Molecular consequences of psychological stress in human aging M. Moreno-Villanueva, A. B¨urkle PII: DOI: Reference:
S0531-5565(14)00350-7 doi: 10.1016/j.exger.2014.12.003 EXG 9548
To appear in:
Experimental Gerontology
Received date: Revised date: Accepted date:
23 October 2014 24 November 2014 2 December 2014
Please cite this article as: Moreno-Villanueva, M., B¨ urkle, A., Molecular consequences of psychological stress in human aging, Experimental Gerontology (2014), doi: 10.1016/j.exger.2014.12.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Molecular consequences of psychological stress in human aging
*
RI
PT
Moreno-Villanueva M and Bürkle A
University of Konstanz, Molecular Toxicology Group, Department of Biology, D-78457
Address all correspondence to: María Moreno-Villanueva, Molecular Toxicology Group,
NU
*
SC
Konstanz, Germany
MA
Department of Biology, Box 628 University of Konstanz, 78457 Konstanz, Germany. Telephone +49 7531 884414; Fax +49 7531 884033
AC CE P
Abstract
TE
D
Email: [email protected]
Psychological stress has often been described as a feeling of being overwhelmed by the necessity of constant adjustment to an individual's changing environment. Stress affects people of all ages, but the lives of the elderly may particularly be affected. Major changes can cause anxiety leading to feelings of insecurity and/or loss of self-esteem and depression. The cellular mechanisms underlying psychological stress are poorly understood. This review focuses on the physical and molecular consequences of psychological stress linked to aging processes and, in particular, how molecular changes induced by psychological stress can compromise healthy aging.
Keywords
ACCEPTED MANUSCRIPT 2 Aging; Psychological stress
psychological
stress
is
an
uncomfortable
RI
By definition,
PT
1. Introduction
emotional
experience
SC
accompanied by predictable biochemical, physiological and behavioral changes (Baum, 1990). To some extent, stress has beneficial effects; an activation of the sympathetic
NU
nervous system secreting the catecholamines adrenaline and noradrenaline, for
MA
example, is essential in the ‘fight-or-flight’ response. However this stress response also implicates immunosuppression, growth inhibition and enhanced catabolism and it is
TE
have health consequences.
D
generally transient. Constant and persistent stress over an extended period of time does
AC CE P
1.1 Physical mechanisms involved in psychological stress
Three systems are directly involved in the physiology of stress: the nervous system, the endocrine system and the immune system, all of which can be affected by perceived threats (Everly, 2006). Two endocrine systems respond to psychological stress: the hypothalamic-pituitary-adrenocortical axis (HPA) and the sympathetic-adrenal-medullary (SAM) system. The primary effector of HPA activation in humans is cortisol, which is responsible for anti-inflammatory responses, metabolism of carbohydrates, lipids and proteins, and gluconeogenesis. Secretion of catecholamines occurs in response to SAM activation, which plays an important role in the regulation of cardiovascular, pulmonary, hepatic, skeletal muscle, and immune systems. Prolonged or repeated activation of the HPA and SAM systems can interfere with the control of other physiological systems,
ACCEPTED MANUSCRIPT 3 resulting in increased risk for physical and psychiatric disorders (Cohen et al., 1995,
PT
McEwen, 1998)
RI
1.2 Psychological stress and diseases
SC
Effects of stress on disease are supported by experimental evidence from animal as well as human studies. Exposure to chronic stress is known to result in long-term or
NU
permanent changes in the emotional, physiological, and behavioral responses, which
MA
influences susceptibility to disease. High stress levels affect the immune, cardiovascular, neuroendocrine and central nervous systems (Anderson, 1998). People who suffer from depression and anxiety are at twice the risk for heart disease than people without these
TE
D
conditions (Anderson and Anderson, 2003). In addition, there is an association between acute and chronic stress and a person's abuse of addictive substances (Sinha, 2008).
AC CE P
Some studies have even suggested that unhealthy chronic stress management, such as overeating "comfort" food items, has contributed to the growing obesity epidemic (Dallman et al., 2003). Effects of stress on the regulation of immune and inflammatory processes have the potential to influence depression as well as infectious, autoimmune, and coronary artery disease and at least some types of cancer (Kiecolt-Glaser et al., 2002). Psychological stress alters immune function through the release of HPA and SAM hormones that bind to and alter the functions of immune cells (Padgett and Glaser, 2003) and cortisol is able to cross the blood brain barrier and bind to receptors in the hippocampus. Long-term production of stress hormones induces memory impairments, shrinking and atrophy of the hippocampus (Lupien et al., 1998). Psychological disorders are also associated with an increase in the production of reactive oxygen species (ROS) (Salim, 2014), and these may damage the DNA and increase cancer risk.
ACCEPTED MANUSCRIPT 4
PT
1.3 Psychological stress and aging
Over time, the brain loses its capability of regulating hormone levels. Aging is associated
RI
with greater HPA axis reactivity to psychological stress (Traustadottir et al., 2005).
SC
Furthermore long-term emotional distress may even increase the risk of Alzheimer's disease (Wilson et al., 2003). Stress comprises both an emotional and a physical
NU
component, and both can be especially detrimental in the elderly. In this context it should
MA
be noted that chronic somatic illness, which is very common in the elderly, is also associated with increased rates of psychological disorders (Harter et al., 2007). Furthermore older people can experience emotional and psychological stress not only
TE
D
related to increased disability and/or difficulty in carrying out daily activities but also related to increased health problems. Additionally, elderly people often experience a
AC CE P
decreased sense of well-being and satisfaction with life, e.g. loneliness, isolation or loss of a loved one.
Successful aging involves the maintenance of mental, physical and social health and it is closely linked with quality of life. Butler (1991) defines it in terms of four dimensions of fitness: physical, intellectual, social, and purpose fitness (Butler, 1991). Physical fitness refers to muscle strength, resilience, and ability. Challenges, which often go hand-inhand with aging and can cause both short-term and chronic stress, may include serious illness, such as cancer, loss of memory, heart disease or arthritis.
