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Stress, our biggest challenge: Part 2

Updated: Apr 15

A long note but to understand stress impacts almost everything in human body we can understand the seriousness of managing stress. If you desire to be healthy stress levels have to be in tolerable limits –otherwise nothing will help.

In part 3 and 4 we discuss what we can do to reduce stress and live better lives.




Effects of Stress on HPA Axis Regulation and Cortisol Dynamics

Cortisol is the primary effector hormone of the HPA axis stress response system. Like other aspects of the endocrine system, the HPA axis is regulated by a negative feedback system, whereby the hypothalamus and the pituitary gland have receptors that detect changes in cortisol levels—for example, cortisol secretion is inhibited when circulating levels rise and is stimulated when levels fall. However, if the HPA axis is repeatedly activated, this trigger increased cortisol output, thereby exposing bodily tissues to excessive concentrations of the hormone (Lovallo 2016McEwen 19982000Miller et al. 2007). Over time, such repetitive activation may lead to tissue damage and contribute to future ill-health by placing excessive pressure on various bodily systems, including the HPA axis (i.e., allostatic load and overload) (McEwen 1998).

Cortisol Responses to Stress and Future Health Risk

A considerable body of research has explored whether individuals who exhibit exaggerated cortisol responses to stress are at increased risk of future ill-health (Bunea et al. 2017Dickerson & Kemeny 2004Lovallo 2016Newman et al. 2007Zorn et al. 2017). This work has been heavily influenced by what is known as the reactivity hypothesis, first applied to examining cardiovascular reactivity to stress (Obrist 1981) and discussed below, which emphasizes that individuals who exhibit the largest increases in BP or heart rate (HR) in response to acute stressors will be at greatest risk of future ill-health. In the context of cortisol reactivity, a number of important studies have found evidence that increased cortisol reactivity to stress is associated with negative health outcomes (e.g., al'Absi & Wittmers 2003Hamer & Steptoe 2012Hamer et al. 20102012). For example, al'Absi & Wittmers (2003) found evidence that enhanced HPA activity in response to an acute stressor was (cross-sectionally) associated with risk of hypertension. Similarly, Hamer et al. (2010), in another cross-sectional investigation, found that heightened reactivity to a stressor was associated with coronary artery calcification (a marker of subclinical coronary atherosclerosis). In a 3-year prospective study of the Whitehall II cohort, Hamer & Steptoe (2012) found a 59% increase in the odds of incident hypertension per standard deviation change in cortisol responsivity to a stressor. In a separate analysis of the same cohort, this group showed that heightened cortisol reactivity to stress was also associated with progression of coronary artery calcification 3 years later (Hamer et al. 2012). Interestingly, these authors noted considerable variation in the cortisol stress responses, with only 40% of participants exhibiting at least 1 mmol/L increase. What about the other 60%? In an exciting development relating to cellular aging, Steptoe et al. (2017) recently found that healthy men and women who were “cortisol responders” to acute stressors had shorter telomeres 3 years later compared to those who were “nonresponders.” These authors argued that cortisol responsivity may mediate, in part, the relationship between psychological stress and cellular aging.

Alongside the work on heightened cortisol reactivity, research has emerged to suggest that smaller increases or blunted cortisol responses to stress may also be indicative of current ill-health or future health risks (Lovallo 2016). Early evidence to suggest that lower cortisol responses to stress are not necessarily protective came from a study of patients who were alcohol dependent and polysubstance abusers. Lovallo et al. (2000) found that control patients exhibited the expected cortisol increase following a speech stress test, whereas patients who were diagnosed as alcohol dependent or alcohol and stimulant dependent did not exhibit a significant cortisol increase. These findings indicated that hyperresponsiveness (also known as a blunted response) may also be a marker of dysregulation of HPA axis functioning.

