Translational Epigenetics Series
Trygve Tollefsbol, Ph.D., D.O., Distinguished Professor - Series Editor
Professor of Biology, University of Alabama at Birmingham, and Senior Scientist, Comprehensive Cancer Center, Comprehensive Center for Healthy, Birmingham, AL, United States
Aging, Comprehensive Diabetes Center and Nutrition Obesity Research Center, Birmingham, AL, United States Director, Cell Senescence Culture Facility, Birmingham, AL, United States
Transgenerational Epigenetics
Edited by Trygve O. Tollefsbol, 2014
Personalized Epigenetics
Edited by Trygve O. Tollefsbol, 2015
Epigenetic Technological Applications
Edited by Y. George Zheng, 2015
Epigenetic Cancer Therapy
Edited by Steven G. Gray, 2015
DNA Methylation and Complex Human Disease
By Michel Neidhart, 2015
Epigenomics in Health and Disease
Edited by Mario F. Fraga and Agustin F. F Fernández, 2015
Epigenetic Gene Expression and Regulation
Edited by Suming Huang, Michael Litt and C. Ann Blakey, 2015
Epigenetic Biomarkers and Diagnostics
Edited by Jose Luis García-Giménez, 2015
Drug Discovery in Cancer Epigenetics
Edited by Gerda Egger and Paola Barbara Arimondo, 2015
Medical Epigenetics
Edited by Trygve O. Tollefsbol, 2016
Chromatin Signaling and Diseases
Edited by Olivier Binda and Martin Fernandez-Zapico, 2016
Genome Stability
Edited by Igor Kovalchuk and Olga Kovalchuk, 2016
Chromatin Regulation and Dynamics
Edited by Anita Göndör, 2016
Neuropsychiatric Disorders and Epigenetics
Edited by Dag H. Yasui, Jacob Peedicayil and Dennis R. Grayson, 2016
Polycomb Group Proteins
Edited by Vincenzo Pirrotta, 2016
Epigenetics and Systems Biology
Edited by Leonie Ringrose, 2017
Cancer and Noncoding RNAs
Edited by Jayprokas Chakrabarti and Sanga Mitra, 2017
Nuclear Architecture and Dynamics
Edited by Christophe Lavelle and Jean-Marc Victor, 2017
Epigenetic Mechanisms in Cancer
Edited by Sabita Saldanha, 2017
Epigenetics of Aging and Longevity
Edited by Alexey Moskalev and Alexander M. Vaiserman, 2017
The Epigenetics of Autoimmunity
Edited by Rongxin Zhang, 2018
Epigenetics in Human Disease, Second Edition
Edited by Trygve O. Tollefsbol, 2018
Epigenetics of Chronic Pain
Edited by Guang Bai and Ke Ren, 2018
Epigenetics of Cancer Prevention
Edited by Anupam Bishayee and Deepak Bhatia, 2018
Computational Epigenetics and Diseases
Edited by Loo Keat Wei, 2019
Pharmacoepigenetics
Edited by Ramón Cacabelos, 2019
Epigenetics and Regeneration
Edited by Daniela Palacios, 2019
Chromatin Signaling and Neurological Disorders
Edited by Olivier Binda, 2019
Transgenerational Epigenetics, Second Edition
Edited by Trygve Tollefsbol, 2019
Nutritional Epigenomics
Edited by Bradley Ferguson, 2019
Prognostic Epigenetics
Edited by Shilpy Sharma, 2019
Epigenetics of the Immune System
Edited by Dieter Kabelitz, 2020
Stem Cell Epigenetics
Edited by Eran Meshorer and Giuseppe Testa, 2020
Epigenetics Methods
Edited by Trygve Tollefsbol, 2020
Histone Modifications in Therapy
Edited by Pedro Castelo-Branco and Carmen Jeronimo, 2020
Environmental Epigenetics in Toxicology and Public Health
Edited by Rebecca Fry, 2020
Genome Stability
Edited by Igor Kovalchuk and Olga Kovalchuk, 2021
Twin and Family Studies of Epigenetics
Edited by Shuai Li and John Hopper, 2021
Epigenetics and Metabolomics
Edited by Paban K. Agrawala and Poonam Rana, 2021
Medical Epigenetics, Second Edition
Edited by Trygve Tollefsbol, 2021
Epigenetics in Precision Medicine
Edited by José Luis García-Giménez, 2022
Epigenetics of Stress and Stress Disorders
Edited by
Nagy A. Youssef, MD, PhD, Director of Clinical Research
Professor of Psychiatry, Department of Psychiatry & Behavioral Health, The Ohio State University College of Medicine, Columbus, OH, United States
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Kristina Reed, BA, Shiloh Cleveland, BA, Jordan Thomas, MA, Aileen Hsu, BS, Annie Jeong, BA, Jessica Nguyen, BS, Aarti Patel, BA, Sheila Zhang, BS, and Jennifer A. Sumner, PhD
Laura Lockwood, DO, Sonia Dela Cruz, MD, and Nagy A. Youssef, MD,
Erika M. Salarda, BSc, Belinda U. Busogi, BSA, and Gabriel R. Fries, BSc, MSc,
Laura Lockwood, DO, Shaoyong Su, PhD, and Nagy A. Youssef, MD, PhD
Shota Nishitani,
Dušan Braný, PhD, Dana Dvorská, PhD, Laura Lockwood, DO, Ján Strnádel, PhD, and Nagy A. Youssef, MD, PhD
Clara Snijders, PhD, Alana I.H. Escoto, MSc, Dewleen G. Baker, MD, Richard L. Hauger, MD, Daniel van den Hove, PhD, Gunter Kenis, PhD, Caroline M. Nievergelt, PhD, Marco P. Boks, MD, PhD, Eric Vermetten, MD, PhD, Fred H. Gage, PhD, Bart P.F. Rutten, MD, PhD, and Laurence de Nijs, PhD
