cells."
While it is not yet clear how psychological stress impacts telomeres, the team suspects stress hormones may play a role.
The next investigative steps
A next step in the research will be determining if prolonged psychological stress has an impact on telomeres in other types of cells, such as cells of the lining of the cardiovascular system.
The scientists also plan to further examine the impact of prolonged psychological stress on immune system cells, which mount the body's healing response to wounds, and defenses against illness. When the immune system needs to rev up, it produces more defense cells, which requires high levels of the telomerase enzyme, in order to maintain telomere length, thus allowing for additional rounds of cell division. The current study suggests that, for people under chronic stress, the telomerase activity of their immune cells might be impaired.
The current study represented a one-time snapshot of the biological markers in the women. Both the caregivers and controls were given a standardized 10-item questionnaire assessing their level of perceived stress during the previous month, and measurements of their objective stress (caregiver status, and duration of caregiving stress) were collected. The data was then correlated with the indices of cell aging (telomerase and telomere length).
The team is now conducting a long-term study in which the length of telomeres will be measured repeatedly in participants to test whether the rate of telomere shortening in individuals with higher reported levels of stress is actually faster than in those with lower reported levels of stress.
If the findings bear out, there would be numerous implications for clinical intervention, says Epel. The effect of prolonged psychological stress on telomeres presumably takes many years, which could make it possible to intervene. The team wants to carry out clinical trials to see if stress reduction interventions, such as meditation, yoga or cognitive-behavioral therapy, would increase telomerase activity and telomere length -- or slow the rate of telomere shortening -- in individuals.
At this point, there is not a routine test for assessing telomerase activity or telomere length in cells, and scientists are years away from knowing enough about the correlation between chronic psychological stress and these biological markers to proceed in this direction.
However, if the evidence that telomere length is a risk factor for disease becomes more established, it's possible, the scientists say, that prematurely shortened telomeres might some day be a traditional health-risk factor, such as high LDL cholesterol. And if this were the case, drugs that activated the telomerase enzyme just enough to forestall over-shortening of telomeres might be administered.
Co-authors of the study were Richard M. Cawthon, MD, PhD, Department of Human Genetics, University of Utah, who also served as a co-senior author; Jue Lin, PhD, UCSF Department of Biochemistry and Biophysics; Firdaus S. Dhabhar, PhD, Department of Oral Biology, College of Dentistry, Molecular Virology, Immunology and Medical Genetics, College of Medicine, Ohio State University; Nancy E. Adler, PhD, UCSF professor and vice chair of psychiatry, and Jason D. Morrow, PhD, Department of Medicine and Pharmacology, Vanderbilt University School of Medicine.
The study was funded by the John D. & Catherine T. MacArthur Foundation, the Hellman Family Fund, the Steven and Michele Kirsch Foundation, the Burroughs Wellcome Fund Clinical Scientists Award in Translational Research, the Dana Foundation and the National Institutes of Health.
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