Surprisingly, over the past 20 years, the health effects of low cortisol and/or blunted cortisol reactivity to stress have received less attention. However, findings from the Dutch Famine Birth Cohort Study have been very influential for our understanding not only of the cortisol reactivity hypothesis but also of the cardiovascular reactivity hypothesis (as outlined below). This cohort study is a large population-based investigation of people who were born in Amsterdam between 1943 and 1947, with a subsample of participants who completed an extensive stress protocol between 2002 and 2004 (Roseboom et al. 2006). In terms of cortisol reactivity to stress, findings from this study showed that lower cortisol stress reactivity was associated with obesity and the risk of developing obesity and with symptoms of depression and anxiety ( de Rooij 2013). Numerous other recent studies have showed that low or blunted cortisol reactivity to stress is associated with high levels of chronic stress and increased risk of negative physical and mental health outcomes (e.g., Lovallo et al. 2019O'Connor et al. 2017Padden et al. 2019Zorn et al. 2017). For example, Padden et al. (2019) reported that blunted cortisol reactivity was the dominant pattern of physiological reactivity that emerged from studies of caregivers of individuals with autism spectrum disorder. In another study, O'Connor et al. (2017) found that individuals who had previously made a suicide attempt exhibited low levels of cortisol in response to an acute stressor compared to control participants. Moreover, the results of a meta-analysis in the area of early-life adversity found evidence of a robust association between early-life adversity and a blunted cortisol response to social stress (Bunea et al. 2017).

Taken together, the evidence is converging to suggest that both heightened and blunted cortisol responses to acute stressors are associated with increased future health risk. To this end, Carroll et al. (2017) have put forward a model of blunted stress reactivity that attempts to integrate the evidence linking exaggerated and blunted stress responses into a single unifying framework. They argue that the health-damaging effects of heightened reactivity to stress are well established especially in relation to cardiovascular pathology; however, our understanding the effects of low or blunted reactivity remains in its infancy. Nevertheless, current theorizing suggests that there is a nonlinear inverted-U relationship, such that high and low levels of cortisol are likely to be deleterious. Similar relationships have been demonstrated for other hormones and important aspects of behavior (cf. O'Connor et al. 2001).

Stress, Cortisol Awakening Response, and Health Outcomes

The diurnal pattern of cortisol production is characterized by two distinct components: the peak levels after awakening [i.e., the cortisol awakening response (CAR)] and the diminishing levels throughout the rest of the day (i.e., the diurnal cortisol slope) (Adam et al. 2017Clow et al. 2010Fries et al. 2009O'Connor et al. 2009Pruessner et al. 1997). As outlined above, cortisol plays an important regulatory function for many of the body's basic biological systems (e.g., metabolic, immune, inflammatory processes), and disruption of its diurnal rhythm is likely to affect the functioning of these systems in ways that may have consequences for health over time (Lupien et al. 2009Sapolsky et al. 2000). A relatively large amount of research has explored the links between diurnal cortisol levels and health outcomes (Adam et al. 2017). We briefly review this literature in the next section, but first we consider the relationship between stress and the CAR.

The CAR, the steep rise in cortisol that occurs in the first 30 to 45 minutes after waking, has been a popular topic of recent research, though its function and regulation are not yet fully understood. There is evidence that the CAR is under different regulatory control from the cortisol that is released across the rest of the day (Clow et al. 2010Schmidt-Reinwald et al. 1999). Moreover, it has been theorized that the function of the CAR is to prepare the individual for the demands of the upcoming day (Powell & Schlotz 2012). The CAR has been linked with stress and a range of health outcomes, though the pattern of results has been mixed (e.g., Adam et al. 2010Chida & Steptoe 2009Clow et al. 2010Gartland et al. 2014O'Connor et al. 2013Steptoe & Serwinski 2016). In terms of psychological stress, a number of studies have found links between stress and increases in the CAR (e.g., De Vugt et al. 2005Wust et al. 2000). Conversely, other evidence has shown that chronic stress may disrupt HPA axis regulation and lead to a blunted CAR (e.g., Mortensen et al. 2019O'Connor et al. 20092013Steptoe & Serwinski 2016Thorn et al. 2006). Furthermore, in terms of health outcomes, a comprehensive meta-analysis by Chida & Steptoe (2009) confirmed similar findings and reported that different psychosocial factors are associated with both enhanced and reduced cortisol awakening responses. In particular, they found that the CAR was positively associated with job stress and general life stress but negatively associated with fatigue, burnout, exhaustion, and post-traumatic stress syndrome. More recently, using a combination of meta-analysis and P-curve analysis, Boggero et al. (2017) also found divergent findings, with depression being linked to higher CAR and post-traumatic stress being linked to lower CAR.