1.4 Molecular consequences of psychological stress and aging
ACCEPTED MANUSCRIPT 5 There is increasing evidence that psychological stress and mental disorders are associated with molecular and cellular signs of accelerated aging. However the exact
PT
mechanisms by which stress influences aging processes are as yet unclear. Strikingly, a large body of data suggest that psychological stress may involve molecules believed to
RI
play a key role in cellular aging. It was demonstrated, for example, that women with the
SC
highest levels of perceived stress have telomeres shorter by the equivalent of at least ten years of additional aging compared to low-stress women (Epel et al., 2004). Recently
NU
several studies have added further weight to the association between traumatic stress
MA
and telomere length (Zhang et al., 2014, Jergovic et al., 2014, Shalev et al., 2014, Boks et al., 2014) suggesting that traumatic stress has an impact on aging at the cellular level. In perfect congruence with this finding are recent data on N-glycosylation profiling of
TE
D
plasma in patients suffering from posttraumatic stress disorders (PTSD): Specific changes in the pattern of N-glycosylation had been shown to occur during aging and
AC CE P
were proposed as a biomarker for physiological aging (Vanhooren et al., 2010). We could show recently that individuals with PTSD and trauma-exposed individuals present a shift in the N-glycosylation profiles equivalent to an advancement of the aging process by 15 years (Moreno-Villanueva, Morath et al., 2013) (Fig. 1). Furthermore, accumulation of nuclear DNA damage has been discussed as a direct cause of aging (Best, 2009). Intriguingly, several studies also demonstrate significant correlations between psychological factors and DNA damage in humans (Gidron et al., 2006). We could show recently that patients suffering from PTSD as well as traumaexposed individuals show an accumulation of DNA damage, as detected by DNA single strand breaks in peripheral blood mononuclear cells (Morath, Moreno-Villanueva et al., 2014) (Fig. 2).
ACCEPTED MANUSCRIPT 6 Interestingly, recent work revealed a pathway involving β-arrestin and the tumour suppressor protein p53, through which DNA damage may accumulate by chronic
PT
activation of the β-adrenergic receptor (Hara et al., 2011). Aging is also associated with increased levels of circulating proinflammatory cytokines, a
RI
phenomenon known as "inflamm-aging" (Michaud et al., 2013). Mental health disorders
SC
have also been associated with elevated circulating pro-inflammatory biomarkers (Maes et al., 2012). Elevated levels of proinflammatory cytokines and chemokine abnormalities
NU
were detected in patients with panic disorder or PTSD (Hoge et al., 2009), and more
MA
generally positive correlations between inflammation and trauma exposure have been reported (Tursich et al., 2014). It should be noted that in the short term, stress hormones
D
inhibit the secretion of proinflammatory cytokines and promote the secretion of anti-
TE
inflammatory cytokines. A chronically activated HPA, however, leads to cortisol resistance, and prolonged chronic stress may increase proinflammatory cytokines while
AC CE P
decreasing anti-inflammatory cytokines (Tian et al., 2014). Likewise, lymphocyte β2adrenergic receptor density was negatively correlated not only with age but also with anxiety, depression, and anger-hostility ratings (Yu et al., 1999). A recent publication shows evidence for the role of glucocorticoids in the diverse molecular mechanisms in response to psychological stress involved in aging and age-related disorders (Hasan et al., 2012).
1.5 Effects of stress therapies on human physiology
Untreated chronic stress can result in serious health conditions including anxiety, insomnia, muscle pain, high blood pressure and a weakened immune system. Chronic stress can be treated with appropriate interventions such as lifestyle and behavioral
ACCEPTED MANUSCRIPT 7 change, psychotherapy, and in some situations, medication (McEwen, 2004). There are several kinds of psychiatric drugs such as antidepressants, anxiolytics, mood stabilizers
PT
and antipsychotics. The antidepressant effect of antipsychotics involves regulation of monoamines, glutamate, gamma-aminobutyric acid (GABA), cortisol, and neurotrophic
RI
factors. However, they have adverse effects including extrapyramidal symptoms, weight
SC
gain, and hyperglycemia (Wang and Si, 2013). Fortunately it has been shown that cognitive therapy can be as effective as medication (DeRubeis et al., 2005). But despite
NU
the extensive use of psychotherapy we still lack a biological perspective on how
MA
psychotherapy works. Changes in neurophysiology, such as heart rate, respiration rate, muscle tension, and galvanic skin resistance, electroencephalography and brain-imaging markers have been detected after psychotherapy (Riess, 2011). Furthermore we have
TE
D
recently shown that accumulated DNA damage in peripheral blood mononuclear cells from PTSD patients disappeared after psychotherapy, providing proof-of-principle of the
AC CE P
effect of psychotherapy on DNA integrity (Morath, Moreno-Villanueva et al., 2014). Also physical exercise affects psychological well-being (Norris et al., 1992). Physical activity plays a key role in the control of neuroendocrine, autonomic and behavioral responses to psychological stress. However, these responses might depend on the intensity of physical activity. Differential effects of the level of physical activity on different stressrelated neurophysiological systems in response to psychosocial stress have been reported (Rimmele et al., 2009). Furthermore physical activity increases production of endorphins, a type of neurotransmitter in the brain, and helps in treating mild forms of depression and anxiety (Fox, 1999).
2. Discussion
ACCEPTED MANUSCRIPT 8 Evidently there is a strong mutual relationship between physical health and psychological health. Due to the impact of psychological stress on human health there is a need for
PT
investigating the pathways involved in psychological stress at the cellular level. Psychological stress can be manifested in a number of biological markers, which may be
RI
useful for a better understanding of the underlying molecular mechanisms. Interestingly
SC
the same biomarkers identifying biological aging, e.g. telomere shortening, accumulated DNA damage, changes in N-glycosylation profiles, elevated levels of proinflammatory
NU
cytokines and deregulated stress hormones response are also found in several
MA
psychological disorders. This supports the idea that psychological stress may accelerate the somatic aging process, thus compromising healthy aging (Fig. 3). Hasan and collaborators propose that excessive release of glucocorticoids is triggered by chronic
TE
D
psychological stress influencing the immune system, central nervous system, and endocrine system and concomitantly promotes aging (Hasan, Rahman et al., 2012). In
AC CE P
conclusion stress not only makes a person feel older, but in a very real sense, it can accelerate aging.
