Lifestyle & Longevity: Chronic Stress And Its Management

Stress is a physiological necessity for survival, and a state we all experience from time to time. Chronic ongoing stress, however, is linked to several negative health outcomes including mental disorders, cardiovascular disease, cancers and ultimately longevity. Chronic stress is the physiological result of our natural stress response being triggered for an extended period of time. The trigger maybe psychological or physical with multiple potential causes, many of which have increased as society has evolved. These include the frenetic pace of life, social media fixation, pressurized work environments, and an increasing absence of social connectivity. General lifestyle health factors including nutrition and exercise may also contribute to negative stress by upsetting the body’s natural balance (homeostasis). Moreover, genetic predispositions, epigenetic changes in response to adverse early life events, and triggering circumstances from day-to-day life, appear to drastically increase susceptibility for some individuals.

This paper explores the role of these contributory factors, the physiological consequences on our health, disease development and longevity and proven methods of reducing or managing stress.

THE NECESSITY OF A STRESS RESPONSE

Our short-term stress response is a critical physiological outcome that has evolved over millennia to help increase our chances of survival when faced with physical or psychological challenges. The term ‘fight or flight’ is often used to describe part of the stress response when we are faced with immediate danger, and was popularized in the early twentieth century by the physiologist, Walter Cannon [Cannon WB et al., 1939].

This type of stress response is triggered following a significant physical or psychological challenge detected by our senses. Physical stressors are considered those that could overburden our physiology – like an infection, or wound for example. Psychological stressors are best described as anticipatory threats —  an example being an environmental danger. Physical and psychological stressors involve different brain circuity – some of which is overlapping [Dayas et al 2001]. This circuitry interfaces with our hormonal (endocrine) system to produce chemical mediators of the stress response. They involve two main pathways the purpose of which is to bring the body back into a dynamic balance (homeostasis), once an immediate threat has been avoided.

One pathway is mediated via what is known as the sympathetic adrenal-medullary (SAM) axis. This is often associated with physical stressors. Here activation via the brain of our sympathetic nervous system results in the release of adrenaline (also called epinephrine) and noradrenaline (norepinephrine) from the medulla region of our adrenal glands located on top of the kidneys. Noradrenaline differs from adrenaline in that it can be released from sympathetic nerve terminals in addition to the adrenal glands, and unlike adrenaline, acts as a neurotransmitter in the central nervous system. Noradrenaline release from a region of the brain known as the locus coeruleus is thought to have a role in behavioral and cognitive adaptations as part of the stress response [Valentino RJ. et al., 2008]

Both noradrenaline and adrenaline function as hormones when circulating in the blood. They act to increase vigilance, elevate the heartbeat and redirect blood flow to the skeletal muscles and brain. They increase blood glucose levels by signaling its release from glycogen stores, constrict blood vessels thereby increasing blood pressure and trigger actions in the central nervous system including promoting wakefulness and sensory signal detection. In parallel, they result in the relaxation of bronchial, intestinal and many other smooth muscles. They can also influence neural circuitry in regions of the brain to influence memory including the prefrontal cortex, amygdala and hippocampus. These effects include impaired memory recall and working memory during stress, and enhanced memory encoding (formation) and emotional memory related directly to a stressor [Cahill L et al., 2003; Tank, A. W., and Lee Wong, D. 2015; Shields GS et al., 2017].

There is also a significant stress pathway through the brain in the form of a feedback loop between two areas known as the hypothalamus and the pituitary gland, which signal to the outer area of our adrenal glands (adrenal cortex). This is collectively known as the hypothalamo-pituitary-adrenocortical (HPA) axis. Here, stress perceived via the central nervous system activates the release of two neuropeptides — corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus, which activate the pituitary gland to release adrenocorticotropic hormone (ACTH). This signal reaches the adrenal cortex, which in turn triggers the release of glucocorticoid hormones, including cortisol into the blood stream. Sufficient cortisol release inhibits further signals from the brain, acting as a negative feedback loop.