Nagy A. Youssef, MD, PhD, Laura Lockwood, DO, Shaoyong Su, PhD, Guang Hao, MD, PhD, and Bart P.F. Rutten, MD, PhD
Naidoo, PhD, Olaia Martínez-Iglesias, PhD, and Ramón Cacabelos, MD, PhD, DMSci
Contributors
Charlotte Bainomugisa, MEpi
Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Faculty of Health, Kelvin Grove, QLD, Australia
Dewleen G. Baker, MD
Department of Psychiatry, University of California; VA Center of Excellence for Stress and Mental Health; VA San Diego Healthcare System, San Diego, CA, United States
Marco P. Boks, MD, PhD
Psychiatry, Brain Center UMC Utrecht, Utrecht, The Netherlands
Dušan Braný, PhD
Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
Belinda U. Busogi, BSA
Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
Ramón Cacabelos, MD, PhD, DMSci
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Corunna, Spain
Shiloh Cleveland, BA
Department of Psychology, University of California, Los Angeles, CA, United States
Sonia Dela Cruz, MD
University of Central Florida/HCA Healthcare Graduate Medical Education Consortium Psychiatry Residency Program of Greater Orlando, Orlando, FL, United States
Daniel van den Hove, PhD
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands; Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany
Dana Dvorská, PhD
Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
Alana I.H. Escoto, MSc
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands
Gabriel R. Fries, BSc, MSc, PhD
Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
xiii
Fred H. Gage, PhD
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, United States
Thorhildur Halldorsdottir, PhD
Department of Psychology, Reykjavik University; Center of Public Health Sciences, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
Guang Hao, MD, PhD
Department of Epidemiology, School of Medicine, Jinan University, Guangzhou, People’s Republic of China
Richard L. Hauger, MD
Department of Psychiatry, University of California; VA Center of Excellence for Stress and Mental Health; VA San Diego Healthcare System, San Diego, CA, United States
Aileen Hsu, BS
Department of Psychology, University of California, Los Angeles, CA, United States
Annie Jeong, BA
Department of Psychology, University of California, Los Angeles, CA, United States
Jayesh Kamath, MD, PhD
Director, Mood & Anxiety Program, Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
Gunter Kenis, PhD
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands
Richard S. Lee, PhD
Department of Psychiatry and Behavioral Sciences, Mood Disorders Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Laura Lockwood, DO
Family Service and Guidance Center, Topeka, KS, United States
Olaia Martínez-Iglesias, PhD
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Corunna, Spain
Divya Mehta, BSc, MSc, PhD
Queensland University of Technology (QUT), Centre for Genomics and Personalised Health, Faculty of Health, Kelvin Grove, QLD, Australia
Janitza L. Montalvo-Ortiz, PhD
Department of Psychiatry, Yale University School of Medicine, VA Connecticut Healthcare System, Errera Community Care Center, Orange, CT, United States
Vinogran Naidoo, PhD
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Corunna, Spain
Jessica Nguyen, BS
Department of Psychology, University of California, Los Angeles, CA, United States
Caroline M. Nievergelt, PhD
Department of Psychiatry, University of California, San Diego, CA, United States
Laurence de Nijs, PhD
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands
Shota Nishitani, PhD
Research Center for Child Mental Development, University of Fukui, Fukui; Division of Developmental Higher Brain Functions, United Graduate School of Child Development, Osaka University, Osaka, Japan
Jeffrey O’Neill, MD
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
Safiye Bahar Ölmez, MD
Department of Psychiatry, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey
Aarti Patel, BA
Department of Psychology, University of California, Los Angeles, CA, United States
Bhargav Patel, MD
Department of Psychiatry and Health Behavior, Medical College of Georgia at Augusta University, Augusta, GA, United States
Parit Patel, MBChB
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
Demietrice Pittman, PhD
US Army, Army Recruiting Command, Joint Base Fort Sam Houston, Houston, TX, United States
Kristina Reed, BA
Department of Psychology, University of California, Los Angeles, CA, United States
Bart P.F. Rutten, MD, PhD
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands
Erika M. Salarda, BSc
Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States
Clara Snijders, PhD
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands
Ján Strnádel, PhD
Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
Arthur Su, MD
University of Connecticut School of Medicine, Farmington, CT, United States
Shaoyong Su, PhD
Department of Medicine, Georgia Prevention Institute, Medical College of Georgia, Augusta University, Augusta, GA, United States
Jennifer A. Sumner, PhD
Department of Psychology, University of California, Los Angeles, CA, United States
Jordan Thomas, MA
Department of Psychology, University of California, Los Angeles, CA, United States
Heiddis B. Valdimarsdottir, PhD
Department of Psychology, Reykjavik University, Reykjavik, Iceland; Icahn School of Medicine at Mount Sinai, Population Health Science and Policy, New York City, NY, United States
Unnur A. Valdimarsdottir, PhD
Center of Public Health Sciences, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, United States
Eric Vermetten, MD, PhD
Brain Research & Innovation Centre, Ministry of Defence, Utrecht; Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands
Sophia Walker, MD
University of Connecticut School of Medicine, Farmington, CT, United States
Onur Yılmaz, MD
Doğuş University, Istanbul, Turkey
Nagy A. Youssef, MD, PhD
Department of Psychiatry & Behavioral Health, The Ohio State University College of Medicine, Columbus, OH, United States
Sheila Zhang, BS
Department of Psychology, University of California, Los Angeles, CA, United States
The physiology of stress and the human body’s response to stress
Introduction
Richard S. Lee, PhD
Department of Psychiatry and Behavioral Sciences, Mood Disorders Center, Johns Hopkins
University School of Medicine, Baltimore, MD, United
States
The term “stress” was first coined by Hans Selye in 1936 when it was used to define “the non-specific response of the body to any demand for change.”1 Stress encompassed what had been known as the “fight-or-flight” response.2 Until our very recent history, the stress response was largely needed and activated for brief bursts of energy for acts of survival of an organism such as evading predators, hunting prey, and securing mates, all of which are requisite survival traits for natural selection. However, the Industrial Revolution in the 18th and 19th centuries changed the human stress experience, the psychosocial remnants of which can still be observed in the very cities in which it started.3 What was finely tuned over eons to enable organisms to exercise competition in nature has become a physiological liability in the modern-day society. The system that had served our ancestors well in evading a lion or engaging in brief skirmishes with other tribes now had to contend with worrying about mortgage or spending hours in traffic; the stress response was not tuned for situations where the stressors became chronic. As a result, humans exposed to chronic stressors began to exhibit a host of ailments driven in part by stress and its associated hormones. Chronic stress exposure contributes to the burden of almost all chronic diseases in the United States, such as heart disease, cancer, stroke, diabetes, and obesity.4
This chapter will begin by examining stress as an environmental factor and how it is unique from other environmental factors such as exposures to infections or toxicants. The cascade of neuroendocrine responses to stress, starting from the experience of real or perceived stressors to the activation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis (HPA axis) that culminates in the release of the stress hormone cortisol, will be discussed. The chapter will also distinguish between acute and chronic stress response and the consequences of the latter on different organ systems with special emphasis on the brain, psychiatric disorders, and behavior. A framework for how chronic stress exposure impacts homeostatic cortisol levels will be proposed. Understanding such a framework necessitates a brief introduction to the molecular mechanisms of how cortisol can affect gene expression changes in the cell, where genetic and epigenetic mechanisms become indispensable. However, the molecular mechanisms of how stress exposure impacts gene function will be discussed in greater detail in another chapter. Instead, it is hoped that the readers will gain a foundational knowledge on stress response and some of the basic stress mechanisms to appreciate many of the detailed chapters in this book.
