Chapter 10: Stress and Disease

Question 1

Background and General Concepts of Stress

Answer 1

1. Stress is broadly defined as a perceived or anticipated threat that activates stress-related systems in the body and the brain (the stress response).
2. The term fight-or-flight response was coined by Walter Cannon to describe how the brain’s perception of threat and rapid physiologic responses prepares the body to deal with threat.
3. Cannon’s view was further developed by Hans Selye in 1946 by demonstrating that internal or external stressors could result in adrenal gland enlargement, immune alterations (increased leukocytes), and gastrointestinal manifestations (ulcers). These global physiologic responses, characterized by Selye, were labeled general adaptation syndrome (GAS).
4. GAS occurs in three stages: the alarm stage; the stage of resistance or adaptation; and the stage of exhaustion. The latter stage is now referred to as allostatic overload. Diseases of adaptation develop if the stage of resistance or adaptation does not restore homeostasis. Although important, this approach is now thought to be greatly oversimplified.
5. Stress research continued into the mid-1950s to show that psychological stressors are as effective as physical stressors in activating adrenal gland hormone secretion. Psychological stressors can be anticipatory and triggered by expectations of an upcoming stressor or can be reactive to a stressor. Both of these psychological stressors are capable of eliciting a physiologic stress response.
6. The emerging link between stress and disease became the basis for the concept of allostasis (stability through change; monitoring the environment for adaptive response). This allostasis concept differs from a “fixed homeostasis model” (i.e., stress-induced heightened physiologic responses eventually returning to a narrow step point range) by involving a dynamic adaptation of the brain to constantly adjust its physiologic operating range to meet future anticipated demands. In other words, returning stress-induced hormone levels
   to prestress levels may not be the most adaptive strategy to cope with impending stressful encounters.
7. Chronic activation of regulatory stress systems has the potential to tax the body and the brain and lead to the emergence of diseases and disorders. In allostatic overload, chronic over-activation of adaptive regulatory physiologic systems may lead to pathophysiology and onset of disease.

Question 2

The Stress Systems

Answer 2

1. The perception or anticipation of threat activates three major physiologic stress systems:
   (a) The hypothalamic–pituitary–adrenal (HPA) axis
   (2) The sympathetic nervous system (SNS)
   (3) The immune system (IS).
   Acute stress-induced activation of these stress systems modulates a broad range of mediators in the body and the brain to protect and meet the physiologic and behavioral demands of the stressor to facilitate recovery.
2. Key physiologic changes involved in allostatic overload include exaggerated or chronic secretion of adrenal cortisol, catecholamines from the SNS, and proinflammatory cytokines that may initiate gene expression changes with widespread effects on the body, and neurobiologic structures and processes.
3. Becoming “stressed out” by allostatic overload may lead to sleep deprivation, heightened insulin and blood glucose levels, increased blood pressure, and reduced parasympathetic activity. These physiologic consequences are often linked to insomnia, chronic pain and fatigue syndromes, obesity, metabolic syndrome, essential hypertension, type 2 diabetes, atherosclerosis and its cardiovascular consequences, osteoporosis, and autoimmune inflammatory and allergic disorders.
4. Activation of the HPA system involves sequential secretion of corticotropin-releasing hormone from the hypothalamus, which stimulates receptors in the anterior pituitary to secrete adrenocorticotropic hormone (ACTH), which, in turn, stimulates the adrenal cortex to secrete the glucocorticoid cortisol.
5. Cortisol secretion induced by stress binds to glucocorticoid receptors to activate diverse biologic actions throughout the body and the brain. The many adaptive functions include, but are not limited to, arousal, cognition, mood, metabolism, maintenance of cardiovascular tone, and effects on the immune system.
6. Cortisol’s main effects involve metabolic processing by mobilizes glucose, amino acids, lipids, and fatty acids and delivers them to the bloodstream. As an example, anabolic effects of cortisol increase the rate of protein synthesis in the liver, whereas the catabolic effects of cortisol increase levels of amino acids, ultimately depleting protein stores in muscle, bone, skin, and connective tissue.
7. Chronic dysregulation of the HPA axis, especially abnormal elevated levels of cortisol, is linked to a wide variety of disorders, including obesity, metabolic syndrome, sleep deprivation, lipid abnormalities, coronary heart disease, diabetes, atherosclerosis, and loss of bone density. In the brain, chronic glucocorticoid secretion may lead to cognitive impairments and emotional disorders. For example, chronic depression is accompanied by shrinkage of the hippocampus and the prefrontal cortex.
8. Activation of the autonomic nervous system (ANS) consists of sympathetic stimulation of the adrenal medulla and nerve endings to rapidly secrete catecholamines (norepinephrine, epinephrine).
9. Epinephrine exerts its chief effects on the cardiovascular system by increasing cardiac output and blood flow to the heart, brain, and skeletal muscles by dilating vessels that supply these organs. It also dilates the airways, thereby increasing delivery of oxygen to the bloodstream.
10. The parasympathetic nervous system balances or restrains the sympathetic system, resulting in slowed heart rates and anti inflammatory effects. During prolonged stress (allostatic overload), the parasympathetic system becomes less effective in opposing the sympathetic system.
11. Stress-induced secretion of HPA hormones and catecholamines (CAs) directly influences the immune system, which plays an adaptive role as a signal organ to alert other systems from internally threatening stimuli (e.g., infection, tissue damage, tumor cells). The release of immune inflammatory mediators (interleukin-6 [IL-6], tumor necrosis factor-β [TNF-β], interferon [IFN]) to protect the body is triggered by bacterial or viral infections, cancer, tissue
    injury, and other stressors.
12. Although inflammation is a normal response and considered beneficial, chronic stress accompanied by prolonged, intrusive, negative thoughts is related to maladaptive psychological functioning which may lead to persistent immune dysregulation. Chronic stress is linked to inflammatory processes and prolonged secretion of proinflammatory cytokines that promote cardiovascular disease, osteoporosis, arthritis, type 2 diabetes mellitus, chronic obstructive pulmonary disease (COPD), and other diseases associated with aging.
13. A clear example of the adverse effects of chronic psychosocial stress is burnout, a syndrome associated with a number of negative impact on workers’ well-being and health. Mechanisms contributing to burnout likely include dysregulation of the HPA axis and the ANS, which are accompanied by impaired immune function and inflammation.