Cortisol acts at several organs throughout the body. Amongst other roles, it mobilizes the production of glucose from glycogen stores in the liver — similar to adrenaline – and thereby helps increase blood glucose to the brain. Its release acts to decrease insulin in the pancreas and increase the breakdown of fats (lipolysis) from adipose tissue for energy. It also has an anti-inflammatory effect overall. This may be beneficial as inflammation  could potentially impede a fight or flight reaction. Also, an initial suppression of the immune response during stress could prevent potentially damaging overreactions by the immune system. In the absence of a stress trigger, cortisol levels naturally follow the body’s circadian rhythm, peaking in the morning and falling at night before sleep.

It’s important to note that both the SAM and HPA axes do not occur in isolation and have multiple points of interaction and cross over, including several brain structures. The purpose of these triggers and physiological responses is generally to address a short term need or danger, particularly to respond quickly to a potential survival situation – like seeing an oncoming car –  and then for the body to return to its prior steady state.

However, if the stress situation is prolonged, the body’s natural response can go into overdrive and from a physiological perspective, prolonged activation is linked to systemic inflammation in the body – which as we will see is the precursor or a biomarker of many chronic diseases – and immune dysfunction [Glaser R, et al., 2005]. Furthermore, prolonged – chronic – stress is indicated in several mental health disorders including depression, anxiety and post-traumatic stress disorder.

Several studies have shown stress pathways contribute to the pathophysiology of disease, including obesity, metabolic syndrome, gastrointestinal disorders, some forms of cancer, auto-immune and cardiovascular diseases [Cutolo M, et al., 2006; Cohen S, et al., 2007; Liu YZ et al., 2017]. We discuss linked disease states and the potential mechanisms that underly them in the next section.

CHRONIC STRESS AS CONTRIBUTORY FACTOR TO DISEASE

STRESS AS A PRECURSOR TO DEPRESSION

One of the most obvious manifestations of chronic stress is its impact on mental health, particularly increased anxiety. According to a report released by the World Health Organization, anxiety disorders affect more than 260 million people—3.6% of the global population. Anxiety is a precursor in the development of depression — stated as being the world’s leading cause of disability by the WHO. In addition, they mention the prevalence of both disorders is increasing, particularly in low- and middle-income countries possibly linked to a burgeoning population, resulting in more affected individuals.

Chronic stress instigates a number of neurotoxic processes including HPA axis dysregulation, inflammation, oxidative stress and neurotransmitter disturbances that are all thought to be implicated in the development of depression – referred to clinically as major depressive disorder (MDD). The over-drive of the HPA axis, associated increases in cortisol and a down-regulation of its negative feedback control in the brain in chronic anxiety is identified as a major precursor to the development of MDD [Pariante C.M., Lightman S.L. 2008]

Sleep disturbances are common in anxiety disorders and particularly in depression, and can manifest in several ways. General somnolence (sleepiness) or lack or energy, combined with early morning awakening are common [Fava M. 2004; Alvaro et al., 2013]. A lack of sleep, specifically,  has major implications, and can worsen symptoms in depression and anxiety.

Other risk factors include adverse life events, childhood adversity combined with genetic predispositions. Studies have shown variations (polymorphisms) in a serotonin transporter (5-HTT) gene, and Brain Derived Neurotrophic Factor (BDNF) could lower resilience to stressors and increase the risk of depression in adulthood [Aguilera et al., 2009].

THE STRESS RESPONSE AND INFLAMMATION

Although there is a large body of research indicating that chronic or severe stress causes inflammation, this appears counter-intuitive at first sight. One of the main hormones released in response to stress, cortisol, is a glucocorticoid, a type of steroid that acts to reduce inflammation by binding to receptors in immune cells and preventing the release of cytokines,  pro-inflammatory chemical mediators. In fact, two main pathways have been identified.  The first is ‘glucocorticoid resistance,’ where prolonged exposure to glucocorticoids results in a reduced sensitivity or ‘resistance’ to their anti-inflammatory effects. This is precisely what happens when the HPA axis has been chronically overactive, but it can also occur when glucocorticoid steroids are taken systemically for medical treatments [Marques, AH et al., 2009].

