Good stress, bad stress and oxidative stress: Insights from anticipatory cortisol reactivity
Introduction
During periods of intense stress, people are sometimes said to have “aged before your eyes.” This popular idiom reflects the widespread cultural belief that chronic psychological stress can accelerate the aging process. Moreover, it is consistent with accumulating evidence that individuals exposed to chronic stress show signs of accelerated biological aging, such as systemic inflammation and shorter telomere length (Epel et al., 2004, Damjanovic et al., 2007, Gouin et al., 2008, Humphreys et al., 2012). Conversely, it implies the coveted possibility that if we could uncover the mechanisms of this process, we might discover the means to postpone the onset of diseases of aging.
The Free Radical Theory of Aging (Harman, 1956) proposed that accumulation of oxidative damage over time causes cellular aging and contributes to the onset of age-related disease. This implies that it might be possible to slow the physical and cognitive decline associated with aging by mitigating oxidative damage. While oxidative damage is not the sole cause of biological aging, it is widely believed to be an important player in the aging process (Muller et al., 2007). Various oxidative damage markers are elevated or involved in age-related diseases such as diabetes (Monnier et al., 2006, Poulsen et al., 2012), cancer (Valko et al., 2006), neurodegenerative diseases (Nunomura et al., 2012, Poulsen et al., 2012) and cardiovascular disease (Gutierrez et al., 2006). Oxidative damage is caused by reactive oxygen species (ROS) unmitigated by antioxidants. Under healthy conditions, ROS production is primarily a byproduct of daily mitochondrial respiration (Gutierrez et al., 2006) that fuels basic metabolic processes. Oxidative stress reflects a state of cellular imbalance, in which ROS production exceeds antioxidant mechanisms that neutralize ROS, resulting in oxidative damage to nearby molecules, such as DNA, RNA and lipids. Some of the most interesting markers in terms of their relevance to disease processes include 8-iso-prostaglandin F2α (IsoP), a marker of lipid peroxidation, 8-hydroxyguanosine (8-oxoG), a marker that primarily reflects damage to RNA, and 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of damage to DNA (Poulsen et al., 2012). IsoP and 8-OHdG are among the most commonly reported markers, in part due to their stability in vivo (Akagi et al., 2003, Milne et al., 2007). 8-oxoG is comparatively less common, but increasingly important (Poulsen et al., 2012); for example, urinary 8-oxoG (but not 8-OHdG) predicted long-term mortality from type 2 diabetes in a recent study (Broedbaek et al., 2011). Although all three markers are considered indicators of oxidative stress, they do not always correlate with one another (Watters et al., 2009), and they may differ for several reasons – e.g., DNA, RNA and lipids differ in their proximity to mitochondria, the primarily producer of ROS, they employ different mechanisms of repair or elimination, and each damage signature may have different pathophysiological consequences (Furukawa et al., 2004, Poulsen et al., 2012).
Psychological stress and distress have been associated with higher levels of oxidative damage (Irie et al., 2003, Epel et al., 2004, Forlenza and Miller, 2006, Gidron et al., 2006). For example, pre-menopausal women caring for a chronically ill child (considered a model of chronic stress exposure) who endorsed greater perceived stress had higher oxidative stress (indexed by the ratio of F2-isoprostanes, or 8-iso-prostaglandin F2α, to vitamin E) and shorter telomere length, a marker of cellular age (Epel et al., 2004). The mechanism remains unclear, and is likely mediated in part by stress-related hormones (e.g., cortisol) as well as health behaviors (Radak et al., 2005, Ballal et al., 2010). If stress-arousal plays an important role, this would suggest that stress-management should be a core component of preventative interventions designed to improve healthy aging.
The glucocorticoid hormone cortisol represents a potentially important mechanism linking chronic stress with accelerated aging. When events are perceived as stressful, and particularly when the stressor evokes negative affect or social threat (Dickerson and Kemeny, 2004), this may induce increased cortisol secretion, which mobilizes the metabolic energy to cope with stressors. One standardized experimental task used to elicit a stress-induced cortisol increase (i.e., “reactivity”) is the Trier Social Stress Task (Kirschbaum et al., 1993). Individuals exhibit relatively stable individual differences in cortisol reactivity to acute stress (Kirschbaum et al., 1995). Hence, individuals with high cortisol reactivity who are exposed to chronic stressors that persistently evoke a reactivity response are more likely to exhibit adverse health effects. 24-h urinary excretion of cortisol has previously been linked cross-sectionally with elevated markers of DNA and RNA damage in older adults (Joergensen et al., 2011); however, that study did not directly link cortisol or oxidative damage markers with psychological stress or stress-induced cortisol reactivity.
