Slow killer: how chronic stress impairs our ability to thrive and live longer

‍Highlights:

• While acute stress is a survival mechanism targeted at maintaining homeostasis, chronic stress is maladaptive and disrupts many bodily mechanisms
• During chronic stress, the release of glucocorticoid hormones becomes disrupted, and extensive exposure to them has a neurotoxic effect
• High levels of stress hormones influence multiple pathways, including insulin and glucose ones
• Chronic stress also increases rates of DNA damage and telomere shortening

Introduction

Stress is a natural response of our bodies to adverse environmental changes, targeted at increasing adaptation to such changes. Our organisms strive when they are at homeostasis – a self-regulation process that maintains the stability required for survival. Stress is crucial for survival, but in case of severe stressors or prolonged exposure can become maladaptive and harmful. In the theory of stress response, developed by Selye in 1936, he concluded that being subjected to prolonged stress could also induce hormonal system breakdown and lead to multiple “diseases of adaptation”.

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Different flavors of stress

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While our bodies can relatively quickly resolve and normalize the effects of acute stress, chronic stress seriously perturbs all the systems (1). Shonkoff et al. (2) suggested a useful classification for different types of stress:

• Positive stress includes stress responses that are moderate, short-lived, and adequately inactivated (a stressor is resolved);
• Tolerable stress refers to potentially harmful stress responses that are slowed down, buffered, and can be a protection against further stressors;
• Toxic stress – a damaging stress response caused by severely adverse traumatic conditions combined with a lack of internal and external resources to cope.

Toxic stress leads to an imbalance of stress hormones, which further induces a “domino effect” on dependent biological systems that collectively collapse (3). To understand how stress becomes toxic, we have to delve into the stress response mechanism first.

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What happens during chronic stress

Hypothalamic-pituitary-adrenocortical (HPA) axis is a key physiological system that responds to stress. HPA presents a precisely regulated communication pathway between the paraventricular nucleus of the hypothalamus, the pituitary gland, and the adrenal glands. Each part of this pathway carries its separate functionality. The hypothalamus, which consists of multiple nuclei, is involved in multiple pathways (i.e., circadian rhythm regulation) that connect the nervous and the endocrine systems. The paraventricular nucleus of the hypothalamus is involved in the release of various hormones, such as vasopressin and oxytocin. The pituitary gland is an endocrine gland that further coordinates endocrine and nervous systems by releasing growth, thyroid, metabolic, and sex hormones. And the adrenal glands, in their turn, are endocrine glands that produce hormones such as adrenaline and the steroids aldosterone and cortisol (in humans). Additionally, pituitary gland, depending on cortisol levels, further coordinates work of thyroid gland (high cortisol levels lead to the inhibition of thyroid hormones production).

Exposure to stressors leads to HPA activation and secretion of glucocorticoid stress hormones (cortisol in humans, corticosterone in rodents) into the bloodstream (4). From the blood, glucocorticoids cross the blood-brain barrier and enter the brain to activate two important signaling pathways (5) – through glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). MRs are easily activated even in basal conditions (when a person is awake and completely rested) due to their high corticosteroid sensitivity (6). On the other hand, GRs respond only to high levels of corticosteroids and are activated during stressful conditions (7).

Glucocorticoid signaling through GRs and MRs coordinates the HPA axis during an acute stress response mediating adaptive changes on both the physiological and behavioral levels (8). During positive or tolerable stress, the autonomous nervous system helps to regulate the stress response (9). The sympathoadrenal system coordinates the sympathetic neural system (part of the nervous system regulating the “fight or flight” response) and activates or inactivates the adrenal gland. At the same time, the parasympathetic neural system (part of the neural system that regulates unconscious bodily functions, or “rest and digest” response) returns the body to homeostasis and deactivates the stress response. But, during prolonged stress, the autonomous nervous system cannot deactivate, the glucocorticoid signaling becomes dysregulated, and the HPA axis becomes chronically activated due to a lack of inhibitory feedback.

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How chronic stress affects our brains

As stress hormones can access the brain, they are able to impact both cognitive processing and emotional states. Various brain regions have different numbers of corticosteroid receptors, and the hippocampus – a brain structure involved in learning and memory – shows the highest density of them (10). Other areas affected by corticosteroids include the prefrontal cortex (responsible for complex cognitive actions, such as decision making) and the amygdala (participates in memory and emotional responses, such as fear, anxiety, and aggression). 

