This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Social Bookmarking   What's this?

Mechanisms Leading to Disease

Bruce S. McEwen, PhD; Eliot Stellar, PhD

Arch Intern Med. 1993;153(18):2093-2101.

Abstract
Objective
This article presents a new formulation of the relationship between stress and the processes leading to disease. It emphasizes the hidden cost of chronic stress to the body over long time periods, which act as a predisposing factor for the effects of acute, stressful life events. It also presents a model showing how individual differences in the susceptibility to stress are tied to individual behavioral responses to environmental challenges that are coupled to physiologic and pathophysiologic responses.

Data Sources
Published original articles from human and animal studies and selected reviews. Literature was surveyed using MEDLINE.

Data Extraction
Independent extraction and cross-referencing by us.

Data Synthesis
Stress is frequently seen as a significant contributor to disease, and clinical evidence is mounting for specific effects of stress on immune and cardiovascular systems. Yet, until recently, aspects of stress that precipitate disease have been obscure. The concept of homeostasis has failed to help us understand the hidden toll of chronic stress on the body. Rather than maintaining constancy, the physiologic systems within the body fluctuate to meet demands from external forces, a state termed allostasis. In this article, we extend the concept of allostasis over the dimension of time and we define allostatic load as the cost of chronic exposure to fluctuating or heightened neural or neuroendocrine response resulting from repeated or chronic environmental challenge that an individual reacts to as being particularly stressful.

Conclusions
This new formulation emphasizes the cascading relationships, beginning early in life, between environmental factors and genetic predispositions that lead to large individual differences in susceptibility to stress and, in some cases, to disease. There are now empirical studies based on this formulation, as well as new insights into mechanisms involving specific changes in neural, neuroendocrine, and immune systems. The practical implications of this formulation for clinical practice and further research are discussed.

(Arch Intern Med. 1993;153:2093-2101)

Author Affiliations
From the Department of Psychology, Yale University, New Haven, Conn.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Measures of Chronic Conditions and Diseases Associated With Aging in the National Social Life, Health, and Aging Project
Williams et al.
J Gerontol B Psychol Sci Soc Sci 2009;64B:i67-i75.
ABSTRACT | FULL TEXT  

Migration and Hypertension: A Cross-Sectional Study Among Neo-Migrants and Settled-Migrants in Delhi, India
Kusuma et al.
Asia Pac J Public Health 2009;21:497-507.
ABSTRACT  

Sleep Homeostasis Modulates Hypocretin-Mediated Sleep-to-Wake Transitions
Carter et al.
J. Neurosci. 2009;29:10939-10949.
ABSTRACT | FULL TEXT  

The Association Between Perceived Discrimination and Obesity in a Population-Based Multiracial and Multiethnic Adult Sample
Hunte and Williams
AJPH 2009;99:1285-1292.
ABSTRACT | FULL TEXT  

Biologic Cost of Caring for a Cancer Patient: Dysregulation of Pro- and Anti-Inflammatory Signaling Pathways
Rohleder et al.
JCO 2009;27:2909-2915.
ABSTRACT | FULL TEXT  

Chronic Fatigue Syndrome and High Allostatic Load: Results From a Population-Based Case-Control Study in Georgia
Maloney et al.
Psychosom. Med. 2009;71:549-556.
ABSTRACT | FULL TEXT  

Isolation stress for 30 days alters hepatic gene expression profiles, especially with reference to lipid metabolism in mice
Motoyama et al.
Physiol. Genomics 2009;37:79-87.
ABSTRACT | FULL TEXT  

Catecholaminergic Systems in Stress: Structural and Molecular Genetic Approaches
Kvetnansky et al.
Physiol. Rev. 2009;89:535-606.
ABSTRACT | FULL TEXT  

A Preliminary Study of Daily Interpersonal Stress and C-Reactive Protein Levels Among Adolescents From Latin American and European Backgrounds
Fuligni et al.
Psychosom. Med. 2009;71:329-333.
ABSTRACT | FULL TEXT  

Allostatic Load and Frailty in the Women's Health and Aging Studies
Szanton et al.
Biol Res Nurs 2009;10:248-256.
ABSTRACT  

Is Positive Well-Being Protective of Mobility Limitations Among Older Adults?
Collins et al.
Journals of Gerontology Series B: Psychological Sciences and Social Science 2008;63:P321-P327.
ABSTRACT | FULL TEXT  

