Stress and the Individual: Mechanisms Leading to Disease
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The adverse effect of psychological stress on health behaviours such as food choice, physical activity and adherence to medication also contributes to T2DM risk.
“The adverse effect of psychological stress on health behaviours such as food choice, physical activity and adherence to medication also contributes to T2DM risk”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [13]
Changes in eating behaviour are a potential response to chronic stress in humans.
“changes in eating behaviour are a potential response to chronic stress in humans 13.”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [13]
The biological changes that occur as a result of chronic stress do not happen in isolation and are often exacerbated by unhealthy behaviours such as poor diet, physical inactivity, smoking and reduced adherence to medication.
“The biological changes that occur as a result of chronic stress do not happen in isolation and are often exacerbated by unhealthy behaviours such as poor diet, physical inactivity, smoking and reduced adherence to medication 13 .”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [13]
Allostatic mediators work as a nonlinear, sometimes reciprocating, network, so too much or too little of each mediator can perturb the entire network, leading to harmful consequences.
“Allostatic mediators work as a nonlinear, sometimes reciprocating, network (Fig. 1), meaning that too much or too little of each mediator can perturb the entire network, leading to harmful consequences.”
From Sleep Deprivation and Circadian Disruption (2015) · cites this paper as [2]
Chronically increased allostasis can lead to disease.
“Because chronically increased allostasis can lead to disease, we introduced the term “allostatic load or overload” to refer to the wear and tear that results from either too much stress or from inefficient management of allostasis, eg, not turning off the response when it is no longer needed.”
From Protective and damaging effects of stress mediators: central role of the brain (2006) · cites this paper as [3]
Cited by
Sorted by citations
Physiology and neurobiology of stress and adaptation: central role of the brain
McEwen, B. S. (2007) · Physiological Reviews · doi:10.1152/physrev.00041.2006 · Cited by 4,981 · see citing works
Self-citationAnda, R. F., Felitti, V. J., Bremner, J. D., Walker, J. D., Whitfield, C., Perry, B. D., Dube, S. R., & Giles, W. H. (2006) · European archives of psychiatry and clinical neuroscience · doi:10.1007/s00406-005-0624-4 · Cited by 4,292 · see citing works
“Stress is known from animal studies to be associated with a broad range of effects on physical health, including cardiovascular disease, hypertension, hyperlipidemia, asthma, metabolic abnormalities, obesity, infection, and other physical disorders (Musselman 1998 Kaplan 1982; Rozanski, McEwen and Stellar 1993; Anda 1…”
BackgroundMasten, A. S., & Cicchetti, D. (2010) · Development and Psychopathology · doi:10.1017/s0954579410000222 · Cited by 1,800 · see citing works
“…upward consequences for brain development, stress reactivity, and symptoms of psychopathology through a complex sequence of processes (Cicchetti, 2002b; Cicchetti & Cannon, 1999; Gunnar & Quevedo, 2007; Lupien et al., 2006; McEwen & Stellar, 1993; Meaney, 2010; Shonkoff, Boyce, & McEwen, 2009).”
BackgroundProtective and damaging effects of stress mediators: central role of the brain
McEwen, B. S. (2006) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2006.8.4/bmcewen · Cited by 1,220 · see citing works
Self-citationGruber, J., Prinstein, M. J., Clark, L. A., Rottenberg, J., Abramowitz, J. S., Albano, A. M., Aldao, A., Borelli, J. L., Chung, T., Davila, J., et al. (2021) · American Psychologist · doi:10.1037/amp0000707 · Cited by 697 · see citing works
Socio‐economic differentials in peripheral biology: Cumulative allostatic load
Seeman, T., Epel, E., Gruenewald, T., Karlamangla, A., & McEwen, B. S. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.05341.x · Cited by 579 · see citing works
Self-citationType 2 diabetes mellitus and psychological stress — a modifiable risk factor
Hackett, R. A., & Steptoe, A. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.64 · Cited by 480 · see citing works
Massoglia, M., & Pridemore, W. A. (2015) · Annual Review of Sociology · doi:10.1146/annurev-soc-073014-112326 · Cited by 479 · see citing works
Colich, N. L., Rosen, M. L., Williams, E. S., & McLaughlin, K. A. (2020) · Psychological Bulletin · doi:10.1037/bul0000270 · Cited by 433 · see citing works
Cicchetti, D., Rogosch, F. A., Gunnar, M. R., & Toth, S. L. (2010) · Child Development · doi:10.1111/j.1467-8624.2009.01393.x · Cited by 337 · see citing works
al’Absi, M., Hatsukami, D., & Davis, G. L. (2005) · Psychopharmacology · doi:10.1007/s00213-005-2225-3 · Cited by 192 · see citing works
Syndemics: a theory in search of data or data in search of a theory?