Methodological issues likely contributed to these mixed findings (see expert consensus guidelines in Stalder et al. 2016). Measurement of the CAR is particularly sensitive to protocol violations (e.g., getting out of bed before the first sample is taken or not providing samples at the correct time). Therefore, future research needs to continue to take steps to minimize issues such as participant nonadherence in order to reduce the noise in these findings (e.g., using electronic containers to collect cortisol samples that record the time of collection). In addition, future studies investigating CAR ought to increase the number of measurement days in order to improve the reliability of the CAR measures (Segerstrom et al. 2014).

In terms of the relationship between stress and the CAR, Steptoe & Serwinski (2016) have argued that higher CAR may be observed under conditions that require individuals to actively cope with the demands of the upcoming day, whereas lower CAR may be observed under severely stressful conditions that cannot be dealt with by active behavioral responses. Alternatively, it is our view that the mixed findings may also be explained in terms of allostatic load and overload. For example, it is possible that moderate to high CAR during periods of increased demand and challenge may reflect the normal adaptive response to a stressful environment (allostatic load). However, in the context of fatigue, post-traumatic stress disorder, and burnout, the lower CAR may reflect dysregulation of the HPA axis following exposure to more severe chronic stress over a long period that is consistent with allostatic overload or so-called toxic stress (McEwen 2018). Indeed, this view is consistent with recent meta-analytical evidence in the context of suicide (O'Connor et al. 2016) and, more generally, with a previous review linking chronic stress and the HPA axis (Miller et al. 2007).

In sum, it is clear that the CAR is an important index of HPA axis activity and provides valuable insights into the relationship between psychological factors, HPA axis function, health, and well-being. As is the case with cortisol reactivity to stress, existing evidence suggests that both low and high CAR may be associated with health risk. Future research ought to establish the precise regulatory function of the CAR, incorporating longitudinal designs and repeated assessments.

Stress, the Diurnal Cortisol Slope, and Health Outcomes

The variation in cortisol levels across the day is large and reaches its nadir at bedtime. Like the CAR, the diurnal cortisol slope has been the focus of a great deal of research, and it has been argued that the disruption of cortisol's circadian rhythm may affect a large range of central and peripheral biological systems that contribute to negative physical and mental health outcomes over time (Adam et al. 2017Lupien et al. 2009). A substantial number of studies have found that there is an association between a flatter cortisol slope and adverse outcomes such as depression, cardiovascular disease, inflammation, fatigue, obesity, and suicide attempt (Matthews et al. 2006Nater et al. 2008O'Connor et al. 2020bSchrepf et al. 2014Ruttle et al. 2013). However, other studies have failed to find associations between the diurnal cortisol slope or have yielded inconsistent or contrary findings (e.g., Turner-Cobb et al. 2011Vedhara et al. 2006).

Despite the burgeoning amount of research in this area, the first systematic review and meta-analysis was published only in 2017: Adam et al. (2017) synthesized 179 associations from 80 studies and found consistent evidence showing that flatter cortisol slopes were associated with poorer health outcomes in 10 out of 12 subtypes of emotional and physical health (i.e., cancer, depression, externalizing, internalizing, fatigue, inflammatory/immune response, obesity/body mass index/adiposity, other mental health, and other physical health). Moreover, they reported that the largest effect size was for the inflammatory/immune outcomes. These findings are important because they confirm that a flatter diurnal cortisol slope is associated with a broad range of health outcomes. The authors argue that these results suggest that there may be a general shared mechanism that is common to multiple disease states (Adam et al. 2017). They suggest that these findings provide convincing support for a direct causal pathway linking flattened diurnal cortisol rhythms to dysregulation in multiple downstream biological and behavioral systems and thus to the development of negative health outcomes.

Adam et al. (2017, p. 37) also introduce the concept of stress-related circadian dysregulation (SCiD) and argue that the association between flatter diurnal cortisol and modifications of circadian biology found by the existing research is a sign of SCiD. They suggest that future research on stress and health should focus on identifying the psychosocial origins of the early signs of stress-induced circadian dysregulations, as these changes across multiple biological systems are likely to lead to major mental and physical health problems in the future. Moreover, they argue that multiple coregulatory systems are involved in the development of SCiD, and that interventions should target multiple levels of the system (e.g., psychological, behavioral, and biological) and ultimately aim to correct the expected circadian rhythms rather than correcting those levels per se. This represents a promising area for future investigation.