Stress, health and ageing: a focus on postmenopausal women
Wolf and Kudielka
Menopause Int 2008;14:129-133.
ABSTRACT | FULL TEXT  

Neighborhood Psychosocial Hazards and Cardiovascular Disease: The Baltimore Memory Study
Augustin et al.
AJPH 2008;98:1664-1670.
ABSTRACT | FULL TEXT  

The Fragile Mind: Early Life Stress and Inflammatory Disease
Jessop
Endocrinology 2008;149:2724-2726.
FULL TEXT  

Coping as a Multisystem Construct Associated With Pathways Mediating HIV-Relevant Immune Function and Disease Progression
Temoshok et al.
Psychosom. Med. 2008;70:555-561.
ABSTRACT | FULL TEXT  

Effects of allostatic load on the social gradient in ischaemic heart disease and periodontal disease: evidence from the Third National Health and Nutrition Examination Survey
Sabbah et al.
J. Epidemiol. Community Health 2008;62:415-420.
ABSTRACT | FULL TEXT  

Coregulation, Dysregulation, Self-Regulation: An Integrative Analysis and Empirical Agenda for Understanding Adult Attachment, Separation, Loss, and Recovery
Sbarra and Hazan
Pers Soc Psychol Rev 2008;12:141-167.
ABSTRACT  

Teaching the interrelationship between stress, emotions, and cardiovascular risk using a classic paper by Walter Cannon
Gwirtz
Adv. Physiol. Educ. 2008;32:18-22.
ABSTRACT | FULL TEXT  

The Anteroventral Bed Nucleus of the Stria Terminalis Differentially Regulates Hypothalamic-Pituitary-Adrenocortical Axis Responses to Acute and Chronic Stress
Choi et al.
Endocrinology 2008;149:818-826.
ABSTRACT | FULL TEXT  

Stress and Blood Pressure During Pregnancy: Racial Differences and Associations With Birthweight
Hilmert et al.
Psychosom. Med. 2008;70:57-64.
ABSTRACT | FULL TEXT  

Psychosocial Aspects of Chronic Disease: ESRD as a Paradigmatic Illness
Cukor et al.
J. Am. Soc. Nephrol. 2007;18:3042-3055.
ABSTRACT | FULL TEXT  

Psychosocial and Physiological Stress Among Women Leaving Welfare
Kneipp et al.
West J Nurs Res 2007;29:864-883.
ABSTRACT  

Do Chronic Stressors Lead to Physiological Dysregulation? Testing the Theory of Allostatic Load
Glei et al.
Psychosom. Med. 2007;69:769-776.
ABSTRACT | FULL TEXT  

Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain
McEwen
Physiol. Rev. 2007;87:873-904.
ABSTRACT | FULL TEXT  

Associations of Salivary Cortisol With Cognitive Function in the Baltimore Memory Study
Lee et al.
Arch Gen Psychiatry 2007;64:810-818.
ABSTRACT | FULL TEXT  

The Effects of Acculturation on Asthma Burden in a Community Sample of Mexican American Schoolchildren
Martin et al.
AJPH 2007;97:1290-1296.
ABSTRACT | FULL TEXT  

Assessing Cortisol Reactivity to a Linguistic Task as a Marker of Stress in Individuals With Left-Hemisphere Stroke and Aphasia
Laures-Gore et al.
JSLHR 2007;50:493-507.
ABSTRACT | FULL TEXT  

Comorbidity in Older Adults: Nosology of Impairment, Diseases, and Conditions
Karlamangla et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2007;62:296-300.
ABSTRACT | FULL TEXT  

Predicting mortality from clinical and nonclinical biomarkers.
Goldman et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2006;61:1070-1074.
ABSTRACT | FULL TEXT  

Gerontology's Future: An Integrative Model for Disciplinary Advancement.
Alkema and Alley
Gerontologist 2006;46:574-582.
ABSTRACT | FULL TEXT  

Do biomarkers of stress mediate the relation between socioeconomic status and health?
Dowd and Goldman
J. Epidemiol. Community Health 2006;60:633-639.
ABSTRACT | FULL TEXT  

High cognitive dietary restraint is associated with increased cortisol excretion in postmenopausal women.
Rideout et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2006;61:628-633.
ABSTRACT | FULL TEXT  