It is generally assumed that cortisol reactivity is best captured by peak secretion, occurring between 21 and 40 min following stressor onset (Dickerson and Kemeny, 2004). However, converging evidence from psychoneuroendocrinology and systems biology (Aschbacher et al., 2012) suggests that transient stress-arousal responses should also be assessed by other features of the dynamic response. It takes approximately 10 min for a stress response initiated in the hypothalamus to promote a detectable increase in peripheral cortisol (Sapolsky et al., 2000), and these kinetics may have clinical importance for health (Aschbacher and Kemeny, 2011, Aschbacher et al., 2012). When the principles of system robustness (Kitano, 2007) are applied to biological stress systems, robustness theory suggests that a heightened response to stress may help the body optimize performance to frequently encountered stressors. This may occur during chronic stress. In animal models, chronic stress exposure reorganizes neural networks regulating neuroendocrine function, providing an anatomical basis for more excitable cortisol responses to stress (Miklos and Kovacs, 2012). Hence, we propose that “anticipatory” cortisol reactivity (i.e., increases during psychological anticipation of the stressor) may be an important marker of a central nervous system that is “primed” for heightened stress-reactivity. Chronically stressed individuals may develop a heightened tendency to anticipate stress and mount a rapid cortisol response, which could increase vulnerability to oxidative stress and accelerate biological aging (Drabant et al., 2011, O’Donovan et al., 2012, Tomiyama et al., 2012).
Although the term “stress” carries a negative connotation, evidence suggests that under certain circumstances, stress exposures may have the potential to enhance an organism's performance and resilience. The first evidence that low-to-moderate doses of stress may have beneficial effects (“eustress”) emerged over a century ago as an “inverted U” relationship between arousal and performance (Yerkes and Dodson, 1908). This psychological principle finds its biological doppelgänger in the myriad examples of inverted U relationships between glucocorticoid actions and various physiological targets (Sapolsky, 1997). For example, cortisol bears an inverted U-shaped relationship with mitochondrial function, a key regulator of oxidative stress (Du et al., 2009). In cell culture models, brief administration of high-dose cortisol resulted in improved mitochondrial function and neuroprotective effects, whereas long-term high-dose cortisol administration dramatically decreased mitochondrial function and promoted cell death (Du et al., 2009). Moreover, at low concentrations, reactive oxygen and lipid species activate cytoprotective pathways that increase antioxidants (Gutierrez et al., 2006). Corticosterone administered at the time of immune activation in doses that mimic a physiological stress response enhances the ensuing immune response, while pharmacological doses or chronic administration are immune-suppressive (Dhabhar and McEwen, 1999).
Extrapolating from these U-shaped relationships, this study hypothesized that greater perceived stress over the previous month and anticipatory cortisol reactivity to an acute stress task will be significantly associated with increased oxidative damage among chronically stressed caregivers. In contrast, among low-stress controls, these same factors either will be not be significantly associated with oxidative damage, or will be associated with decreased oxidative damage, a manifestation of eustress and psychobiological resilience (Fig. 1). The conceptual framework was tested simultaneously in a full moderated mediation model with two primary component hypotheses: (1) anticipatory cortisol reactivity will mediate associations between perceived stress and oxidative damage markers, and (2) the indirect path from perceived stress to oxidative damage via cortisol reactivity will be significant among chronically stressed caregivers, but not among age-matched low-stress controls. Secondarily, we explored the “eustress” hypothesis in controls, or the idea that moderate stress may have salutary effects on oxidative damage.
Section snippets
Participants
This study was conducted as part of a larger study of caregiving stress and biological aging among post-menopausal women. A subset of 48 participants from the larger study participated in an acute laboratory stress task and had data available for analysis in the current study. Twenty-five participants were caregivers of a relative with dementia and twenty-three were age-matched controls with healthy spouses. Caregivers had provided care for 4.7 years on average (range: 8 months–11.42 years).