For older people, who are already at increased risk for illnesses, the managing of stress is particularly important. Older people are more likely to be offered medical therapies such as pharmaceuticals. But drug therapy can produce adverse effects and compliance problems. Other studies have found that social interactions can help older people stay mentally sharp and may reduce the risk of Alzheimer's (Wilson et al., 2007). Moreover individuals with adequate social relationships have a 50% greater likelihood of survival compared to those with poor or insufficient social relationships (Holt-Lunstad et al., 2010). Exercise can actually help block the effects of aging on cortisol levels. A recent study found that physically fit women in their mid-60s had essentially the same response to
ACCEPTED MANUSCRIPT 9 stress as a group of unfit women in their late 20s. In contrast, women in their mid-60s mid who were nott physically fit released much larger amounts of cortisol in response to stress
PT
(Traustadottir, Traustadottir, Bosch et al., 2005). 2005 These findings suggest that appropriate exercise training may be an effective way of modifying some of the neuroendocrine changes
SC
RI
associated with aging.
The importance of psychological treatment for patients with all kinds of somatic diseases
NU
iss being increasingly recogni recognized. ed. However the molecular mechanisms involved in
MA
psychological stress responses are still poorly poor understood and there is a need for understanding nding the effects of psychotherapy on cellular processes. Learning to manage
AC CE P
3. Figures
TE
D
stress might give us a better chance to live a long and healthy life.
ACCEPTED MANUSCRIPT 10 Fig. 1 Scatterplot between the GlycoAge Test and Traumatic load (Reprinted from (Moreno-Villanueva, Villanueva, Morath et al., 2013) Transl Psychiatry, with permission). Low Low-stress
PT
controls, trauma-exposed exposed and PTSD subjects are represented. Higher values in the
AC CE P
TE
D
MA
NU
SC
RI
GlycoAge Test are positively correlated with Traumatic load.
Fig.2 ig.2 DNA damage and DNA repair in patients suffering from post-traumatic post traumatic stress disorders (Reprinted from (Morath, Moreno-Villanueva Moreno Villanueva et al., 2014) Psychother Psychosom, with permission). Fluorescence signal is inversely correlated to DNA strand breaks; a) higher levels of endogenous DNA strand breaks in trauma-exposed trauma exposed and PTSD patients compared to control individuals; b) x-ray-induced x induced DNA repair, no significant differences were detected between the three groups.
ACCEPTED MANUSCRIPT
AC CE P
TE
D
MA
NU
SC
RI
PT
11
Fig. 3 Psychological stress affects physiological aging process creating a downward spiral. Lose of physical functions in the elderly promotes depression and anxiety and this in turn might accelerate the physiological aging process.
References
Anderson, N. B., 1998. Levels of Analysis in Health Science: A Framework for Integrating Socialbehavioral and Biomedical Research. Annals of the New York Academy of Sciences 840: 563-576. Anderson, N. B. and Anderson, P. E. 2003. Emotional Longevity: Longevity: what erally determines how long you live. New York, Viking.
ACCEPTED MANUSCRIPT 12 Baum, A., 1990. Stress, intrusive imagery, and chronic distress. Health Psychol 9(6): 653-675.
PT
Best, B. P., 2009. Nuclear DNA damage as a direct cause of aging. Rejuvenation Res 12(3): 199-208.
RI
Boks, M. P., Mierlo, H. C., Rutten, B. P., Radstake, T. R., De Witte, L., Geuze, E.,
SC
Horvath, S., Schalkwyk, L. C., Vinkers, C. H., Broen, J. C. and Vermetten, E., 2014. Longitudinal changes of telomere length and epigenetic age related to traumatic stress
NU
and post-traumatic stress disorder. Psychoneuroendocrinology. Baltimore:, John
MA
Butler, R., 1991. Guiding autobiography groups for older adults. Hopkins University Press.
Cohen, S., Kessler, R. C. and Gordon, U. L. 1995. Strategies for measuring stress in
TE
D
studies of psychiatric and physical disorder. Measuring Stress: A Guide for Health and Social Scientists. S. Cohen, R. C. Kessler and U. L. Gordon. New York, NY: Oxford
AC CE P
University Press: 3-26.
Dallman, M. F., Pecoraro, N., Akana, S. F., La Fleur, S. E., Gomez, F., Houshyar, H., Bell, M. E., Bhatnagar, S., Laugero, K. D. and Manalo, S., 2003. Chronic stress and obesity: a new view of "comfort food". Proc Natl Acad Sci U S A 100(20): 1169611701.
DeRubeis, R. J., Hollon, S. D., Amsterdam, J. D., Shelton, R. C., Young, P. R., Salomon, R. M., O'Reardon, J. P., Lovett, M. L., Gladis, M. M., Brown, L. L. and Gallop, R., 2005. Cognitive therapy vs medications in the treatment of moderate to severe depression. Arch Gen Psychiatry 62(4): 409-416. Epel, E. S., Blackburn, E. H., Lin, J., Dhabhar, F. S., Adler, N. E., Morrow, J. D. and Cawthon, R. M., 2004. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A 101(49): 17312-17315.
ACCEPTED MANUSCRIPT 13 Everly, G. 2006. Physiology of stress. Managing Stress: Principles and Strategies for Health and Wellbeing. B. S. Brian and L. Seaward. Canada, Jones and Bartlett
PT
Publishers: 34-48. Fox, K. R., 1999. The influence of physical activity on mental well-being. Public Health
RI
Nutr 2(3A): 411-418.
SC
Gidron, Y., Russ, K., Tissarchondou, H. and Warner, J., 2006. The relation between psychological factors and DNA-damage: a critical review. Biol Psychol 72(3): 291-304.
NU
Hara, M. R., Kovacs, J. J., Whalen, E. J., Rajagopal, S., Strachan, R. T., Grant, W.,
MA
Towers, A. J., Williams, B., Lam, C. M., Xiao, K., Shenoy, S. K., Gregory, S. G., Ahn, S., Duckett, D. R. and Lefkowitz, R. J., 2011. A stress response pathway regulates DNA damage through beta2-adrenoreceptors and beta-arrestin-1. Nature 477(7364):
TE
D
349-353.
Harter, M., Baumeister, H., Reuter, K., Jacobi, F., Hofler, M., Bengel, J. and Wittchen, H.