Stress and Hair Cortisol

An exciting recent advance in the area of stress and health research is the assessment of cortisol in hair. Hair cortisol provides an alternative biomarker of HPA axis activation, free from many of the limitations of other existing biological measures (saliva, urine, and blood). Following the discovery of glucocorticoids in hair in 2004 (Raul et al. 2004), researchers have been exploring the reliability and validity of hair cortisol measurement. A 1-cm hair segment (closest to the scalp) provides a measure of average cortisol secretion over the past month, whereas a 3-cm hair segment provides a measure of cortisol secretion over the past three months. Recent reviews have found that hair cortisol is a reliable indicator of chronic stress and is positively associated with body mass index, waist-to-hip ratio, pregnancy in women undergoing in vitro fertilization, and cardiometabolic risk factors for cardiovascular disease (CVD) such as high BP, diabetes, and adiposity (e.g., Lob & Steptoe 2019Massey et al. 2016Stalder et al. 2017Wright et al. 2015). Future research ought to incorporate hair cortisol measures in the study design and include multiple assessments, ideally in longitudinal studies.

Effects of Stress on Autonomic Nervous System Regulation and Dynamics

The evidence for the role of the ANS in stress and health is overwhelming and extensive. The sympathetic nervous system (SNS), associated with energy mobilization and the fight-or-flight response, and the parasympathetic nervous system (PNS), associated with vegetative and restorative functions and with rest-and-digest, represent the two major branches of the ANS. In good health conditions, these systems are normally in dynamic balance, with the PNS dominating. However, as outlined above, under conditions of stress an imbalance can occur in which fight-or-flight responses are chronically activated, leading to excessive wear and tear on physiological systems (allostatic load). One mechanism that links the ANS to BP is the baroreflex. Pressure-sensitive receptors in the carotid and aortic arches sense increases and decreases in BP and transmit those signals to the brain to produce reflex adjustments in BP via the regulation of sympathetic and parasympathetic outflows in order to maintain blood flow to vital organs such as the brain and heart (Benarroch 2008). Thus, ANS activity as indexed by myocardial contractility, peripheral vascular resistance, HR, and heart rate variability (HRV) works to regulate BP via the baroreflex. Importantly, there is emerging evidence for an important role of the baroreflex in long-term BP regulation (Thrasher 2006).

Autonomic imbalance, in which SNS tone is high and PNS tone is low, is associated with a wide range of disorders and diseases both mental and physical, including internalizing disorders, externalizing disorders, and psychotic disorders as well as cardiometabolic diseases such as hypertension, coronary heart disease, and diabetes (Beauchaine & Thayer 2015Thayer et al. 2010). One of the leading proponents of the autonomic imbalance concept, the cardiologist Stevo Julius, noted that one of the major causes of this autonomic imbalance is the chronic activation of the defense/vigilance response (Julius 1995). From a psychological perspective this defense/vigilance response is associated with perseverative cognition (e.g., worry, rumination, and angry brooding), and a recent meta-analysis has linked such perseverative cognition to endocrine, cardiovascular, and autonomic activities such as increased cortisol, BP, and HR and decreased vagally mediated HRV (Ottaviani et al. 2015). Other meta-analyses have linked perseverative cognition to poorer health behaviors (Clancy et al. 20162020). As noted above, both increased and decreased or blunted responses have been associated with increased risk.

Numerous models of stress have tried to explain these relationships. One of the early models was the recurrent activation model, or the so-called reactivity hypothesis (Krantz & Manuck 1984). In this model, repeated activation of stress systems would lead to poor health outcomes. However, evidence for the generalizability of these increased responses to laboratory tasks to real-life stress responses was found to be limited (Lovallo 2016), thus suggesting other mechanisms through which stress can influence physiological responses. Another early approach that has been largely overlooked is the prevailing state model (Manuck & Krantz 1984). In this model, the large laboratory responses generalized not to exaggerated acute responses but to large generally elevated response levels (i.e., prevailing state) in real life. More recently, as mentioned above, some scholars have proposed models suggesting that blunted responses may be associated with increased risk (Carroll et al. 2017). One way in which these various models can be reconciled is the generalized unsafety theory of stress (GUTS) (Brosschot et al. 201620172018). This model proposes that the fight-or-flight response is in fact the default response that is more or less always on unless turned off by safety. This actually comports well with the autonomic imbalance model advanced by Julius and its association with the defense/vigilance response. As stated by Julius (1995), large-magnitude responses of physiological systems to threat (reactivity) are adaptive, from an evolutionary perspective, and may have been selected for in our ancestors. However, when these responses are prolonged by anticipatory activation or delayed recovery, they can lead to chronic ANS imbalance (i.e., prevailing state). Excessive activation of these systems can lead to their overuse and dysregulation (i.e., blunted responses or allostatic overload). Importantly, Julius notes that in contemporary life it is necessary to dampen this default defense response to reduce the deleterious effects of this previously adaptive rapid and strong defense reaction (Julius 1995). Research increasingly suggests that this is accomplished by the recognition of safety, and that failures to recognize safety signals, rather than perceptions of threat, may be associated with poor mental and physical health (Brosschot et al. 201620172018Craske et al. 2012Mayne et al. 2018). Needless to say, much more work is needed to further validate these intriguing ideas. In the next sections, we provide some of the empirical support for the association of the ANS (particularly BP and HRV) with stress and health.