Chronic Exposure to Everyday Discrimination and Coronary Artery Calcification in African-American Women: The SWAN Heart Study
Lewis et al.
Psychosom. Med. 2006;68:362-368.
ABSTRACT | FULL TEXT  

Reduction in Allostatic Load in Older Adults Is Associated With Lower All-Cause Mortality Risk: MacArthur Studies of Successful Aging
Karlamangla et al.
Psychosom. Med. 2006;68:500-507.
ABSTRACT | FULL TEXT  

Childhood Cognitive Performance and Risk of Mortality: A Prospective Cohort Study of Gifted Individuals
Martin and Kubzansky
Am J Epidemiol 2005;162:887-890.
ABSTRACT | FULL TEXT  

Justice at Work and Reduced Risk of Coronary Heart Disease Among Employees: The Whitehall II Study
Kivimaki et al.
Arch Intern Med 2005;165:2245-2251.
ABSTRACT | FULL TEXT  

Physiological Wet Laboratory Facilities in Colleges of Nursing
Schaffer and Yucha
Biol Res Nurs 2005;7:130-134.
ABSTRACT  

Cortisol, Testosterone, and Coronary Heart Disease: Prospective Evidence From the Caerphilly Study
Smith et al.
Circulation 2005;112:332-340.
ABSTRACT | FULL TEXT  

Allostatic Load: A Mechanism of Socioeconomic Health Disparities?
Szanton et al.
Biol Res Nurs 2005;7:7-15.
ABSTRACT  

An Immune Risk Phenotype, Cognitive Impairment, and Survival in Very Late Life: Impact of Allostatic Load in Swedish Octogenarian and Nonagenarian Humans
Wikby et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2005;60:556-565.
ABSTRACT | FULL TEXT  

Negative Interaction and Heart Disease in Late Life: Exploring Variations by Socioeconomic Status
Krause
J Aging Health 2005;17:28-55.
ABSTRACT  

Shingles Immunity and Health Functioning in the Elderly: Tai Chi Chih as a Behavioral Treatment
Irwin et al.
Evid Based Complement Alternat Med 2004;1:223-232.
ABSTRACT | FULL TEXT  

Microarousals During Sleep Are Associated With Increased Levels of Lipids, Cortisol, and Blood Pressure
Ekstedt et al.
Psychosom. Med. 2004;66:925-931.
ABSTRACT | FULL TEXT  

Six-Year Outcome of Cognitive Behavior Therapy for Prevention of Recurrent Depression
Fava et al.
Am. J. Psychiatry 2004;161:1872-1876.
ABSTRACT | FULL TEXT  

How Psychological Therapy may Prolong Survival in Cancer Patients: New Evidence and a Simple Theory
Cunningham and Watson
Integr Cancer Ther 2004;3:214-229.
ABSTRACT  

Social Determinants of Health: Implications for Environmental Health Promotion
Schulz and Northridge
Health Educ Behav 2004;31:455-471.
ABSTRACT  

Stressor-Selective Role of the Ventral Subiculum in Regulation of Neuroendocrine Stress Responses
Mueller et al.
Endocrinology 2004;145:3763-3768.
ABSTRACT | FULL TEXT  

Psychobiological Mechanisms of Resilience and Vulnerability: Implications for Successful Adaptation to Extreme Stress
Charney
Focus 2004;2:368-391.
ABSTRACT | FULL TEXT  

Psychoneuroimmunology: Then and Now
Fleshner and Laudenslager
Behav Cogn Neurosci Rev 2004;3:114-130.
ABSTRACT  

Updating Theory on Organizational Stress: the Asynchronous Multiple Overlapping Change (AMOC) Model of Workplace Stress
Sikora et al.
Human Resource Development Review 2004;3:3-35.
ABSTRACT  

How Are Biomarkers Related to Physical and Mental Well-Being?
Seplaki et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2004;59:B201-B217.
ABSTRACT | FULL TEXT  

Psychobiological Mechanisms of Resilience and Vulnerability: Implications for Successful Adaptation to Extreme Stress
Charney
Am. J. Psychiatry 2004;161:195-216.
ABSTRACT | FULL TEXT  

CNS Glucagon-Like Peptide-1 Receptors Mediate Endocrine and Anxiety Responses to Interoceptive and Psychogenic Stressors
Kinzig et al.
J. Neurosci. 2003;23:6163-6170.
ABSTRACT | FULL TEXT  

Workplace Social Support and Ambulatory Cardiovascular Activity in New York City Traffic Agents
Karlin et al.
Psychosom. Med. 2003;65:167-176.
ABSTRACT | FULL TEXT  

Connecting the Dots Linking Mind, Behavior, and Disease: The Biological Concomitants of Coping Patterns: Commentary on "Attachment and Cancer: A Conceptual Integration"
Temoshok
Integr Cancer Ther 2002;1:387-391.
 