Such deregulation creates a vicious circle as each of the affected brain structures is, in turn, involved in stress hormones secretion regulation (11). And, simultaneously, these structures play a major role in perceiving a situation as stressful. Thus, chronic production of stress hormones is strongly linked with an increased risk for multiple psychopathologies (12). If secreted for too long, the same stress hormones that are essential for survival have a damaging effect on physical and mental health. Once glucocorticoid hormones are permanently increased, it also dysregulates multiple major biological pathways in the body and the brain, such as insulin, glucose, lipids, and brain neurotransmitter pathways. This dysregulation further impairs various bodily systems, including cardiac, immune, metabolic, and neurological. 

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Chronic stress and diseases 

Unpredictable and uncontrollable chronic stressors are associated with an increased level of inflammation (13). Glucocorticoids are well known for their immunosuppressive and anti-inflammatory properties (14). They can reduce the expression of several pro-inflammatory cytokines (e.g., tumor necrosis factor α (TNF-α), interleukin-6 (IL-6)) and increase the expression of anti-inflammatory cytokines (e.g., IL-10, TNF-β). But recent studies demonstrated that glucocorticoids also have a pro-inflammatory impact on the immune system (15). Intense stressors over-activate the immune system, leading to the imbalance of inflammation and anti-inflammation. Multiple studies have confirmed pro-inflammation induced by stress (16). 

Stress-caused deregulation of pathways combined with chronic low-level inflammation is linked to the development of multiple diseases, among them cardiovascular disease (17), diabetes (18), and various cancers (19). Since receptors for stress hormones are broadly expressed in immune cells, chronic stress drastically impacts the immune system. It has been recognized as a trigger of autoimmune conditions (20), irritable bowel syndrome (21), Alzheimer’s disease, and related conditions (22).

It is important to notice that stress can be not only a reason but also a consequence of disease. The psychological stress from disrupting day-to-day life due to a medical condition may lead to exacerbated cellular stress accompanied by inflammation (23). 

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Effects on mental health and cognitive abilities

Chronic stress, as was mentioned above, is associated with multiple mental disorders. Early studies in the 50s demonstrated that long-term corticosteroid therapy could lead to significant mental and cognitive deficits named “steroid psychosis”. The constant exposure to high levels of stress hormones also impacts behavior and psychological well-being. Studies have shown that, through affecting the hippocampus, chronic stress impairs learning, attention, and memory processes (24). Emotional regulation is also heavily affected (25).

Two disorders most closely associated with enduring exposure to the stressor are post-traumatic stress disorder (PTSD) and depression. However, stress hormones have a different impact on these two conditions. While PTSD is most likely connected to the pre-existing vulnerability to stress and is associated with reduced concentrations of glucocorticoids, depression is characterized by increased levels of glucocorticoids and reduced hippocampal volume. While PTSD is related to a major traumatic event, depression and burnout are strongly linked to chronic occupational stress or workplace stress (26).

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Chronic stress and aging 

Chronic stress and aging are strongly linked in multiple ways. Firstly, the effects of chronic stress simulate the effects of “normal” aging in many ways. For instance, rats receiving chronic subcutaneous administration of glucocorticoid hormones showed a permanent depletion of hippocampal corticosterone receptors, accompanied by loss of hippocampal neurons, similar to that seen during aging (27). Constant low-level inflammation has also been observed in aging and negatively impacts longevity. A recent study by Gellner et al. also showed that chronic stress disrupts neuron functionality and leads to the development of motor deficits in mice (28). Interestingly, even graying of hair can be accelerated due to stress exposure through activation of sympathetic nerves and subsequent burst release of noradrenaline (29).

Chronic exposure to stressors has also been linked to DNA damage (30) and accelerated telomere shortening (31) – two important hallmarks of aging. However, it is not yet clear if the detrimental effects of chronic stress are fully related to other hallmarks of aging, such as cellular senescence. In a study by Harvanek et al., the researchers employed the GrimAge epigenetic clock to demonstrate that cumulative stress leads to increased epigenetic aging (32). In another study, Rentscher et al. (33) showed that chronic stress exposure is associated with greater p16 gene expression (protein coded by this gene is one of the markers of cellular senescence).

Conclusions

Chronic stress dysregulates and damages multiple bodily systems and increases the risk of developing multiple diseases. If left unattended, chronic stress exposure can shorten both health- and lifespan. According to the MacArthur Study of Successful aging, higher levels of chronic stress during aging are strongly associated with the incidence of physical decline, cognitive impairment, and all-cause mortality (33).

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This article is the first part of the 2-part article. If you would like to know more about what we can do about chronic stress, please, read the article “Resilience – a key to tackling chronic stress”.

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