AC CE P
U., 2007. Increased 12-month prevalence rates of mental disorders in patients with chronic somatic diseases. Psychother Psychosom 76(6): 354-360. Hasan, K. M., Rahman, M. S., Arif, K. M. and Sobhani, M. E., 2012. Psychological stress and aging: role of glucocorticoids (GCs). Age (Dordr) 34(6): 1421-1433. Hoge, E. A., Brandstetter, K., Moshier, S., Pollack, M. H., Wong, K. K. and Simon, N. M., 2009. Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder. Depress Anxiety 26(5): 447-455. Holt-Lunstad, J., Smith, T. B. and Layton, J. B., 2010. Social relationships and mortality risk: a meta-analytic review. PLoS Med 7(7): e1000316. Jergovic, M., Tomicevic, M., Vidovic, A., Bendelja, K., Savic, A., Vojvoda, V., Rac, D., Lovric-Cavar, D., Rabatic, S., Jovanovic, T. and Sabioncello, A., 2014. Telomere
ACCEPTED MANUSCRIPT 14 shortening and immune activity in war veterans with posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 54: 275-283.
PT
Kiecolt-Glaser, J. K., McGuire, L., Robles, T. F. and Glaser, R., 2002. Emotions, morbidity, and mortality: new perspectives from psychoneuroimmunology. Annu Rev
RI
Psychol 53: 83-107.
SC
Lupien, S. J., de Leon, M., de Santi, S., Convit, A., Tarshish, C., Nair, N. P., Thakur, M., McEwen, B. S., Hauger, R. L. and Meaney, M. J., 1998. Cortisol levels during human
NU
aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1(1): 69-73.
MA
Maes, M., Fisar, Z., Medina, M., Scapagnini, G., Nowak, G. and Berk, M., 2012. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And
20(3): 127-150.
TE
D
new drug candidates--Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology
AC CE P
McEwen, B. S., 1998. Protective and damaging effects of stress mediators. N Engl J Med 338(3): 171-179.
McEwen, B. S., 2004. Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann N Y Acad Sci 1032: 1-7. Michaud, M., Balardy, L., Moulis, G., Gaudin, C., Peyrot, C., Vellas, B., Cesari, M. and Nourhashemi, F., 2013. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 14(12): 877-882. Morath, J., Moreno-Villanueva, M., Hamuni, G., Kolassa, S., Ruf-Leuschner, M., Schauer, M., Elbert, T., Burkle, A. and Kolassa, I. T., 2014. Effects of psychotherapy on DNA strand break accumulation originating from traumatic stress. Psychother Psychosom 83(5): 289-297.
ACCEPTED MANUSCRIPT 15 Moreno-Villanueva, M., Morath, J., Vanhooren, V., Elbert, T., Kolassa, S., Libert, C., Burkle, A. and Kolassa, I. T., 2013. N-glycosylation profiling of plasma provides
PT
evidence for accelerated physiological aging in post-traumatic stress disorder. Transl Psychiatry 3: e320.
RI
Norris, R., Carroll, D. and Cochrane, R., 1992. The effects of physical activity and
SC
exercise training on psychological stress and well-being in an adolescent population. J Psychosom Res 36(1): 55-65.
NU
Padgett, D. A. and Glaser, R., 2003. How stress influences the immune response.
MA
Trends Immunol 24(8): 444-448.
Riess, H., 2011. Biomarkers in the psychotherapeutic relationship: the role of physiology, neurobiology, and biological correlates of E.M.P.A.T.H.Y. Harv Rev Psychiatry 19(3):
TE
D
162-174.
Rimmele, U., Seiler, R., Marti, B., Wirtz, P. H., Ehlert, U. and Heinrichs, M., 2009. The
AC CE P
level of physical activity affects adrenal and cardiovascular reactivity to psychosocial stress. Psychoneuroendocrinology 34(2): 190-198. Salim, S., 2014. Oxidative stress and psychological disorders. Curr Neuropharmacol 12(2): 140-147.
Shalev, I., Moffitt, T. E., Braithwaite, A. W., Danese, A., Fleming, N. I., Goldman-Mellor, S., Harrington, H. L., Houts, R. M., Israel, S., Poulton, R., Robertson, S. P., Sugden, K., Williams, B. and Caspi, A., 2014. Internalizing disorders and leukocyte telomere erosion: a prospective study of depression, generalized anxiety disorder and posttraumatic stress disorder. Mol Psychiatry 19(11): 1163-1170. Sinha, R., 2008. Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci 1141: 105-130.
ACCEPTED MANUSCRIPT 16 Tian, R., Hou, G., Li, D. and Yuan, T. F., 2014. A possible change process of inflammatory cytokines in the prolonged chronic stress and its ultimate implications for
PT
health. ScientificWorldJournal 2014: 780616. Traustadottir, T., Bosch, P. R. and Matt, K. S., 2005. The HPA axis response to stress in
RI
women: effects of aging and fitness. Psychoneuroendocrinology 30(4): 392-402.
SC
Tursich, M., Neufeld, R. W., Frewen, P. A., Harricharan, S., Kibler, J. L., Rhind, S. G. and Lanius, R. A., 2014. Association of trauma exposure with proinflammatory activity: a
NU
transdiagnostic meta-analysis. Transl Psychiatry 4: e413.
MA
Vanhooren, V., Dewaele, S., Libert, C., Engelborghs, S., De Deyn, P. P., Toussaint, O., Debacq-Chainiaux, F., Poulain, M., Glupczynski, Y., Franceschi, C., Jaspers, K., van der Pluijm, I., Hoeijmakers, J. and Chen, C. C., 2010. Serum N-glycan profile shift
TE
D
during human ageing. Exp Gerontol 45(10): 738-743. Wang, P. and Si, T., 2013. Use of antipsychotics in the treatment of depressive
AC CE P
disorders. Shanghai Arch Psychiatry 25(3): 134-140. Wilson, R. S., Evans, D. A., Bienias, J. L., Mendes de Leon, C. F., Schneider, J. A. and Bennett, D. A., 2003. Proneness to psychological distress is associated with risk of Alzheimer's disease. Neurology 61(11): 1479-1485. Wilson, R. S., Krueger, K. R., Arnold, S. E., Schneider, J. A., Kelly, J. F., Barnes, L. L., Tang, Y. and Bennett, D. A., 2007. Loneliness and risk of Alzheimer disease. Arch Gen Psychiatry 64(2): 234-240. Yu, B. H., Joel, M. D., dimsdale, E., Paul, M. D. and Mills, J., 1999. ß-Adrenergic Receptor Responsiveness. Neuropsychopharmacology 21(1). Zhang, L., Hu, X. Z., Li, X., Li, H., Smerin, S., Russell, D. and Ursano, R. J., 2014. Telomere length - a cellular aging marker for depression and Post-traumatic Stress Disorder. Med Hypotheses 83(2): 182-185.
