Stress is an ambiguous term better understood biologically through the concepts of “allostasis” and “allostatic load,” with the former referring to the active process by which the body responds to daily stressors and maintains homeostasis, and the latter referring to the physiological and behavioral consequences of either too much stress or from inefficient management of allostasis (McEwen, 2007.) In this context, the term “stressed” is analogous with allostasis, while allostatic load is analogous with “stressed out (McEwen, 2005.)”

Allostasis refers to the body’s ability to achieve stability through change, and involves the release of chemical mediators of the stress response, primarily cortisol, sympathetic and parasympathetic hormones and neurotransmitters, cytokines and metabolic hormones. Allostatic load, in contrast, is the wear and tear that results from the sustained release of these mediators due to (a) repeated “hits” from multiple stressors, (b) a lack of adaptation or habituation, (c) prolonged response due to delayed shutdown, and/or (d) inadequate response that leads to compensatory hyperactivity of other mediators (McEwen, 2011.)

Both acute and chronic stress can contribute to disease onset and progression (Cohen S, Janicki-Deverts D, Miller GE, 2007.) Acute stress may play a contributory role in the development of symptoms that are allergic or atopic in nature, vasomotor, gastrointestinal, or psychological. Chronic stress may contribute to the development of several physical, behavioral and/or neuropsychiatric disorders including anxiety, depression, cognitive dysfunction, sleep disorders, cardiovascular disease, obesity, type 2 diabetes mellitus, and osteoporosis, amongst many others (Chrousos GP, 2009.) 

A primary effector of the stress response is the hypothalamic-pituitary-adrenal (HPA) axis, dysregulation of which plays a fundamental role in the development of stress-related pathophysiology (Tsigos C, Chrousos GP, 2002.) Altered HPA axis activity and dysregulation of the adaptive stress response can be divided into two patterns; (1) increased HPA axis activity and stress system hyperarousal, (Jankord R, Herman JP, 2008) and (2) decreased HPA axis activity and stress system hyporarousal (Heim C, Ehlert U, Hellhammer DH, 2000.) These different pathophysiological presentations of chronic stress have been associated with different clinical manifestations (see table 1) (Tsigos C, Kyrou I, Kassi E, et al, 2016.)

Table 1: Examples of Clinical Conditions Associated with Altered HPA Axis Activity


The brain is the central mediating organ of the stress response as it determines what is stressful and directs the physiological and behavioral aspects of stress (McEwen BS, 2017.) Deleterious effects of chronic stress include changes to the structure and function of the brain, in particular atrophy of nerve cells in the hippocampus (involved in learning and memory) and prefrontal cortex (working memory, executive function) and hypertrophy of amygdala (fear response), which, in turn, can contribute to impaired HPA axis regulation and increased vulnerability to chronic stress (McEwen BS, 2004.) A healthy brain is therefore crucial for maintaining resiliency to stress and subsequently safeguarding mental and physical wellbeing (Juster RP, McEwen BS, Lupien SJ, 2010.)

From an integrative, systems biology perspective stress-related disorders can be viewed as the result of an interplay between an individual’s environment, genetic predisposition, neural processing and subsequent dynamic, compensatory, and proactive adjustments in the activities of chemical mediators of the stress response (Goldstein DS, 2013.) Clinical management should therefore focus on improving external coping resources and stress-related physiology, including reducing strain on the body’s adaptive physiological systems and opening windows of opportunity for the brain to repair, adapt, and become more resilient (McEwen BS, 2016.)

Dietary modification and nutritional interventions can be used to support unique clinical and pathophysiological presentations by influencing behavioral and biological aspect of the stress response (Waladkhani AR, Hellhammer J, 2008) (Head KA, Kelly GS, 2009.) Optimization of nutritional status may improve the response of the HPA-axis to stress, with some evidence to support a role for nutritional interventions such as multivitamin and mineral complexes, magnesium, vitamin C (ascorbic acid) and omega-3 polyunsaturated fatty acids (omega-3 PUFA), although research specifically examining the effect of nutrients on HPA-axis function is sparse.

One study found that supplementation with a multivitamin containing B-vitamins in relatively healthy adults resulted in a near-significant trend towards an increased cortisol awakening response over a 16-week period, suggesting an improved adaptive response to stress (Camfield DA, Wetherell MA, Scholey AB, et al, 2013.) Magnesium also appears to influence HPA axis function, with supplementation shown to attenuate elevation in cortisol and increase ACTH secretion in response to physical stress (Dmitrašinović G, Pešić V, Stanić D, Plećaš-Solarović B, Dajak M, Ignjatović S, 2016) (Cinar V, Mogulkoc R, Baltaci AK, Polat Y, 2008.) And in patients with primary insomnia, magnesium supplementation was found to significantly decrease serum cortisol concentration (Abbasi B, Kimiagar M, Sadeghniiat K, Shirazi MM, Hedayati M, Rashidkhani B, 2012.) Treatment with vitamin C has been shown to reduce cortisol reactivity to acute physiological stress, (Brody S, Preut R, Schommer K, Schürmeyer TH, 2002) (Plotnick MD, D’Urzo KA, Gurd BJ, Pyke KE, 2017) and lower basal cortisol levels within 2-weeks (Yeom HH et al, 2008.) Finally, dietary supplementation with omega-3 PUFA has been shown to reduce cortisol in healthy adults, (Delarue J, Matzinger O, Binnert C, Schneiter P, Chioléro R, Tappy L, 2003) patients with major depressive disorder, (Jazayeri S, Keshavarz SA, Tehrani-Doost M, Djalali M, Hosseini M, Amini H, Chamari M, Djazayery A, 2010) and abstinent alcoholics (Barbadoro P, Annino I, Ponzio E, Romanelli RM, D’Errico MM, Prospero E, Minelli A, 2013.)

Improving an individual’s nutritional status could therefore be useful clinically for the management of stress-related illness with physiological evidence of HPA-axis dysfunction. Salivary cortisol is a sensitive measure of dynamic HPA axis activity and can be used in a clinical setting (Gozansky WS, Lynn JS, Laudenslager ML, Kohrt WM, 2005.) Biochemical assessment of nutritional status may help personalize interventions by identifying people with sub-optimal nutritional intakes and increased physiological requirements. Currently, the evaluation of HPA-axis dysfunction and personalized nutrition are clinically implemented for the management of stress related illness. More research, however, is needed to clarify the potential of this promising approach.



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