Effects of Stress on Blood Pressure, Heart Rate, Heart Rate Variability, and Their Dynamics

Numerous studies and meta-analyses have linked BP responses to mental stress to poor health outcomes. This literature is extensive, and here we only summarize some recent reviews and fundamental studies. Gasperin et al. (2009) reported a meta-analysis of cohort studies on the effect of psychological stress on BP reactivity and recovery. They identified 6 eligible cohort studies representing over 34,000 participants. Greater BP responses to psychological stress (i.e., greater reactivity as well as higher recovery levels) were associated with a 21% greater risk of elevated BP 11 years later relative to those with smaller BP responses. The authors suggest that management of psychological stress may be an important component of hypertension management. Landesbergis et al. (2013) examined the association between job strain and ambulatory BP. They reported the results of a meta-analysis of 22 cross-sectional studies and showed that a single exposure to job strain was associated with higher ambulatory systolic BP (SBP) and diastolic BP (DBP). Specifically, they showed that job strain was associated with 3.43 mm Hg higher SBP and 2.07 mm Hg higher DBP during working hours, 2.55 mm Hg higher SBP and 1.90 mm Hg higher DBP at home, and 3.67 mm Hg higher SBP and 2.06 mm Hg higher DBP during sleep. This latter finding is particularly relevant, as sleep should represent a period of relative safety and a lack of BP dipping at night is associated with end organ damage such as left ventricular hypertrophy, myocardial infarction, and stroke (Cuspidi et al. 2010).

Similarly, numerous studies have shown an association between ANS imbalance, as indexed by high HR and low vagally mediated HRV, and poor health outcomes. Some of this work has been summarized elsewhere (Thayer & Lane 2007Thayer et al. 2010) and will not be detailed here. With respect to the role of stress, two systematic reviews have examined the effect of work stress on HRV. Jarczok et al. (2013) systematically reviewed the association between work stress and HRV and found 19 studies representing over 8,000 employees from 10 countries published between 1976 and 2008. The authors reported that adverse work conditions were generally associated with decreased HRV. A recent update of this analysis examined 18 studies published between 2013 and 2019, representing over 29,000 participants, and reported that adverse work conditions again were generally associated with decreased HRV (Jarczok et al. 2020). Given that a recent large study reported that low levels of vagally mediated HRV were associated with elevated risk in the clinical range (odds ratios ranging from 1.5 to 3.5) for a wide range of biomarkers, these reviews of work stress suggest that such stress may have important implications for the risk of developing a wide range of cardiometabolic and inflammatory diseases (Jarczok et al. 2019).

Kivimäki & Steptoe (2018) provide a comprehensive review on the role of stress in the development and progression of cardiovascular disease. They show that pooling data from several large studies into mega-studies has led to an increased understanding of the role of psychological stress in CVD. For example, they reviewed studies on the etiology of CVD in the general population and reported hazard ratios ranging from 1.13 to 2.07 for the association of psychological stressors (as indexed by work stress and childhood stress) with CVD, coronary heart disease, and stroke. They conclude, however, that the evidence for scalable interventions to reduce such risk is scarce. These reviews provide strong evidence that psychological stress can have deleterious effects on health via the ANS. We next examine some primary studies that have investigated the effects of stress on ANS dynamics, including delayed recovery especially during the nighttime.