S0531-5565(14)00350-7 doi: 10.1016/j.exger.2014.12.003 EXG 9548
To appear in:
Experimental Gerontology
Received date: Revised date: Accepted date:
23 October 2014 24 November 2014 2 December 2014
Please cite this article as: Moreno-Villanueva, M., B¨ urkle, A., Molecular consequences of psychological stress in human aging, Experimental Gerontology (2014), doi: 10.1016/j.exger.2014.12.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Molecular consequences of psychological stress in human aging
*
RI
PT
Moreno-Villanueva M and Bürkle A
University of Konstanz, Molecular Toxicology Group, Department of Biology, D-78457
Address all correspondence to: María Moreno-Villanueva, Molecular Toxicology Group,
NU
*
SC
Konstanz, Germany
MA
Department of Biology, Box 628 University of Konstanz, 78457 Konstanz, Germany. Telephone +49 7531 884414; Fax +49 7531 884033
AC CE P
Abstract
TE
D
Email: [email protected]
Psychological stress has often been described as a feeling of being overwhelmed by the necessity of constant adjustment to an individual's changing environment. Stress affects people of all ages, but the lives of the elderly may particularly be affected. Major changes can cause anxiety leading to feelings of insecurity and/or loss of self-esteem and depression. The cellular mechanisms underlying psychological stress are poorly understood. This review focuses on the physical and molecular consequences of psychological stress linked to aging processes and, in particular, how molecular changes induced by psychological stress can compromise healthy aging.
Keywords
ACCEPTED MANUSCRIPT 2 Aging; Psychological stress
psychological
stress
is
an
uncomfortable
RI
By definition,
PT
1. Introduction
emotional
experience
SC
accompanied by predictable biochemical, physiological and behavioral changes (Baum, 1990). To some extent, stress has beneficial effects; an activation of the sympathetic
NU
nervous system secreting the catecholamines adrenaline and noradrenaline, for
MA
example, is essential in the ‘fight-or-flight’ response. However this stress response also implicates immunosuppression, growth inhibition and enhanced catabolism and it is
TE
have health consequences.
D
generally transient. Constant and persistent stress over an extended period of time does
AC CE P
1.1 Physical mechanisms involved in psychological stress
Three systems are directly involved in the physiology of stress: the nervous system, the endocrine system and the immune system, all of which can be affected by perceived threats (Everly, 2006). Two endocrine systems respond to psychological stress: the hypothalamic-pituitary-adrenocortical axis (HPA) and the sympathetic-adrenal-medullary (SAM) system. The primary effector of HPA activation in humans is cortisol, which is responsible for anti-inflammatory responses, metabolism of carbohydrates, lipids and proteins, and gluconeogenesis. Secretion of catecholamines occurs in response to SAM activation, which plays an important role in the regulation of cardiovascular, pulmonary, hepatic, skeletal muscle, and immune systems. Prolonged or repeated activation of the HPA and SAM systems can interfere with the control of other physiological systems,
ACCEPTED MANUSCRIPT 3 resulting in increased risk for physical and psychiatric disorders (Cohen et al., 1995,
PT
McEwen, 1998)
RI
1.2 Psychological stress and diseases
SC
Effects of stress on disease are supported by experimental evidence from animal as well as human studies. Exposure to chronic stress is known to result in long-term or
NU
permanent changes in the emotional, physiological, and behavioral responses, which
MA
influences susceptibility to disease. High stress levels affect the immune, cardiovascular, neuroendocrine and central nervous systems (Anderson, 1998). People who suffer from depression and anxiety are at twice the risk for heart disease than people without these
TE
D
conditions (Anderson and Anderson, 2003). In addition, there is an association between acute and chronic stress and a person's abuse of addictive substances (Sinha, 2008).
AC CE P
Some studies have even suggested that unhealthy chronic stress management, such as overeating "comfort" food items, has contributed to the growing obesity epidemic (Dallman et al., 2003). Effects of stress on the regulation of immune and inflammatory processes have the potential to influence depression as well as infectious, autoimmune, and coronary artery disease and at least some types of cancer (Kiecolt-Glaser et al., 2002). Psychological stress alters immune function through the release of HPA and SAM hormones that bind to and alter the functions of immune cells (Padgett and Glaser, 2003) and cortisol is able to cross the blood brain barrier and bind to receptors in the hippocampus. Long-term production of stress hormones induces memory impairments, shrinking and atrophy of the hippocampus (Lupien et al., 1998). Psychological disorders are also associated with an increase in the production of reactive oxygen species (ROS) (Salim, 2014), and these may damage the DNA and increase cancer risk.
ACCEPTED MANUSCRIPT 4
PT
1.3 Psychological stress and aging
Over time, the brain loses its capability of regulating hormone levels. Aging is associated
RI
with greater HPA axis reactivity to psychological stress (Traustadottir et al., 2005).
SC
Furthermore long-term emotional distress may even increase the risk of Alzheimer's disease (Wilson et al., 2003). Stress comprises both an emotional and a physical
NU
component, and both can be especially detrimental in the elderly. In this context it should
MA
be noted that chronic somatic illness, which is very common in the elderly, is also associated with increased rates of psychological disorders (Harter et al., 2007). Furthermore older people can experience emotional and psychological stress not only
TE
D
related to increased disability and/or difficulty in carrying out daily activities but also related to increased health problems. Additionally, elderly people often experience a
AC CE P
decreased sense of well-being and satisfaction with life, e.g. loneliness, isolation or loss of a loved one.
Successful aging involves the maintenance of mental, physical and social health and it is closely linked with quality of life. Butler (1991) defines it in terms of four dimensions of fitness: physical, intellectual, social, and purpose fitness (Butler, 1991). Physical fitness refers to muscle strength, resilience, and ability. Challenges, which often go hand-inhand with aging and can cause both short-term and chronic stress, may include serious illness, such as cancer, loss of memory, heart disease or arthritis.