An alternative pathway is hypocortisolism – reduced levels of cortisol – caused by conditions such as Addison’s disease, an autoimmune disease where the adrenal glands become damaged, or issues with the signals originating from the hypothalamus or pituitary gland that mediate the release of cortisol [Betterle C et al., 2019; Huecker MR, et al., 2021 StatPearls Publishing]. The direct consequence of both mechanisms is decreased inflammatory control. This is linked to an increased susceptibility to inflammatory and autoimmune diseases. [Silverman MN, Sternberg EM. 2012; Liu YZ et al., 2017].

A recent study has implicated increases in the gene expression (epigenetic changes) of Tumor Necrosis Factor (TNF) during chronic stress, linking it to inflammation [Palma-Gudiel H, et al., 2021]. TNF increases are observed in several autoimmune and inflammatory disorders, including rheumatoid arthritis and inflammatory bowel disease [Brenner D, et al., 2015]. Furthermore, they have been linked to the pathogenesis of these diseases, and anti-TNF therapy put forward as one possible treatment [Jang DI, et al 2021].

STRESS, OBESITY AND METABOLIC SYNDROME

A number of studies have linked stress, and dysregulation of the HPA axis to a higher BMI and specifically, upper body and visceral obesity, increased waist circumferences, high blood pressure and a predisposition to the development of type 2 diabetes. [Kyrou I, et al 2006; Bose, M et al 2009; Farag NH, et al., 2008]. The latter effects are known collectively as metabolic syndrome (MetS).

Cortisol has been shown to increase the level of white adipose tissue in the abdominal area and may cause cravings for energy dense food [Fardet L, Feve B. 2014]. Furthermore, studies indicate that obese patients have high levels of cortisol exposure as measured in hair, a more reliable indicator of long-term exposure than blood, saliva and urine. This is upon comparison to individuals who are of normal weight or overweight (vs obese) [Wester VL, et al., 2014; Jackson, SE et al., 2017]

STRESS AS A CONTRIBUTOR TO CARDIOVASCULAR DISEASE

Epidemiological data indicate that chronic stress is a predictor for the long-term development of coronary heart disease [Turner AI, et al 2020; Steptoe, A., Kivimäki, M. 2012]. In addition, some short-term stressors have also been implicated in triggering myocardial infarction (heart attacks) [Steptoe, A., Kivimäki, M. 2012].

Interestingly, a reversible condition – known variously as ‘stress cardiomyopathy,’ ‘broken-heart syndrome’ or ‘tako-tsubo cardiomyopathy,’ that results in the ballooning of the left ventricle of the heart, has been linked specifically to chronic emotional stress [Kurisu S, et al., 2002; Seth, PS et al., 2003]. It mimics a myocardial infarction and occurs in the absence of other usual causes, like coronary stenosis (a blocked artery), for instance.

Although the pathways connecting stress and the onset of cardiovascular disease need specific elucidation, some clear candidates exist. An increase in blood pressure and heart rate is a known outcome of activation of the SAM axis in response to stress. This is an effect mediated by the catecholamines — noradrenaline and adrenaline, as we discussed before. When this is combined with deleterious metabolic effects through the HPA axis, and other possible underlying health issues, the increased potential risk for cardiovascular disease is made plausible [Ginty AT, et al., 2017]

STRESS, IMMUNE EFFECTS AND CANCER

There are many pathways for cross-communication between our stress response and immune system. For example, several types of white blood cells (leukocytes) responsible for our innate immunity – the fast, first line of defense against pathogens – are directly modulated by the hormone mediators of stress. Two types of adrenoceptors (alpha and beta), that bind noradrenaline and adrenaline, and the glucocorticoid receptors that are activated by cortisol, exist on the surface of many leukocytes [Segerstrom SC. and Miller JE. 2004]. T-cells and B-cells that mediate adaptive immunity (antibody-mediated) also bind noradrenaline and adrenaline.

Diverse research studies examining the effects of stress on the immune system often draw a distinction between the effects of short-term stress, of the ‘fight or ‘flight’ type, lasting minutes to hours, versus chronic or long-term stress. The latter being defined as lasting for several hours per day over weeks and months.