Question 3

Chronic Stress at an Early Age Increases the Risk of Developing
Long-Lasting Pathophysiologic Alterations Linked to Poor Health and
to Disease

Answer 3

1. Children exposed to prenatal or postnatal stressors increase the risk of developing long-lasting pathophysiologic alterations linked to poor health and to disease.
2. High levels of stress-induced maternal cortisol secretion could cross the placental barrier and enter the fetus to cause low birth weight and increase the risk of disease in later life, including obesity, cardiovascular conditions (e.g., hypertension), and behavioral disorders (e.g., depression and attention-deficit/hyperactivity disorder).
3. Early exposure to psychosocial stressors (e.g., parental, sexual, or emotional abuse, low socioeconomic status [SES] or poverty) are linked to the development of dysregulated HPA and ANS leading to a chronic pro-inflammatory state that increases the risk of disease.
4. Early life stressors may impair brain systems that govern executive functions involved in attention, self-awareness, impulse control behavior that regulate emotions, and adaptive coping behavior.

Question 4

Negative Effects of Stress on Telomere Length, Aging, and Disease

Answer 4

1. Telomeres are deoxyribonucleic acid (DNA)–based caps located at
   the end of chromosomes to protect genetic information and degradation during cell division.
2. Telomere shortening or attrition is linked to biologic aging and can be accelerated by a number of conditions associated with inflammation and oxidative stress. Shorter telomere length found in white blood cells reflects an increased risk of aging-related morbidity and mortality and is associated with a range of conditions in people with obesity, smoking, type 2 diabetes, and low SES.
3. Stress has a major role on telomere shortening that can begin in utero by increasing early telomere damage, inflammation, and greater rate of leukocyte division.
4. Studies showed that childhood stress predicts telomere erosion and heightened inflammatory response to psychosocial stress and elevated risk of developing depression and metabolic disorders.

Question 5

Coping and Intervention Strategies

Answer 5

1. Coping styles affect the ability of a person to handle stress. Personality characteristics, such as academic achievement, motivation, and optimism, increase likelihood of successfully dealing with stress. In addition, people who engage in coping strategies that receive social support develop greater stress resilience and improved psychological and physiologic outcomes.
2. Maladaptive coping responses to stress, such as increased smoking, decreased exercise and sleep, and poor diets, are likely to alter adaptive immune functions and increase susceptibility to disease.
3. Engagement in exercise as a means of coping with stress has beneficial effects at all ages. Exercise has the potential to rebalance neurotransmitter effects that were altered by stress. Exercise also may improve the neuro-immune status (i.e., inflammation) by inhibiting the secretion of pro-inflammatory cytokines. Exercise increases brain metabolism that improves cognitive functions that could be compromised by chronic exposure to stress.
4. Another major benefit of exercise is to reduce obesity, a major contributor of the pathophysiology of diabetes, heart disease, metabolic disorders, liver disease, cancer, inflammatory disorders, mental illnesses, and premature death. Coping with stress and obesity by exercising reduces adipose tissue, attenuates serum pro-inflammatory cytokine levels, and creates an anti-inflammatory environment.
5. Mindfulness therapy is increasingly used to reduce the chronic impact of allostatic load on health. This therapy involves monitoring current experiences with acceptance and is effective in coping with various medical conditions, including chronic pain, depression, and attenuating the negative perception of stress.
6. Mindfulness appears to improve health by modulating the stress induced secretion of cortisol by the HPA and by dampening brain regions activated by stress that play a role in the generation of stress reactions.
7. In young children exposed to constant uncontrolled environmental or psychosocial stressors, school-based, structured mindfulness interventions appear effective in mitigating the toxic effects of stress by decreasing negative coping behavior, anxiety and depression, self harm, and flatten the elevated cortisol curve. Children receiving mindfulness interventions show improvement in their sleep, self-esteem, well-being, and reduction in hostility. Mindfulness teaches valuable coping skills that potentially reduce the likelihood of at-risk children developing chronic diseases in adulthood.