1.4 Molecular consequences of psychological stress and aging
ACCEPTED MANUSCRIPT 5 There is increasing evidence that psychological stress and mental disorders are associated with molecular and cellular signs of accelerated aging. However the exact
PT
mechanisms by which stress influences aging processes are as yet unclear. Strikingly, a large body of data suggest that psychological stress may involve molecules believed to
RI
play a key role in cellular aging. It was demonstrated, for example, that women with the
SC
highest levels of perceived stress have telomeres shorter by the equivalent of at least ten years of additional aging compared to low-stress women (Epel et al., 2004). Recently
NU
several studies have added further weight to the association between traumatic stress
MA
and telomere length (Zhang et al., 2014, Jergovic et al., 2014, Shalev et al., 2014, Boks et al., 2014) suggesting that traumatic stress has an impact on aging at the cellular level. In perfect congruence with this finding are recent data on N-glycosylation profiling of
TE
D
plasma in patients suffering from posttraumatic stress disorders (PTSD): Specific changes in the pattern of N-glycosylation had been shown to occur during aging and
AC CE P
were proposed as a biomarker for physiological aging (Vanhooren et al., 2010). We could show recently that individuals with PTSD and trauma-exposed individuals present a shift in the N-glycosylation profiles equivalent to an advancement of the aging process by 15 years (Moreno-Villanueva, Morath et al., 2013) (Fig. 1). Furthermore, accumulation of nuclear DNA damage has been discussed as a direct cause of aging (Best, 2009). Intriguingly, several studies also demonstrate significant correlations between psychological factors and DNA damage in humans (Gidron et al., 2006). We could show recently that patients suffering from PTSD as well as traumaexposed individuals show an accumulation of DNA damage, as detected by DNA single strand breaks in peripheral blood mononuclear cells (Morath, Moreno-Villanueva et al., 2014) (Fig. 2).
ACCEPTED MANUSCRIPT 6 Interestingly, recent work revealed a pathway involving β-arrestin and the tumour suppressor protein p53, through which DNA damage may accumulate by chronic
PT
activation of the β-adrenergic receptor (Hara et al., 2011). Aging is also associated with increased levels of circulating proinflammatory cytokines, a
RI
phenomenon known as "inflamm-aging" (Michaud et al., 2013). Mental health disorders
SC
have also been associated with elevated circulating pro-inflammatory biomarkers (Maes et al., 2012). Elevated levels of proinflammatory cytokines and chemokine abnormalities
NU
were detected in patients with panic disorder or PTSD (Hoge et al., 2009), and more
MA
generally positive correlations between inflammation and trauma exposure have been reported (Tursich et al., 2014). It should be noted that in the short term, stress hormones
D
inhibit the secretion of proinflammatory cytokines and promote the secretion of anti-
TE
inflammatory cytokines. A chronically activated HPA, however, leads to cortisol resistance, and prolonged chronic stress may increase proinflammatory cytokines while
AC CE P
decreasing anti-inflammatory cytokines (Tian et al., 2014). Likewise, lymphocyte β2adrenergic receptor density was negatively correlated not only with age but also with anxiety, depression, and anger-hostility ratings (Yu et al., 1999). A recent publication shows evidence for the role of glucocorticoids in the diverse molecular mechanisms in response to psychological stress involved in aging and age-related disorders (Hasan et al., 2012).
1.5 Effects of stress therapies on human physiology
Untreated chronic stress can result in serious health conditions including anxiety, insomnia, muscle pain, high blood pressure and a weakened immune system. Chronic stress can be treated with appropriate interventions such as lifestyle and behavioral
ACCEPTED MANUSCRIPT 7 change, psychotherapy, and in some situations, medication (McEwen, 2004). There are several kinds of psychiatric drugs such as antidepressants, anxiolytics, mood stabilizers
PT
and antipsychotics. The antidepressant effect of antipsychotics involves regulation of monoamines, glutamate, gamma-aminobutyric acid (GABA), cortisol, and neurotrophic
RI
factors. However, they have adverse effects including extrapyramidal symptoms, weight
SC
gain, and hyperglycemia (Wang and Si, 2013). Fortunately it has been shown that cognitive therapy can be as effective as medication (DeRubeis et al., 2005). But despite
NU
the extensive use of psychotherapy we still lack a biological perspective on how
MA
psychotherapy works. Changes in neurophysiology, such as heart rate, respiration rate, muscle tension, and galvanic skin resistance, electroencephalography and brain-imaging markers have been detected after psychotherapy (Riess, 2011). Furthermore we have
TE
D
recently shown that accumulated DNA damage in peripheral blood mononuclear cells from PTSD patients disappeared after psychotherapy, providing proof-of-principle of the
AC CE P
effect of psychotherapy on DNA integrity (Morath, Moreno-Villanueva et al., 2014). Also physical exercise affects psychological well-being (Norris et al., 1992). Physical activity plays a key role in the control of neuroendocrine, autonomic and behavioral responses to psychological stress. However, these responses might depend on the intensity of physical activity. Differential effects of the level of physical activity on different stressrelated neurophysiological systems in response to psychosocial stress have been reported (Rimmele et al., 2009). Furthermore physical activity increases production of endorphins, a type of neurotransmitter in the brain, and helps in treating mild forms of depression and anxiety (Fox, 1999).
2. Discussion
ACCEPTED MANUSCRIPT 8 Evidently there is a strong mutual relationship between physical health and psychological health. Due to the impact of psychological stress on human health there is a need for
PT
investigating the pathways involved in psychological stress at the cellular level. Psychological stress can be manifested in a number of biological markers, which may be
RI
useful for a better understanding of the underlying molecular mechanisms. Interestingly
SC
the same biomarkers identifying biological aging, e.g. telomere shortening, accumulated DNA damage, changes in N-glycosylation profiles, elevated levels of proinflammatory
NU
cytokines and deregulated stress hormones response are also found in several
MA
psychological disorders. This supports the idea that psychological stress may accelerate the somatic aging process, thus compromising healthy aging (Fig. 3). Hasan and collaborators propose that excessive release of glucocorticoids is triggered by chronic
TE
D
psychological stress influencing the immune system, central nervous system, and endocrine system and concomitantly promotes aging (Hasan, Rahman et al., 2012). In
AC CE P
conclusion stress not only makes a person feel older, but in a very real sense, it can accelerate aging.
For older people, who are already at increased risk for illnesses, the managing of stress is particularly important. Older people are more likely to be offered medical therapies such as pharmaceuticals. But drug therapy can produce adverse effects and compliance problems. Other studies have found that social interactions can help older people stay mentally sharp and may reduce the risk of Alzheimer's (Wilson et al., 2007). Moreover individuals with adequate social relationships have a 50% greater likelihood of survival compared to those with poor or insufficient social relationships (Holt-Lunstad et al., 2010). Exercise can actually help block the effects of aging on cortisol levels. A recent study found that physically fit women in their mid-60s had essentially the same response to
ACCEPTED MANUSCRIPT 9 stress as a group of unfit women in their late 20s. In contrast, women in their mid-60s mid who were nott physically fit released much larger amounts of cortisol in response to stress
PT
(Traustadottir, Traustadottir, Bosch et al., 2005). 2005 These findings suggest that appropriate exercise training may be an effective way of modifying some of the neuroendocrine changes
SC
RI
associated with aging.