Short-term stress can actually enhance the immune system to an extent, particularly the innate response, mobilizing white blood cells against pathogens. This may be an evolutionary adaptation to anticipate impending injury to the body [Dhabhar, F.S. 2014].

In contrast, chronic stress starts to suppress the adaptive and innate immune response by decreasing immune cell numbers and function. This often co-occurs with low-grade inflammation through a disruption in the balance of pro-inflammatory cytokines, and is also linked to pathological autoimmune responses [Glaser R, et al 2005; Dhabhar, F.S. 2014].

Another effect that has been observed from chronic stress is an increase in the activation of latent viruses [Morey JN, et al 2015]. These are viruses that have previously been present at very low levels, or dormant in the body and re-emerge to cause illness. For example, varicella zoster— sometimes referred to as ‘chickenpox,’ lies dormant in nerve tracts (dorsal root ganglion). One possible causative factor related to its re-emergence as herpes zoster, often called shingles, has been linked to chronic stress [Thomas SL, Hall AJ. 2004].  In a study by Schmader K, et al., in 1990, psychological stress factors within the last 6 months more than doubled your risk of developing shingles. Individuals with cold sores, from the herpes simplex virus, may also note their reappearance in times of stress, although this can be attributed to a temporarily compromised immune system (T cell activity) that can no longer repress the virus [Zhang et al., 2017].

Several studies have implicated chronic stress, and its ability to suppress protective immunity in cancer progression. Stress induced changes in immune cell function (via the HPA axis) may mean they are unable to control tumor cells, increasing tumor development and the potential for metastatic cancer [Lutgendorf SK et al., 2010; Antoni MH, Dharbar, FS. 2019]. Furthermore, approximately 15% of all cancers are linked with concurrent viral infection as a risk factor — for example, human papilloma viruses (HPV) in cervical cancer, or Epstein-Barr virus in lymphoma. As mentioned above, immune dysfunction resulting from stress can reactivate these latent viruses and/or enhance viral progression [Antoni H., et al 2006]. Furthermore, stress-induced immune changes will implicitly alter the potential efficacy of immunotherapy-based cancer treatment.

The relationship with the SAM axis on tumor proliferation is complex and dependent on cancer type. For example, increases in noradrenaline and adrenaline can potentially increase circulating tumor promoting proteins in some cancer types (via the beta-adrenergic receptor) or have a protective effect in others (via the alpha adrenergic receptor)  [Armaiz-Pena GN, et al., 2013].

STRESS AND LONGEVITY

A number of studies have looked into the link between stress, telomerase activity and telomere length. Telomeres are DNA-protein complexes found at the end of our chromosomes. They shorten every time a cell replicates as we age. When they reach a critical length the cell dies. As a result, telomere length and the activity of the enzyme that helps maintain their length — telomerase – are seen as proxy determinants of ageing.

A study in 2004, looked at the correlation between stress and telomere length in the blood cells of healthy premenopausal women. Those with the highest levels of perceived stress had telomeres that indicated an additional 10 years of ageing, compared to those who had low stress levels [Epel ES,. et al., 2004].

Another meta-analysis study examined the links between stress, cortisol levels and telomere length. It showed that individuals that have acute reactivity to stress, as measured by fast spikes in salivary cortisol, exhibited statistically significant shorter telomere length (-13%). Subgroup analyses showed that female subjects and children were particularly susceptible to changes [Jiang Y, et al 2019].

Some recent research also links the pathophysiological effects of chronic stress with the specific ageing of the immune system —  known as ‘immunosenescence.’ It mimics what happens naturally as we age, and results in a weakened immune response to challenges, coupled with low grade inflammation [Fulop T, et al., 2017].

STRESS AND THE GUT: MULTIPLE CONNECTIONS

The gastrointestinal (GI) tract is particularly susceptible to dysfunction as a result of stress. Several research studies have indicated this happens through multiple interlinked pathways including the gut-brain axis, immune system, circulating hormone mediators, and changes in the balance of our gut microbiome [Mayer EA., 2000; Bhatia, V and Tandon, RK, 2005; Foster, JA et al., 2017].