Epigenetics of Stress and Stress Disorders. https://doi.org/10.1016/B978-0-12-823039-8.00017-4
Stress as an environmental factor
Sometimes it may take an observer a moment of pause before considering stress as an environmental factor. That is because triggering the stress response may not require that a person be directly exposed to or ingest some physical substance. For instance, it is well established that environmental toxicants such as lead wield a pernicious effect on neurodevelopment when exposed even at low quantities.5 Likewise, ionizing radiation, such as those emitted by X-ray machines or a nuclear power plant, causes double stranded breaks in DNA.6 However, one can be sitting perfectly still in his car stuck in traffic on the 495 Beltway in DC and yet, his stress hormone level is through the roof. Other than the DC pollution seeping through the car’s ventilation system, no external chemical or physical factor has entered the person to precipitate the stress response. The mere perception or thought of nonimmediate events can trigger a stress response. Stress can also be highly subjective. For instance, the stressful experience of solving mathematical problems in front of a group of people, such as those administered during the Trier Social Stress Test,7 may not be challenging to calculus teachers who routinely perform these tasks in front of dozens of students. Even when a person is physically attacked, the stress response is not due to the sustained physical damage, but rather the person’s awareness of the possibility of harm. Yet, the impact of stress can be just as detrimental to the body as many real, physical environmental factors.
Stress is considered an environmental factor because stressors, which can be situational, mental, or physical in nature, are external and can lead to powerful physiological responses in the human body even without any physical contact. In other words, stressors, whether real or perceived, are a consequence of our interactions with the environment even if they only manifest themselves as mere thoughts in the minds of the “stressee.” In contrast, the response to these external stressors is almost always internal and may require no direct, physical contribution from the environment.
The basics of the stress response
What happens when the stress response is provoked? Once stress has been perceived by the brain, actions of the amygdala, the fear center of the brain, and the hypothalamus activate the sympathetic nervous system that in a matter of seconds lead to the release of cortisol, adrenaline (epinephrine), and noradrenaline (norepinephrine) from the adrenal glands. These actions then activate the HPA axis and involve a cascade of neuroendocrine hormones that culminates in the additional release of the stress hormone cortisol. First, the paraventricular nuclei or PVN, a small subpopulation of neurons in the hypothalamus, release the corticotropin releasing hormone or factor (CRH or CRF), and the release activity is dependent on the anticipation of the outcome.8 CRH released from the PVN travels downward to the anterior pituitary via the hypophyseal transport system of capillaries that connect the two structures.9 Activation of CRH receptors (CRHR1) on the anterior pituitary promotes the release of adrenocorticotropic hormones (ACTH) that are released into the blood circulation.10 ACTH reaching the adrenal glands binds and activates the melanocortin receptor type 2 (MC2R)11 that finally leads to the release of cortisol into the bloodstream. Collectively, as mentioned, these three endocrine tissues make up the HPA axis responsible for mounting the stress response and releasing cortisol. While secondary to the sympathetic nervous system in terms of time for activation (minutes vs seconds),12 the HPA axis plays a more prominent role in chronic diseases due to the prolonged availability of cortisol
Sympathetic and parasympathetic systems
in the bloodstream, although there is evidence to suggest that both the sympathetic nervous system and the HPA axis are interconnected and contribute to the impact of stress exposure on the body.13
There are additional factors that are released at the same time as cortisol and constitute a part of the stress response. Additional factors that are integral to the stress response are pro-inflammatory cytokines such as IL-1B and IL-6 that provoke the immune system14, 15 and hormones such as prolactin and testosterone.16, 17 Release of these types of cytokines may seem counterintuitive given the immunesuppressive nature of cortisol. However, chronic exposure to stress has a prolonged suppressing effect on the immune system, as steroid medications or derivatives of cortisol such as dexamethasone or prednisone are used to treat autoimmune diseases such as rheumatoid arthritis or asthma, or recently the inflammatory “cytokine storm” associated with COVID-19.18
Sympathetic and parasympathetic systems
Together, the endocrine factors elicit a specific set of physiological response in the human body. It is entirely geared toward the expenditure of energy in the form of glucose for mounting the “fight or flight” response. The activation of the stress response mediated by the sympathetic nervous system and the HPA axis involves the immediate increase in heart rate, blood pressure, and glucose release aimed toward providing energy to the muscles. Alertness and vigilance are also increased.19 In the animal kingdom, the gazelle is able to outmaneuver the charging cheetah, or the male walrus bull is able to overpower another challenger to his harem. A human equivalent may be giving a presentation at a board meeting or running to catch a train. In all of these instances of stress response activation, the stressors are acute for the most part and the body returns to its prestress, homeostatic baseline following the resolution of the conflict.