Tsai, A. C. (2018) · Social Science & Medicine · doi:10.1016/j.socscimed.2018.03.040 · Cited by 185 · see citing works
Cicchetti, D., Rogosch, F. A., Toth, S. L., & Sturge-Apple, M. L. (2011) · Development and Psychopathology · doi:10.1017/s0954579411000307 · Cited by 168 · see citing works
Applying a biopsychosocial model to migraine: rationale and clinical implications
Rosignoli, C., Ornello, R., Onofri, A., Caponnetto, V., Grazzi, L., Raggi, A., Leonardi, M., & Sacco, S. (2022) · The Journal of Headache and Pain · doi:10.1186/s10194-022-01471-3 · Cited by 138 · see citing works
Olvera Alvarez, H. A., Kubzansky, L. D., Campen, M. J., & Slavich, G. M. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.06.002 · Cited by 133 · see citing works
“Allostatic load as described by (McEwen and Stellar, 1993) refers to the “wear and tear” the body experiences in response to repeated allostatic activations caused by persistent perception of psychosocial stressors.”
The Role of HPA Axis and Allopregnanolone on the Neurobiology of Major Depressive Disorders and PTSD
Almeida, F. B., Pinna, G., & Barros, H. M. T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115495 · Cited by 130 · see citing works
Becker, W. J., Belkin, L. Y., Conroy, S. A., & Tuskey, S. (2021) · Journal of Management · doi:10.1177/0149206319890655 · Cited by 73 · see citing works
“Furthermore, there is a well-established link between anxiety and health outcomes, such as poor physical and mental health and premature mortality (e.g., Keller et al., 2012; McEwen, 2017; McEwen & Stellar, 1993; Watson & Pennebaker, 1989).”
BackgroundWiss, D. A., Avena, N., & Gold, M. (2020) · Nutrients · doi:10.3390/nu12113521 · Cited by 66 · see citing works
Perceived weight discrimination and chronic medical conditions in adults with overweight and obesity
Udo, T., Purcell, K., & Grilo, C. M. (2016) · International Journal of Clinical Practice · doi:10.1111/ijcp.12902 · Cited by 64 · see citing works
Clinical utility of demoralization: A systematic review of the literature
Woźniewicz, A., & Cosci, F. (2023) · Clinical Psychology Review · doi:10.1016/j.cpr.2022.102227 · Cited by 44 · see citing works
Cannizzaro, E., Ramaci, T., Cirrincione, L., & Plescia, F. (2019) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph16204031 · Cited by 39 · see citing works
Obeng-Gyasi, S., Li, Y., Carson, W. E., Reisinger, S., Presley, C. J., Shields, P. G., Carbone, D. P., Ceppa, D. P., Carlos, R. C., & Andersen, B. L. (2022) · JAMA Network Open · doi:10.1001/jamanetworkopen.2022.21626 · Cited by 34 · see citing works
Barthel, M.-C., Fricke, K., Muehlhan, M., Vogel, S., & Alexander, N. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105996 · Cited by 34 · see citing works
African Penguin tolerance to humans depends on historical exposure at colony level
PICHEGRU, L., EDWARDS, T. B., DILLEY, B. J., FLOWER, T. P., & RYAN, P. G. (2016) · Bird Conservation International · doi:10.1017/s0959270915000313 · Cited by 26 · see citing works
Lemaigre, C., & Taylor, E. P. (2019) · Child Abuse & Neglect · doi:10.1016/j.chiabu.2018.11.013 · Cited by 24 · see citing works
Boneva, R. S., Lin, J.-M. S., Wieser, F., Nater, U. M., Ditzen, B., Taylor, R. N., & Unger, E. R. (2019) · Frontiers in Pediatrics · doi:10.3389/fped.2019.00195 · Cited by 22 · see citing works
Effects of nicotine and stress exposure across generations in C57BL/6 mice
Yohn, N. L., Caruso, M. J., & Blendy, J. A. (2019) · Stress · doi:10.1080/10253890.2018.1532991 · Cited by 13 · see citing works
Kascakova, N., Petrikova, M., Furstova, J., Hasto, J., Geckova, A. M., & Tavel, P. (2022) · BMC Public Health · doi:10.1186/s12889-022-14160-2 · Cited by 14 · see citing works
Pu, Y., & Kong, Z. (2026) · American Journal of Men's Health · doi:10.1177/15579883261441859 · Cited by 1 · see citing works
“This idea is formalized in allostatic load theory, which holds that physiological wear and tear result from chronic activation of stress systems (McEwen & Gianaros, 2010; McEwen & Stellar, 1993).”
Xu, H.-M., Liu, Z.-C., Wang, X., Zhao, W.-J., Zhang, C., Yang, Z., Zhou, T., Zhang, J., Kai-feng, P., & Li, W. (2026) · BMC Public Health · doi:10.1186/s12889-026-28127-0 · Cited by 1 · see citing works
“The cumulative physiological cost of maintaining allostasis under chronic stressors is conceptualized as allostatic load (AL), which can be quantified through a composite index of biomarkers across neuroendocrine, metabolic, immune, kidney, and cardiovascular systems [12, 14].”
