The word “stress” is often used in daily discourse to reflect the pattern of our busy lives. For some, stress comes and goes, but when stress becomes chronic—usually from unresolved uncertainty—serious bodily damage can manifest.1 During a stressful event, neuroendocrine, cardiovascular, and emotional responses become activated1 and can disturb the body’s normal physiological equilibrium.2 Over the past decade, studies have shown that chronic stress can also induce genome-wide epigenetic changes and the distribution of molecules in the brain,3,4 the central organ of stress and adaptation to stress.5 What’s more, maternal genetic changes that result from high cortisol exposure may even be passed down to future generations.6
In the following video, IFM Executive Director of Medical Education Robert Luby, MD, discusses inflammation, stress, and chronic conditions:
A 2017 study of patients with Cushing’s Syndrome (CS) in remission found genome-wide changes in DNA methylation.7 Patients exposed to high amounts of cortisol, as is characteristic of CS, had less DNA methylation compared to healthy individuals, and these changes were associated with persistent neuropsychological consequences like fatigue, depression, and anxiety. The findings suggest that long-standing hypercortisolism reduces global DNA methylation, specifically in genes that are known to attenuate the sensitivity of the glucocorticoid receptor, and therefore may induce hyperactivity of the HPA axis.7
Early Life Stress
Early life adverse events and poor maternal care have been linked to changes in GC receptor (NR3C1) DNA methylation.7 Gene-environment interactions are key to how the brain develops, and adverse and stressful childhood experiences (ACE) have a powerful effect on lifelong trajectories of health and disease.3 In fact, stressors that occur early in development have greater and more enduring effects than stressors that occur in adulthood.3
A 2014 review points to a substantial body of evidence connecting early life stress to later life neurodegenerative, cognitive, cardiometabolic, and psychiatric diseases.6 For the fetus, these effects are mediated through alterations in both the maternal and fetal hypothalamic-pituitary-adrenal (HPA) axis leading to in-utero exposure to excess glucocorticoids. After birth, impairment of interactions between mother and infant (like maternal separation or deprivation) was shown to disrupt the neuroendocrine regulations, such as the upregulation of hippocampal glucocorticoid receptor and hypothalamic corticotropin?releasing factor, along with increasing corticosterone and adrenocorticotropic hormone levels. These disruptions may cause behavioral problems in adulthood, such as impaired memory and learning, anxiety, and depressive-like behaviors.6
The epigenetic effects of stress can also be seen within the womb. Research from 2008 suggests that maternal stress levels may affect the gestational development of a fetus in the third trimester.6 In the study, a maternally depressed/anxious mood resulted in the increased methylation of a CpG?rich region in the promoter and exon1F of the GR gene (NR3C1) in the cord blood of newborns, and these effects on methylation of the NR3C1 gene have been shown to be persistent beyond infancy, suggesting a functional consequence of this epigenetic variation on HPA stress reactivity.6
A 2018 population-based study provides empirical support for a relationship between maternal anxiety over time and risk of childhood developmental delays.8 The authors of this study suggest that identifying and supporting mothers experiencing high anxiety symptoms in the perinatal period may mitigate the risk of these delays in children.8
In addition to epigenetic effects, chronic stress challenges overall health. People living in a volatile and insecure environment have altered brain architecture and a high risk of depression, cognitive impairment, myocardial infarction, and stroke.1 Chronic stress can also exacerbate pro-inflammatory diseases and increase susceptibility to infections and cancer.9
Patients suffering from chronic stress should be encouraged to improve their sleep quality and quantity, improve social support, promote a positive outlook on life, maintain a healthy diet, avoid smoking, and undertake regular moderate physical activity.5 Functional Medicine clinicians can utilize tools such as the IFM Diet, Nutrition, and Lifestyle Journal, found in the IFM Toolkit, to identify areas where patients might modify their behavior to achieve positive outcomes. By examining lifestyle choices related to diet and exercise, Functional Medicine practitioners are able to assess the body’s complex physiological processes and help patients make meaningful, lasting lifestyle changes that can decrease chronic disease risk.