One area of emerging research focuses on circadian variation of ANS activity and its association with psychological stress. As mentioned above, nighttime or sleep should represent a period of restoration, relative safety, and associated relative decreases in SNS and increases in PNS activity. It has long been reported that elevated HR and BP at night are associated with increased mortality. For example, it has been reported that relative to those with a 10% or greater decrease in SBP or HR at night, individuals who had no SBP decrease but an HR decrease had a hazard ratio for mortality of 1.39, those who had a SBP decrease but no HR decrease had a hazard ratio of 1.46, and those who had neither a HR or a SBP decrease had a hazard ratio of 1.9 (Ben-Dov et al. 2007). Both acute and chronic stress have been associated with a blunted HRV increase at night. In a study of healthy young adults, it was reported that the acute stress of an impending public speech was associated with a blunted nighttime increase in HRV the night before the speech (Hall et al. 2004). Work stress has also been associated with a blunted HRV increase at night, particularly in older workers (Loerbroks et al. 2010). Psychological factors have been associated with nighttime BP as well. Numerous studies have reported associations between stress, job strain, hostility, and perceived discrimination, as well as social integration, social support, and BP dipping, with the deleterious psychological factors being associated with less BP dipping and the salubrious psychological factors being associated with greater BP dipping (e.g., Fallo et al. 2002Fan et al. 2013Tomfohr et al. 2010). For example, a systematic review of the association between social support and BP dipping reported that greater functional social support was associated with a moderate-to-large effect on BP dipping (Fortmann & Gallo 2013). These effects of stress on HRV and BP may be associated via the baroreflex. For example, one study found that lower HRV was associated with blunted BP dipping in patients with resistant hypertension (Salles et al. 2014). Another study reported that low HRV predicted the development of a nondipping BP pattern 2 years later (Dauphinot et al. 2010). Future studies are needed to more fully explicate the associations between psychological factors such as stress and circadian variations in ANS activity.

Models of the effects of stress on ANS function suggest that both large and small responses may be associated with poorer health outcomes. Ultimately, prolonged stress responses are needed to produce deleterious health effects, and data collected during periods of rest or sleep may be particularly informative. Integrative models such as GUTS may help reconcile these seemingly contradictory findings.

The Role of Social Genomics in Elucidating the Relationship Between Stress and Health

Technological and scientific developments in our understanding of the human genome are now providing fascinating insights into the molecular mechanisms by which stress influences health. Specifically, the recognition that gene expression can be influenced by the environment, combined with the development of powerful methods that permit the simultaneous mapping of the entire human genome (Cole 2019), has allowed investigators to explore whether and how external factors like stress regulate the activity of our genes and, therefore, influence health.

This exploration started just over a decade ago with a small study that focused not on stress but on its coconspirator, social isolation (Cole et al. 2007). Drawing on decades of research showing that socially isolated individuals have an increased risk of disease and mortality, the group examined whether patterns of gene expression differed in a systematic way between individuals reporting high versus low levels of subjective loneliness (based on responses to the UCLA Loneliness Scale) over a 3-year period. They observed that the immune cells of chronically lonely individuals were characterized by an upregulation or increased expression of pro-inflammatory genes, and the downregulation of genes associated with antiviral resistance and antibody production. Put another way, the genes associated with increasing the risk of or exacerbating inflammation-related conditions were more likely to be switched on, and those associated with protection from viral illness were more likely to be switched off. These findings provided for the first time a molecular explanation for the increased risk of disease observed in individuals with low levels of social support. It was not long before chronic stress would be listed among a host of different adverse experiences associated with this distinctive pattern of gene expression (Cole et al. 2007Miller et al. 2014), which has become known as the conserved transcriptional response to adversity (CTRA).

Stress Results Not in the Downregulation but in the Dysregulation of Immunity

Taken together, these works on how varying indices of adversity influence the human genome have precipitated an important paradigm shift in our understanding of how stress affects health. In particular, they challenge the once dominant view that stress results in ill-health because it gives rise to widespread suppression of the immune system. On the contrary, it is now clear that chronic stress can precipitate changes in gene expression associated with both the upregulation and the downregulation of the immune system (Cole 2013). This, in turn, helps to explain the once seemingly anomalous observation that stress can be associated with diseases involving increased activity of the immune system (e.g., inflammation-related diseases such as heart disease and autoimmune conditions) as well as diseases associated with immune suppression (e.g., impaired responses to viral infections and vaccinations).