Liang, Y., & Booker, C. L. (2024) · Figshare · doi:10.6084/m9.figshare.26679047
Gatta, E. (2016) · theses.fr (ABES) · doi:10.70675/eb10021dz791ez4d44z8f03zb272dfadb7fb
“This lays the groundwork for appearance of stress-related disorders, particularly involving the cardiovascular and immune systems (McEwen and Stellar, 1993).”
BackgroundExpériences adverses durant l'enfance et entrée dans la vie adulte
Biscond, M. (2022) · theses.fr (ABES) · doi:10.70675/86d5d288z17f1z4ce5zad4cz6b997763d87d
Is homeostatic efficiency a positive aspect of health and well-being?
Colditz, I. G. (2026) · Peer Community Journal · doi:10.24072/pcjournal.808
Prenatal allostatic load and adverse pregnancy outcomes: a systematic review and meta-analysis
Zhao, M., Zheng, H., Qi, D., Zhang, X., Ba, L., Wang, B., & Hong, X. (2026) · PeerJ · doi:10.7717/peerj.21756
“The AL concept describes the relationship between stress and disease development based on allostasis—the organism’s ability to achieve stability through change ( McEwen & Stellar, 1993 ; McEwen & Seeman, 1999 ).”
Latent Class Characteristics and Influencing Factors of Allostatic Load Among Pregnant WomenPreprint
Zhao, G., Xu, Y., & Li, Y. (2026) · Research Square · doi:10.21203/rs.3.rs-10895691/v1
Lucas, V. A., Reyes, H. L. M., Maselko, J., Stoner, M. C. D., Rosenberg, M. S., DeLong, S. M., Bhushan, N. L., Moffett, B., Beidelman, E. T., Klein, M., et al. (2026) · SSM - Mental Health · doi:10.1016/j.ssmmh.2026.100706
Angelier, F., Costantini, D., Houdelier, C., & Marasco, V. (2026) · BioEssays · doi:10.1002/bies.70184
“Many studiesin humansand otheranimals have shown clear deleterious consequences of such chronic activation, including disruptive effects on brain functioning, lifelong mental and metabolic disorders, and reduced longevity [ 5].”
Age trajectories of emotional balance: the impact of war-related stress
Pisaruk, A. (2026) · Problems of ageing and longevity (Ukraine) · doi:10.71012/pro-ageing-2026-3-02
Mundo, S. R. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1938670
Burga, A., & Chen, S. (2026) · Social Science & Medicine · doi:10.1016/j.socscimed.2026.119882
Mun, Y., Choi, H., & Kim, S. (2026) · Asian Women · doi:10.64446/aw.2026.9.42.3.535
Dempsey, A., Harnett, Z., Gallagher, S., & Howard, S. (2026) · Biological Psychology · doi:10.1016/j.biopsycho.2026.109410
Liu, J., Wu, J., & Zhang, X. (2026) · Journal of Affective Disorders · doi:10.1016/j.jad.2026.122574
Verheyen, L., Alfano, R., Sleurs, H., Giesberts, N., Bijnens, E. M., Reimann, B., Martens, D. S., Ottoy, S., Malina, R. M., Nawrot, T. S., et al. (2026) · Environmental Science & Technology · doi:10.1021/acs.est.6c04150
Alipour, M., Sahoo, S., Imrey, P. B., et al. (2026) · JSES Reviews Reports and Techniques · doi:10.1016/j.xrrt.2026.100900
Bu, L., & Wang, Z. (2026) · European Journal of Psychotraumatology · doi:10.1080/20008066.2026.2730909
“Theoretical accounts of stress biology emphasise that repeated interpersonal threat can recalibrate allo-static systems through immune, autonomic, and neuroendocrine pathways (McEwen, 1993, 1998; Miller et al., 2011; Slavich & Irwin, 2014).”
Wang, H., Zhuang, L., Zhang, X., Yu, T., Liu, T., & Yang, X. (2026) · Frontiers in Psychology · doi:10.3389/fpsyg.2026.1922137
Wang, F., 杨世昌, Li, L., Wang, L., Chen, S., Chang, J., Yang, Q., Gao, K., & Chen, P. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1845849
- Authors
- McEwen, B. S.
- Corresponding author
- McEwen, Bruce S.
- Venue
- Archives of Internal Medicine
- Publisher
- American Medical Association (AMA)
- Published
- 1993-09-27
- Volume
- 153
- Issue
- 18
- Pages
- 2093
- ISSN
- 0003-9926 (ISSN-L)
- OpenAlex
- W7214176958
- Cited by
- 103
- References
- 0
- Citations by year
- 2026: 50 · 2025: 1 · 2024: 6 · 2023: 9 · 2022: 2 · 2021: 7 · 2020: 5 · 2019: 3 · 2017: 2 · 2016: 3 · 2015: 5 · 2014: 1 · 2013: 2 · 2012: 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Internal Medicine (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Health Professions › General Health Professions › Health, psychology, and well-being
- Social Sciences › Psychology › Social Psychology › Stress and Burnout Research
- Keywords
- stress, individual differences, psychological stress, stress response
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review