It is important to note that the stress response that has evolved throughout evolution has been honed mostly as a transient response. Mobilization of energy to tackle what for most of the animals is life-anddeath situations is relatively short in duration and comes at a great cost. During this period, activities of several important bodily functions become marginalized in terms of priority. Processes involved in storing away energy, fighting infections, digesting food, and engaging in reproductive transactions come to a halt.20 These are reasonable short-term inconveniences given that a failure to mount an effective “fight or flight” response to survive predation renders these otherwise essential endeavors moot. However, once the stressor has subsided, the system must return to normal for the animal to continue its life. Therefore the body has also developed a rapid negative feedback system to quickly restore the body to the baseline state. The parasympathetic nervous system is engaged to achieve homeostasis.21 Importantly, increased levels of cortisol in the bloodstream, in addition to its primary role of making glucose available, initiate the suppression of CRH and ACTH release from their respective tissues, ultimately causing the attenuation of additional cortisol release. The acute release of stress hormones and the repertoire of coping behavior that they facilitate are ideally suited for the animal kingdom and many instances in the human experience where the stressors are sporadic and brief in nature.
An argument could be made that acute stressors are beneficial for the most part, so long as the organism does not sustain physical harm. For animals avoiding predation and competing for food and mates, stressors provide the means by which their genetic fitness could be tested. Having succeeded through the stressors meant not only the continued opportunities for propagation, but increased fitness and probability to survive the next stressor. The increase in fitness included better physiological
response through stronger muscles and cardiovascular system as well as the increases in mental acuity and learned response. In humans, similar adaptive response is also in play, as exposure to acute stressors and transient activation of the sympathetic nervous system is beneficial to physical fitness and mental acuity. One such example is vigorous physical exercise. Exercise can be seen as an acute stressor that causes the release of cortisol and adrenaline for the purpose of predefined energy expenditure.22 Its benefits are many, from prevention of cardiovascular disease, diabetes, obesity, and others that are associated, interestingly, with chronic stress exposure. In particular, regular intermittent exercise can also prevent neurological disorders such as Alzheimer’s disease23, 24 and the amelioration of psychiatric disorders such as anxiety and depression.25, 26 Unfortunately, as we will see, the development of the modern society and the resulting social infrastructure has created an environment where the stressors are long lasting and recurrent. Such an environment has led to a prolonged activation of the HPA axis with detrimental physiological consequences, especially to the brain.