The importance of psychological treatment for patients with all kinds of somatic diseases
NU
iss being increasingly recogni recognized. ed. However the molecular mechanisms involved in
MA
psychological stress responses are still poorly poor understood and there is a need for understanding nding the effects of psychotherapy on cellular processes. Learning to manage
AC CE P
3. Figures
TE
D
stress might give us a better chance to live a long and healthy life.
ACCEPTED MANUSCRIPT 10 Fig. 1 Scatterplot between the GlycoAge Test and Traumatic load (Reprinted from (Moreno-Villanueva, Villanueva, Morath et al., 2013) Transl Psychiatry, with permission). Low Low-stress
PT
controls, trauma-exposed exposed and PTSD subjects are represented. Higher values in the
AC CE P
TE
D
MA
NU
SC
RI
GlycoAge Test are positively correlated with Traumatic load.
Fig.2 ig.2 DNA damage and DNA repair in patients suffering from post-traumatic post traumatic stress disorders (Reprinted from (Morath, Moreno-Villanueva Moreno Villanueva et al., 2014) Psychother Psychosom, with permission). Fluorescence signal is inversely correlated to DNA strand breaks; a) higher levels of endogenous DNA strand breaks in trauma-exposed trauma exposed and PTSD patients compared to control individuals; b) x-ray-induced x induced DNA repair, no significant differences were detected between the three groups.
ACCEPTED MANUSCRIPT
AC CE P
TE
D
MA
NU
SC
RI
PT
11
Fig. 3 Psychological stress affects physiological aging process creating a downward spiral. Lose of physical functions in the elderly promotes depression and anxiety and this in turn might accelerate the physiological aging process.
References
Anderson, N. B., 1998. Levels of Analysis in Health Science: A Framework for Integrating Socialbehavioral and Biomedical Research. Annals of the New York Academy of Sciences 840: 563-576. Anderson, N. B. and Anderson, P. E. 2003. Emotional Longevity: Longevity: what erally determines how long you live. New York, Viking.
ACCEPTED MANUSCRIPT 12 Baum, A., 1990. Stress, intrusive imagery, and chronic distress. Health Psychol 9(6): 653-675.
PT
Best, B. P., 2009. Nuclear DNA damage as a direct cause of aging. Rejuvenation Res 12(3): 199-208.
RI
Boks, M. P., Mierlo, H. C., Rutten, B. P., Radstake, T. R., De Witte, L., Geuze, E.,
SC
Horvath, S., Schalkwyk, L. C., Vinkers, C. H., Broen, J. C. and Vermetten, E., 2014. Longitudinal changes of telomere length and epigenetic age related to traumatic stress
NU
and post-traumatic stress disorder. Psychoneuroendocrinology. Baltimore:, John
MA
Butler, R., 1991. Guiding autobiography groups for older adults. Hopkins University Press.
Cohen, S., Kessler, R. C. and Gordon, U. L. 1995. Strategies for measuring stress in
TE
D
studies of psychiatric and physical disorder. Measuring Stress: A Guide for Health and Social Scientists. S. Cohen, R. C. Kessler and U. L. Gordon. New York, NY: Oxford
AC CE P
University Press: 3-26.
Dallman, M. F., Pecoraro, N., Akana, S. F., La Fleur, S. E., Gomez, F., Houshyar, H., Bell, M. E., Bhatnagar, S., Laugero, K. D. and Manalo, S., 2003. Chronic stress and obesity: a new view of "comfort food". Proc Natl Acad Sci U S A 100(20): 1169611701.
DeRubeis, R. J., Hollon, S. D., Amsterdam, J. D., Shelton, R. C., Young, P. R., Salomon, R. M., O'Reardon, J. P., Lovett, M. L., Gladis, M. M., Brown, L. L. and Gallop, R., 2005. Cognitive therapy vs medications in the treatment of moderate to severe depression. Arch Gen Psychiatry 62(4): 409-416. Epel, E. S., Blackburn, E. H., Lin, J., Dhabhar, F. S., Adler, N. E., Morrow, J. D. and Cawthon, R. M., 2004. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A 101(49): 17312-17315.
ACCEPTED MANUSCRIPT 13 Everly, G. 2006. Physiology of stress. Managing Stress: Principles and Strategies for Health and Wellbeing. B. S. Brian and L. Seaward. Canada, Jones and Bartlett
PT
Publishers: 34-48. Fox, K. R., 1999. The influence of physical activity on mental well-being. Public Health
RI
Nutr 2(3A): 411-418.
SC
Gidron, Y., Russ, K., Tissarchondou, H. and Warner, J., 2006. The relation between psychological factors and DNA-damage: a critical review. Biol Psychol 72(3): 291-304.
NU
Hara, M. R., Kovacs, J. J., Whalen, E. J., Rajagopal, S., Strachan, R. T., Grant, W.,
MA
Towers, A. J., Williams, B., Lam, C. M., Xiao, K., Shenoy, S. K., Gregory, S. G., Ahn, S., Duckett, D. R. and Lefkowitz, R. J., 2011. A stress response pathway regulates DNA damage through beta2-adrenoreceptors and beta-arrestin-1. Nature 477(7364):
TE
D
349-353.
Harter, M., Baumeister, H., Reuter, K., Jacobi, F., Hofler, M., Bengel, J. and Wittchen, H.
AC CE P
U., 2007. Increased 12-month prevalence rates of mental disorders in patients with chronic somatic diseases. Psychother Psychosom 76(6): 354-360. Hasan, K. M., Rahman, M. S., Arif, K. M. and Sobhani, M. E., 2012. Psychological stress and aging: role of glucocorticoids (GCs). Age (Dordr) 34(6): 1421-1433. Hoge, E. A., Brandstetter, K., Moshier, S., Pollack, M. H., Wong, K. K. and Simon, N. M., 2009. Broad spectrum of cytokine abnormalities in panic disorder and posttraumatic stress disorder. Depress Anxiety 26(5): 447-455. Holt-Lunstad, J., Smith, T. B. and Layton, J. B., 2010. Social relationships and mortality risk: a meta-analytic review. PLoS Med 7(7): e1000316. Jergovic, M., Tomicevic, M., Vidovic, A., Bendelja, K., Savic, A., Vojvoda, V., Rac, D., Lovric-Cavar, D., Rabatic, S., Jovanovic, T. and Sabioncello, A., 2014. Telomere
ACCEPTED MANUSCRIPT 14 shortening and immune activity in war veterans with posttraumatic stress disorder. Prog Neuropsychopharmacol Biol Psychiatry 54: 275-283.