How socioeconomic status may "get under the skin" and affect the heart
McEwen and Mirsky
Eur Heart J 2002;23:1727-1728.
FULL TEXT  

Circadian Clock Functioning Is Linked to Acute Stress Reactivity in Rats
Weibel et al.
J Biol Rhythms 2002;17:438-446.
ABSTRACT  

Access to Resources for Substance Users in Harlem, New York City: Service Provider and Client Perspectives
Galea et al.
Health Educ Behav 2002;29:296-311.
ABSTRACT  

Negative Interaction and Changes in Functional Disability During Late Life
Krause and Shaw
Journal of Social and Personal Relationships 2002;19:339-359.
ABSTRACT  

Social Relationships, Gender, and Allostatic Load Across Two Age Cohorts
Seeman et al.
Psychosom. Med. 2002;64:395-406.
ABSTRACT | FULL TEXT  

Effects of Environmental Predictability and Personal Mastery on Self-Regulatory and Physiological Processes
Pham et al.
Pers Soc Psychol Bull 2001;27:611-620.
ABSTRACT  

The Health of Women in Transition from Welfare to Employment
Kneipp et al.
West J Nurs Res 2000;22:656-682.
ABSTRACT  

High Urinary Catecholamine Excretion Predicts Mortality and Functional Decline in High-Functioning, Community-Dwelling Older Persons: MacArthur Studies of Successful Aging
Reuben et al.
Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2000;55:618M-624.
ABSTRACT | FULL TEXT  

Experimental diabetes in rats causes hippocampal dendritic and synaptic reorganization and increased glucocorticoid reactivity to stress
Magarinos and McEwen
Proc. Natl. Acad. Sci. USA 2000;97:11056-11061.
ABSTRACT | FULL TEXT  

Energetic response to repeated restraint stress in rapidly growing mice
Laugero and Moberg
Am. J. Physiol. Endocrinol. Metab. 2000;279:E33-E43.
ABSTRACT | FULL TEXT  

Altered Stress-Induced Anxiety in Adenylyl Cyclase Type VIII-Deficient Mice
Schaefer et al.
J. Neurosci. 2000;20:4809-4820.
ABSTRACT | FULL TEXT  

Interpersonal Flourishing: A Positive Health Agenda for the New Millennium
Ryff and Singer
Pers Soc Psychol Rev 2000;4:30-44.
ABSTRACT  

Prevention of Recurrent Depression With Cognitive Behavioral Therapy: Preliminary Findings
Fava et al.
Arch Gen Psychiatry 1998;55:816-820.
ABSTRACT | FULL TEXT  

Protective and Damaging Effects of Stress Mediators
McEwen
NEJM 1998;338:171-179.
FULL TEXT  

Price of Adaptation--Allostatic Load and Its Health Consequences: MacArthur Studies of Successful Aging
Seeman et al.
Arch Intern Med 1997;157:2259-2268.
ABSTRACT  

Drug Abuse: Hedonic Homeostatic Dysregulation
Koob and Moal
Science 1997;278:52-58.
ABSTRACT | FULL TEXT  

Hopelessness and 4-Year Progression of Carotid Atherosclerosis : The Kuopio Ischemic Heart Disease Risk Factor Study
Everson et al.
Arterioscler. Thromb. Vasc. Bio. 1997;17:1490-1495.
ABSTRACT | FULL TEXT  

Effects of Fasting and Glucose Load on Free Cortisol Responses to Stress and Nicotine
Kirschbaum et al.
J. Clin. Endocrinol. Metab. 1997;82:1101-1105.
ABSTRACT | FULL TEXT  

Stress, a Gift to Doctors
Platt
Arch Intern Med 1994;154:819-819.
ABSTRACT  

Stress, a Gift to Doctors-Reply
McEwen and Rodin
Arch Intern Med 1994;154:819-819.
ABSTRACT  

Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation
Shanks et al.
Proc. Natl. Acad. Sci. USA 2000;97:5645-5650.
ABSTRACT | FULL TEXT