Mindfulness-based interventions have also been shown to help alleviate chronic stress–related symptoms.10,11 Recent empirical research points to several components through which mindfulness meditation exerts its effects: (a) attention regulation, (b) body awareness, (c) emotion regulation, and (d) change in perspective on the self.11 Functional and structural neuroimaging studies suggest that mindfulness practice is associated with neuroplastic changes in the anterior cingulate cortex, insula, temporoparietal junction, frontolimbic network, and default mode network structures.11
But can meditation effect change at the cellular level? Recent investigations using functional genomics have helped researchers understand the molecular pathways involved in mind-body therapies.12 A 2014 review supports the correlation of transcriptomic, and thus epigenetic, changes with mind-body therapies like meditation, yoga, tai chi, qigong, biofeedback, progressive muscle relaxation, guided imagery, hypnosis, and deep breathing exercises.12 A 2017 study found that yoga and meditation-based lifestyle interventions significantly reduced the rate of cellular aging in a healthy population.13
Similar genome-regulating effects have been found for Kirtan Kriya meditation14 and for a mindfulness-based stress reduction program.15 These data show that psychological interventions can reverse stress-induced genome-wide transcriptional responses, which may in turn have implications for human health.16 A 2012 study investigated whether tai chi practice resulted in positive epigenetic changes at the molecular level, and found that in the tai chi cohort, all six marks demonstrate significant slowing (by 5-70%) of the age-related methylation losses or gains observed in the controls, suggesting that tai chi practice may be associated with measurable beneficial epigenetic changes.17
“We are now exposed to chronic stress and chronic sources of inflammation. This is how the Functional Medicine paradigm can help clinicians: not by trying to stop inflammation and stop stress as the drivers of chronic disease, per se, but to help the patient change the way they’re living and change their environment away from an inflammatory environment,” says IFM Executive Director of Medical Education Robert Luby, MD. “Evidence is emerging that positive experiences create a positive milieu in the patient, which promotes health and wellness, including and especially the health of the immune system.”
- Peters A, McEwen BS, Friston K. Uncertainty and stress: why it causes diseases and how it is mastered by the brain. Prog Neurobiol. 2017;156:164-188. doi:10.1016/j.pneurobio.2017.05.004.
- Leonard BE, Song C. Stress, depression, and the role of cytokines. In: Dantzer R, Wollman EE, Yirmiya R, eds. Cytokines, Stress, and Depression. Advances in Experimental Medicine and Biology, Volume 461. Boston, MA: Springer; 1999:251-265. doi:10.1007/978-0-585-37970-8_14.
- Zannas AS, West EA. Epigenetics and the regulation of stress vulnerability and resilience. Neuroscience. 2014;264:157-170. doi:10.1016/j.neuroscience.2013.12.003.
- Stankiewicz AM, Swiergiel AH, Lisowski P. Epigenetics of stress adaptations in the brain. Brain Res Bull. 2013;98:76-92. doi:10.1016/j.brainresbull.2013.07.003.
- McEwen B. Neurobiological and systemic effects of chronic stress. Chronic Stress. 2017;1:1-11. doi:10.1177/2470547017692328.
- Vaiserman AM. Epigenetic programming by early-life stress: evidence from human populations. Dev Dyn. 2015;244(3):254-265. doi:10.1002/dvdy.24211.
- Glad CA, Andersson-Assarsson JC, Berglund P, Bergthorsdottir R, Ragnarsson O, Johannsson G. Reduced DNA methylation and psychopathology following endogenous hypercortisolism – a genome-wide study. Sci Rep. 2017;7:44445. doi:10.1038/srep44445.
- Mughal MK, Giallo R, Arnold P, et al. Trajectories of maternal stress and anxiety from pregnancy to three years and child development at 3 years of age: findings from the All Our Families (AOF) pregnancy cohort. J Affect Disord. 2018;234:318-326. doi:10.1016/j.jad.2018.02.095.
- Shields GS, Slavich GM. Lifetime stress exposure and health: a review of contemporary assessment methods and biological mechanisms. Soc Personal Psychol Compass. 2017;11(8):e12335. doi:10.1111/spc3.12335.
- Garland EL, Hanley AW, Baker AK, Howard MO. Biobehavioral mechanisms of mindfulness as a treatment for chronic stress: an RDoC perspective. Chronic Stress. 2017;1:1-14. doi:10.1177/2470547017711912.
- Hölzel B, Lazar SW, Gard T, Schuman-Olivier Z, Vago DR, Ott U. How does mindfulness meditation work? Proposing mechanisms of action from a conceptual and neural perspective. Perspect Psychol Sci. 2011;6(6):537-559. doi:10.1177/1745691611419671.
- Niles H, Mehta DH, Corrigan AA, Bhasin MK, Denninger JW. Functional genomics in the study of mind-body therapies. Ochsner J. 2014;14(4):681-695. [link]
- Tolahunase M, Sagar R, Dada R. Impact of yoga and meditation on cellular aging in apparently healthy individuals: a prospective, open-label single-arm exploratory study. Oxid Med Cell Longev. 2017;2017:7928981. doi:10.1155/2017/7928981.
- Black DS, Cole SW, Irwin MR, et al. Yogic meditation reverses NF-?B and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial. Psychoneuroendocrinology. 2013;38(3):348-355. doi:10.1016/j.psyneuen.2012.06.011.
- Creswell JD, Irwin MR, Burklund LJ, et al. Mindfulness-based stress reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial. Brain Behav Immun. 2012;26(7):1095-1101. doi:10.1016/j.bbi.2012.07.006.
- Slavich GM, Cole SW. The emerging field of human social genomics. Clin Psychol Sci. 2013;1(3):331-348.
- Ren H, Collins V, Clarke SJ, et al. Epigenetic changes in response to tai chi practice: a pilot investigation of DNA methylation marks. Evid Based Complement Alternat Med. 2012;2012:841810. doi:10.1155/2012/841810.
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