PT
Kiecolt-Glaser, J. K., McGuire, L., Robles, T. F. and Glaser, R., 2002. Emotions, morbidity, and mortality: new perspectives from psychoneuroimmunology. Annu Rev
RI
Psychol 53: 83-107.
SC
Lupien, S. J., de Leon, M., de Santi, S., Convit, A., Tarshish, C., Nair, N. P., Thakur, M., McEwen, B. S., Hauger, R. L. and Meaney, M. J., 1998. Cortisol levels during human
NU
aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1(1): 69-73.
MA
Maes, M., Fisar, Z., Medina, M., Scapagnini, G., Nowak, G. and Berk, M., 2012. New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And
20(3): 127-150.
TE
D
new drug candidates--Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology
AC CE P
McEwen, B. S., 1998. Protective and damaging effects of stress mediators. N Engl J Med 338(3): 171-179.
McEwen, B. S., 2004. Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann N Y Acad Sci 1032: 1-7. Michaud, M., Balardy, L., Moulis, G., Gaudin, C., Peyrot, C., Vellas, B., Cesari, M. and Nourhashemi, F., 2013. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 14(12): 877-882. Morath, J., Moreno-Villanueva, M., Hamuni, G., Kolassa, S., Ruf-Leuschner, M., Schauer, M., Elbert, T., Burkle, A. and Kolassa, I. T., 2014. Effects of psychotherapy on DNA strand break accumulation originating from traumatic stress. Psychother Psychosom 83(5): 289-297.
ACCEPTED MANUSCRIPT 15 Moreno-Villanueva, M., Morath, J., Vanhooren, V., Elbert, T., Kolassa, S., Libert, C., Burkle, A. and Kolassa, I. T., 2013. N-glycosylation profiling of plasma provides
PT
evidence for accelerated physiological aging in post-traumatic stress disorder. Transl Psychiatry 3: e320.
RI
Norris, R., Carroll, D. and Cochrane, R., 1992. The effects of physical activity and
SC
exercise training on psychological stress and well-being in an adolescent population. J Psychosom Res 36(1): 55-65.
NU
Padgett, D. A. and Glaser, R., 2003. How stress influences the immune response.
MA
Trends Immunol 24(8): 444-448.
Riess, H., 2011. Biomarkers in the psychotherapeutic relationship: the role of physiology, neurobiology, and biological correlates of E.M.P.A.T.H.Y. Harv Rev Psychiatry 19(3):
TE
D
162-174.
Rimmele, U., Seiler, R., Marti, B., Wirtz, P. H., Ehlert, U. and Heinrichs, M., 2009. The
AC CE P
level of physical activity affects adrenal and cardiovascular reactivity to psychosocial stress. Psychoneuroendocrinology 34(2): 190-198. Salim, S., 2014. Oxidative stress and psychological disorders. Curr Neuropharmacol 12(2): 140-147.
Shalev, I., Moffitt, T. E., Braithwaite, A. W., Danese, A., Fleming, N. I., Goldman-Mellor, S., Harrington, H. L., Houts, R. M., Israel, S., Poulton, R., Robertson, S. P., Sugden, K., Williams, B. and Caspi, A., 2014. Internalizing disorders and leukocyte telomere erosion: a prospective study of depression, generalized anxiety disorder and posttraumatic stress disorder. Mol Psychiatry 19(11): 1163-1170. Sinha, R., 2008. Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci 1141: 105-130.
ACCEPTED MANUSCRIPT 16 Tian, R., Hou, G., Li, D. and Yuan, T. F., 2014. A possible change process of inflammatory cytokines in the prolonged chronic stress and its ultimate implications for
PT
health. ScientificWorldJournal 2014: 780616. Traustadottir, T., Bosch, P. R. and Matt, K. S., 2005. The HPA axis response to stress in
RI
women: effects of aging and fitness. Psychoneuroendocrinology 30(4): 392-402.
SC
Tursich, M., Neufeld, R. W., Frewen, P. A., Harricharan, S., Kibler, J. L., Rhind, S. G. and Lanius, R. A., 2014. Association of trauma exposure with proinflammatory activity: a
NU
transdiagnostic meta-analysis. Transl Psychiatry 4: e413.
MA
Vanhooren, V., Dewaele, S., Libert, C., Engelborghs, S., De Deyn, P. P., Toussaint, O., Debacq-Chainiaux, F., Poulain, M., Glupczynski, Y., Franceschi, C., Jaspers, K., van der Pluijm, I., Hoeijmakers, J. and Chen, C. C., 2010. Serum N-glycan profile shift
TE
D
during human ageing. Exp Gerontol 45(10): 738-743. Wang, P. and Si, T., 2013. Use of antipsychotics in the treatment of depressive
AC CE P
disorders. Shanghai Arch Psychiatry 25(3): 134-140. Wilson, R. S., Evans, D. A., Bienias, J. L., Mendes de Leon, C. F., Schneider, J. A. and Bennett, D. A., 2003. Proneness to psychological distress is associated with risk of Alzheimer's disease. Neurology 61(11): 1479-1485. Wilson, R. S., Krueger, K. R., Arnold, S. E., Schneider, J. A., Kelly, J. F., Barnes, L. L., Tang, Y. and Bennett, D. A., 2007. Loneliness and risk of Alzheimer disease. Arch Gen Psychiatry 64(2): 234-240. Yu, B. H., Joel, M. D., dimsdale, E., Paul, M. D. and Mills, J., 1999. ß-Adrenergic Receptor Responsiveness. Neuropsychopharmacology 21(1). Zhang, L., Hu, X. Z., Li, X., Li, H., Smerin, S., Russell, D. and Ursano, R. J., 2014. Telomere length - a cellular aging marker for depression and Post-traumatic Stress Disorder. Med Hypotheses 83(2): 182-185.