Allostasis and allostatic load
Prolonged HPA axis activation due to chronic stress exposure is not unique to humans but is an integral part of the human experience in the 21st century. The workweek for some translates to more than 60 h/ week to meet deadlines. There is a family to support and mortgage and car payments to make. There are many anxiogenic social events on a daily basis, whether they be from the supervisor, a spouse, or the elected leadership. There is also a pandemic that has greatly diminished the (positive) physical social interactions that are needed for wellbeing. In fact, prolonged social isolation is a potent stressor that also activates the HPA axis and has been used in animals to study various symptoms of depression such as anhedonia, learned helplessness, and cognitive deficits.27–31 All of these stressors contribute to the overburdening of the HPA axis and cause deleterious symptoms in multiple organ systems. Here, we introduce the term allostasis and allostatic load to describe the body’s maladaptive response to chronic stress. Allostasis refers to the ability and desire of the body to return to homeostasis following stress exposure.32 As mentioned before, the actions of the sympathetic nervous system, the HPA axis, and their hormones cortisol and adrenaline to mount a stress response and the negative feedback system involving cortisol and the parasympathetic nervous system altogether constitute an adaptive response designed to reestablish homeostasis once the stressor has passed. Unfortunately, many man-made events and circumstances have created environments where allostasis cannot be rapidly achieved. Repeated and/or prolonged stressful events impact the HPA axis by flooding the bloodstream with cortisol and adrenaline. The negative feedback system and the parasympathetic nervous system become impaired, and hypercortisolemia continues to wreak havoc on different organ systems. The term allostatic load was first coined by McEwen and Stellar in 1993 and refers to the degree to which the amount of “wear and tear” or disease burden that chronic stress has exacted on the body.33 In instances of acute stress, allostatic load is minimal. However, with allostasis being overburdened by chronic or repetitive stress, the allostatic load becomes substantial and the overall stress response becomes maladaptive.
Allostatic load and disease burden
The sequelae of increased allostatic load are many and serve as a testament to the pernicious effects of chronic stress. Many of the symptoms logically follow the long-term effects of the adaptive response in
terms of energy utilization and marginalization of processes that are secondary to immediate survival. For instance, increased risk to cardiovascular disease, hypertension, and diabetes makes intuitive sense, since acute stressors cause increased heart rate, blood pressure, and hyperglycemia, respectively.34, 35 Also, impaired fertility, disruptions in GI function, and susceptibility to infections are likely to be long-term manifestations of noncritical processes that have become marginalized during the “fight or flight” response.36–38 In contrast, there are some that may be counterintuitive such as obesity, since acute stressors favor energy utilization rather than storage.39 Regardless, it is important to note that stress exposure plays such a significant role in the development of diseases that occupy such prominent positions in terms of disease burden and prevalence in the United States.4 It would be of critical importance to be able to empirically assess the extent to which chronic stress exposure contributes to these diseases.
Great effort has been made to operationalize the concept of allostatic load in terms of physiological parameters that can be measured. The MacArthur Successful Aging Study concluded that the major determinants of allostatic load include systolic and diastolic blood pressure, waist hip ratio, LDL cholesterol, HbA1C, DHEA-S, norepinephrine, epinephrine, and the glucocorticoid cortisol.40 Although many of these measurements also have nonstress-related causes, they are nonetheless important assessments for estimating the cumulative “wear and tear” on the body and can be recapitulated in a myriad of animal models of stress that have excluded other contributing factors such as high-fat diet.41–44 The contribution of chronic stress to any particular disease cannot be accurately assessed in humans due to the difficulty of controlling for genetic diversity, food intake, environmental exposures, and behavior as one can when using animal models. Instead, human studies must involve large swaths of the population, and these confounding factors have to be controlled for by statistics.
The potential role for allostatic load in the human population can be best exemplified by the two Whitehall studies of British civil servants. The first study examined 17,530 male civil servants and observed that the grade of employment was a stronger predictor for coronary heart disease (CHD) mortality than any other major coronary risk factors.45 The second Whitehall study was longitudinal and prospective in design and examined 10,314 participants that included both male and female civil servants.46 In addition to replicating the inverse correlation between grade level and CHD mortality of the first study, the second study also focused on psychosocial factors such as stressful work environment, lack of social support, and financial difficulties, all of which were also inversely correlated with the employment grade. While there is no universally accepted causal factor(s) for these relationships, it is widely believed that chronic psychosocial stress (or “job strain”) likely played a prominent role given its contribution to CHD and other metabolic diseases.47, 48
Allostatic load and the brain
One of the organs associated with chronic stress exposure not mentioned before (but of primary focus in this book) is the brain. As mentioned previously, acute stress, for the most part, can be beneficial to multiple organ systems, and the brain is no exception. Exposure to acute stress is associated with enhanced short-term memory and memory consolidation.49, 50 These benefits are further supported by increased neurogenesis and neuroprotection following exposure to acute stress.51–53 Interestingly, a recent work using animal models of stress reported that acute stress inoculation can even increase resilience against future stressors.54 In contrast, chronic stress exposure generally has the opposite effect