The discovery and characterization of the CTRA has had other notable implications for our understanding of the relationship between stress and health. One of these pertains to the debate regarding the utility of the term “stress” and whether it should only be employed in contexts where a serious threat to well-being is likely (Kagan 2016). Pursuant to Kagan's criticism, the literature on stress and gene expression has fallen into the trap of conceptualizing stress in a variety of ways, most commonly through objective measures of adversity as well as subjective experiences (Cole et al. 2011Miller et al. 2008). Although both conceptualizations have been shown to be associated with the CTRA pattern, Cole observes that activation of this pattern is often more strongly associated with subjective experiences of adversity than with objective indices (Cole 2013). Does this suggest that our focus should be only on indices that capture the subjective experience of stress? Perhaps. But as objective indices of stressor exposure can also be associated with genomic changes (and because some forms of stress manifest outside conscious awareness; see Mehl et al. 2017), it would seem preferable that we continue our permissive conceptualization of stress. However, rather than adopting a singular perspective, we should accommodate both objective stressors and subjective responses in models that have sufficient power to delineate their combined consequences on human health (Miller & Chen 2006).

Enhancing Our Understanding of the Role Played by Cortisol

A further area in which social genomics has helped our understanding of the stress–illness relationship concerns the role played by the HPA axis as a mediator. As discussed above, the activation of this axis and the subsequent release of glucocorticoids are incontrovertible consequences of stress. Indeed, the immunomodulatory properties of cortisol have played a large part in sustaining the view that stress leads to ill-health due to widespread suppression of the immune system. However, the contradiction at the heart of this hypothesis is that if cortisol results in ill-health because it suppresses the immune system, then why does it not also protect us from conditions that arise or are exacerbated by increased immune system activity (e.g., inflammation-related and autoimmune diseases; see Miller et al. 2002Raison & Miller 2003)? This led to the evolution of the glucocorticoid resistance hypothesis (Miller et al. 2002), which proposes that, although the HPA axis continues to produce cortisol in response to chronic stress, the persistence of inflammation in the presence of cortisol occurs because glucocorticoid receptors on immune cells become desensitized over time. In other words, the immune cells become blunted to the signal to switch off, resulting in a mild but persistent level of inflammation. Both human and animal studies have provided support for this hypothesis (Cohen et al. 2012Miller et al. 2008). The combination of genome-wide expression analysis with bioinformatics has allowed us to understand the nature of this blunting in more detail, and the evidence suggests that chronic exposure to cortisol results in both the reduced expression of anti-inflammatory genes and the increased activity of the transcription factors promoting inflammation (Cole 2013).

Interventions and Gene Expression: A Promising Area of Enquiry

We must acknowledge, however, that much of the evidence reviewed here of the association between indices of adversity such as stress and patterns of gene expression is correlational. This of course raises two questions. First, are these relationships causal, and if so, in what direction (i.e., does stress alter gene expression or do these patterns of gene expression give rise to stress)? Second, are observed effects amenable to change? Results from early trials show great promise. A range of interventions often deployed in the context of stress, such as yoga, mindfulness, and cognitive behavioral therapy, have shown evidence of post-intervention alterations in gene expression (Antoni et al. 2012Black et al. 2013Bower et al. 2014Creswell et al. 2012). These interventions have ranged from 8 to 12 weeks in duration and have been conducted with healthy individuals and people with disease. These findings clearly illustrate significant changes to the CTRA profile after the intervention, which is consistent with a reduction in pro-inflammatory gene expression (Antoni et al. 2012Bower et al. 2014Creswell et al. 2012) and, to a lesser degree, an upregulation of antiviral immunity (Black et al. 2013). Studies in animal models have also confirmed that stress and social adversity can causally increase inflammatory gene expression and decrease antiviral gene expression (Cole et al. 2015Snyder-Mackler et al. 2016).

So our current understanding of how stress influences health has benefited immeasurably from social genomics. It has allowed us to move away from the simplistic view that stress only results in immune suppression and to explain the paradox of stress being able to simultaneously affect both disease processes that thrive during periods of immune activity and those that require immune suppression. It has also facilitated a more sophisticated understanding of the role of the HPA axis as a mediator of the stress–health relationship. At the same time the research on interventions has served to consolidate the view not only that stress can alter our well-being, but also that psychological interventions can attenuate these deleterious effects. Questions abound regarding the potency of the intervention effects and whether they could result in clinically relevant improvements in health. Similarly, it remains unclear which factors determine whether individuals exposed to stress will succumb to diseases associated with an upregulation of genes associated with inflammation or to disease associated with a downregulation of viral immunity. There is little doubt that social genomics will continue to contribute to this discourse.



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