The gut is one of the only organs that has an independently functioning nerve network — known as the enteric nervous system (ENS) [Spencer NJ. et al., 2020]. This dense network of neurons transmit signals predominantly through the neurotransmitter acetylcholine, but also GABA, serotonin (5HT) and vasoactive intestinal peptide (VIP).  Furthermore, it is important to note that there is a direct, two-way connection from the brain to the gut, via the vagus nerve. The vagus nerve can stimulate the HPA axis, and has anti-inflammatory roles in the gut. Some preliminary research has also shown that regulation of the vagus nerve signals travelling to the brain (afferent fibers) can occur as a result of changes in the gut microbiota, and play roles in depression and anxiety [Bonaz et al., 2017].

There are two other known pathways through which the gut microbiome can interplay with the stress response. First, it is known to play a central role in the immune and inflammatory response, through the gut-immune axis. Secondly, microbes in the gut can directly produce neurotransmitters, or their precursors that can cross the blood brain barrier [Strandwitz P. et al., 2018]

These multiple influences link stress as a potential contributor to adverse GI symptoms and disease. Indeed, ulcerative colitis and Crohn’s disease (conditions collectively termed inflammatory bowel disease – IBD), heartburn, gastric ulcers, lower abdominal pain, nausea and vomiting are just some of the GI symptoms and disorders connected to stress [Bhatia, V and Tandon, RK., 2005]. In common parlance the concept of ‘giving oneself an ulcer’ through heightened stress will be familiar.

PROVEN MECHANISMS TO MINIMISE CHRONIC STRESS

The scientific literature establishes a clear if complex link between chronic stress and negative health outcomes. Avoiding or minimizing chronic stress is therefore critical for our overall health and longevity. What then can we do to mitigate the risk?

EXERCISE

There is strong research evidence that regular aerobic exercise, of a duration as short as 30 minutes repeated 3-5 times a week can help counteract chronic stress. This should be the sort that raises your heart and breathing rate – like brisk walking or running [Anderson E, Shivakumar, G. 2013]. Indeed, three out of four studies reviewed in a meta-analysis by Kandola and colleagues  showed that increased cardiorespiratory fitness was associated with lower levels of anxiety [Kandola A, et al 2019]. In other studies, exercise and running have been put forward as effective adjunct therapies to improve mood (in combination with other approaches, including CBT or antidepressant medication) [Otto et al., 2007]. Yoga may also be beneficial to reducing symptoms of anxiety [Saeed SA., et al., 2010]. Exercise is thought to decrease the reactivity of the HPA axis and SNS system, and improve feelings of wellbeing, through reward pathways in the brain and opioid release.

SLEEP

The optimal sleep level according to recent research is between 7-8 hours per night for adults [Daza EJ et al., 2019; Chaput J,P et al., 2018]. Sleep deprivation has been shown to perturb immune function and is associated with increased anxiety levels [Pires GN. et al 2016]. Hence, aiming to optimize sleep hygiene (ie a healthy sleep environment and routines) and the number of hours spent asleep will often be beneficial in reducing stress.

NUTRITIONAL FACTORS TO HELP MITIGATE STRESS

As discussed above, the stress response can be modulated through the gut-immune axis and gut-brain axis to help regulate the stress response. A key beneficial regulator of these axes is a healthy gut-microbiome. Optimal diets for gut microbiome health (and indeed overall health) contain complex carbohydrates, fiber-rich foods, low levels of animal fats, plant-derived proteins, polyphenol-rich foods, that also includes pro- and prebiotics.

Although there is no single blueprint for a healthy gut microbiome, there are recognized microbe populations that are known to be critical. In fact, a number of research groups have specifically linked an elevated stress response and stress-related disorders to an unhealthy imbalance in the gut microbiome. This is further supported by human and animal studies that show treatment with prebiotics and probiotics can attenuate the stress response [Foster, JA. et al., 2017]. Other clinical studies indicate that introducing certain beneficial bacterium into the diet through probiotics helps reduce anxiety and stress in healthy volunteers [Allen AP et al., 2016; Patterson E et al., 2020]. Our article on ‘The Human Gut Microbiome’ explains these pathways in more detail.