Group comparisons
Caregivers (CGs) and controls (NCs) did not significantly differ on age, BMI, Caucasian race/ethnicity, education, being a previous smoker, alcohol use, and the presence of any physician-diagnosed medical problem (all p's > .12). There was a non-significant trend for CG to report less exercise than NC (p = .09). CG were significantly more likely to use NSAIDs (9 CG versus 2 NC, p = .04), but reported no differences in the use of statins or vitamins potentially containing antioxidants (all p's > .60).
Discussion
Psychological stress and its biological mediators are increasingly recognized as important factors that influence the rate of biological aging. However, the field is still in the process of defining a road map to clarify under what circumstances psychological stress activates “eustress” responses and psychobiological resilience mechanisms, or alternatively, promotes premature aging and morbidity (Dhabhar et al., 2012). Whereas substantially more is known with regards to the beneficial and
Role of funding sources
This research was supported in part by funding from the NIH/NIA grant R01 AG030424-01A2, as well as support for the first author from the NIH/NHLBI grant K23 HL112955 and The Institute for Integrative Health, Baltimore, MD. The CTSI CCRC and the Core Immunology Lab were supported by NIH/NCRR UCSF-CTSI Grant No. UL1 RR024131. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Conflict of interest
No authors have conflicts of interest to declare.
Acknowledgments
We thank Aric Prather, Shamini Jain and the Samueli Institute, Jean Tillie and Wendy Wolfson for their technical and intellectual contributions to the study.
References (54)
- et al.
Linking disease symptoms and subtypes with personalized systems-based phenotypes: a proof of concept study
Brain Behav. Immun.
(2012) - et al.
New directions in linking the dynamics of affective and stress-arousal systems
Brain Behav. Immun.
(2011) - et al.
Stress-induced redistribution of immune cells-from barracks to boulevards to battlefields: a tale of three hormones – Curt Richter Award Winner
Psychoneuroendocrinology
(2012) - et al.
Experiential, autonomic, and neural responses during threat anticipation vary as a function of threat intensity and neuroticism
Neuroimage
(2011) - et al.
Dynamics of telomerase activity in response to acute psychological stress
Brain Behav. Immun.
(2010) - et al.
RNA as a new target for toxic and protective agents
Mutat. Res.
(2008) - et al.
Psychological determinants of the cortisol stress response: the role of anticipatory cognitive appraisal
Psychoneuroendocrinology
(2005) - et al.
The relation between psychological factors and DNA-damage: a critical review
Biol. Psychol.
(2006) - et al.
Depressive state relates to female oxidative DNA damage via neutrophil activation
Biochem. Biophys. Res. Commun.
(2003) - et al.
Psychobiological allostasis: resistance, resilience and vulnerability
Trends Cogn. Sci.
(2011)
The effect of escitalopram versus placebo on perceived stress and salivary cortisol in healthy first-degree relatives of patients with depression – a randomised trial
Psychiatry Res.
Reorganization of synaptic inputs to the hypothalamic paraventricular nucleus during chronic psychogenic stress in rats
Biol. Psychiatry
Trends in oxidative aging theories
Free Radic. Biol. Med.
Stress appraisals and cellular aging: a key role for anticipatory threat in the relationship between psychological stress and telomere length
Brain Behav. Immun.
RNA modifications by oxidation: a novel disease mechanism?
Free Radic. Biol. Med.
Does cellular aging relate to patterns of allostasis? An examination of basal and stress reactive HPA axis activity and telomere length
Physiol. Behav.
Free radicals, metals and antioxidants in oxidative stress-induced cancer
Chem. Biol. Interact.
Comparison of glucocorticoid-receptor binding kinetics with predictions from a biomolecular model
J. Biol. Chem.
Significance of 8-hydroxy-2′-deoxyguanosine levels in patients with chronic renal failure
Nephrology
Obesogenic high fat western diet induces oxidative stress and apoptosis in rat heart
Mol. Cell. Biochem.
Urinary markers of nucleic acid oxidation and long-term mortality of newly diagnosed type 2 diabetic patients
Diabetes Care
Who's stressed? Distributions of psychological stress in the United States in probability samples from 1983, 2006, and 2009
J. Appl. Soc. Psychol.
A global measure of perceived stress
J. Health Soc. Behav.
Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients
J. Immunol.
Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection and immunopathology
Ann. N.Y. Acad. Sci.
Enhancing versus suppressive effects of stress hormones on skin immune function
PNAS
Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research
Psychol. Bull.
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