Other nutrients with research support for mitigating stress pathways are Omega-3 polyunsaturated fatty acids. They have key roles in the body, including being part of cell membranes. Our body cannot make Omega 3s, so we need to take them in through food, and western diets typically lack good source. Indeed, meta analyses of 19 clinical trials showed that the intake of Omega-3 (2000mg or more, where 60%+ is in the form of eicosapentaenoic acid — EPA) resulted in a significant reduction in anxiety symptoms in affected individuals when compared to controls [Su KP et al., 2018]. Dietary rich sources of omega-3 in the optimal EPA form of Omega-3 are oily fish. Walnuts, flaxseed and flaxseed oils also contain a version of Omega-3 — Alpha-linolenic acid (ALA) that the body can convert, somewhat insufficiently, to EPA.

Caffeine is a widely consumed psychoactive compound found in tea, coffee and energy drinks. High doses of caffeine have been shown to increase adrenaline, blood pressure and cortisol levels, and likely activate the HPA axis [Lovallo, WR et al., 2005]. Eliminating or sticking to lower doses of caffeine, a single cup of coffee for example, could therefore be beneficial for alleviating a heightened stress response.

MINDFULNESS AND MEDITATION

There is increasing scientific evidence that mindfulness based interventions and meditation, can help improve symptoms of anxiety in individuals, either in combination with other methods outlined here, or alone [Hofmann SG, Gómez AF. 2017].

COGNITIVE BEHAVIOURAL THERAPY

If stress has become chronic or poses ongoing issues, cognitive behavioral therapy with a clinically trained practitioner is a peer-reviewed scientifically-validated treatment for improving symptoms. Practitioners provide interventions to counteract the negative cognitions (thoughts) that can drive psychological stress [Borza. L. 2017].

SOCIAL CONNECTIVITY

Humans evolved to be social, and our ancestors lived in extended family groups. Loneliness and social isolation have been shown to increase both SAM and HPA activation and decrease inflammatory control, immunity and sleep [Cacioppo JT, et al 2013]. Taking regular time out to connect with other people in a meaningful way, face to face, can therefore have a beneficial effect for stress reduction. Note, by contrast, that excessive ‘social media’ use, although a popular way of connecting with others online, is associated with increased levels of anxiety and stress and should therefore be avoided [Shensa A. et al 2018].

TAKING TIME OUT FOR RELAXATION

Hobbies, interests and time for general relaxation, where we unplug and disconnect from work, and the frenetic pace of life are critical to reducing psychological stress. [Sharifian N, et al 2020]

In particular, walking in nature has been seen to improve mood in those with major depressive disorders [Berman MG, et al 2012].

MEDICAL TREATMENT

Seeking the help of a healthcare professional is advised if chronic stress is causing problematic issues over an extended period. Pharmacological interventions (treatment with medicines) may be advised in some cases.

ALCOHOL

Imbibing alcohol has long been used as a stress-reduction technique. It can reduce inhibitions, elevate mood and boost confidence in the presence of social anxiety triggers. These outcomes are achieved incredibly quickly via the brain-reward pathways (dopamine), opioid release and GABAA receptor [Turton, S et al., 2020]. In the longer term, alcohol acts to decrease activity in the same pathways, increase anxiety and is a depressant [Turton, S et al 2020; Le Marquand D et al., 1994]. Unfortunately this beneficial relationship often leads to a negative codependence and explains why alcoholism is present in a significant percentage of mental health disorders, particularly with men. We explore the effects of alcohol on mood further in our article ‘Alcohol: a health and longevity disruptor. How much is too much?’

CONCLUSION

Stress as a physiological response serves a critical function to human survival and wellbeing. We have summarized how ongoing chronic stress can disturb homeostasis, and contribute to the pathophysiology of disease and be deleterious to our health. There are a multitude of physiological mechanisms involved, several are linked to downstream inflammatory effects via the immune system that are instigated by the overdrive of the HPA axis. Although stress cannot be eliminated from modern day existence, utilizing stress reduction techniques can help mitigate the development and minimize the effects of chronic stress and the health risks that poses.

© SX2 VENTURES (2021)

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