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Abstract

Depression is the most common presenting mental health disorder in primary care. It is also a major contributor to somatic complaints, worsening of chronic medical conditions, poor quality of life, and suicide. Current pharmacologic and psychotherapeutic approaches avert less than half of depression’s cumulative burden on society. However, there is a growing body of research describing both how maladaptive lifestyle choices contribute to the development and worsening of depression and how lifestyle-oriented medical interventions can reduce the incidence and severity of depression. This research, largely derived from an emerging field called epigenetics, elucidates the interactions between our lifestyle choices and those epigenetic factors which mediate our tendencies toward either health, or the onset, if not worsening of disease. The present review highlights how lifestyle choices involving diet, physical activity, sleep, social relationships, and stress influence epigenetic processes positively or negatively, and thereby play a significant role in determining whether one does or does not suffer from depression. The authors propose that medical training programs consider and adopt lifestyle medicine oriented instructional initiatives that will enable tomorrow’s primary care providers to more effectively identify and therapeutically intervene in the maladaptive choices contributing to their patients’ depression.

Keywords

depression epigenetics lifestyle medicine primary care

‘Often unrecognized however is how lifestyle and environmental factors can significantly influence the development of chronic illness, including depression.’

Depression currently affects over 264 million people worldwide and is recognized as the second leading cause of disease globally.^1,2 In the United States, an estimated 17.3 million (7.1%) of all adults have suffered from at least 1 major depressive episode.^3,4 Depression is also the most common presenting mental health condition in primary care and often associated with somatic complaints, which represent more than half of all outpatient medical visits.^5,6 For individuals, the impact of depression can be devastating as it can worsen the clinical outcomes of other comorbid chronic medical conditions (eg, cardiometabolic diseases, respiratory illnesses, pain syndromes, etc), decrease one’s quality of life, shorten one’s life span by 5 to 10 years, adversely affect other ongoing disabilities, accelerate aging processes, and lead to suicide.^2,4-8 Less recognized, however, is depression’s influence on multiple biological factors, including oxidative stress, neuroinflammation, neurotransmitter dysregulation, decreased levels of neurotrophic factors, alterations in neuroendocrine and immune systems, increased cell apoptosis, telomere length shortening, and reduced stem cell proliferation that ultimately affect the brain’s structure.^9,10 The prevalence and severity of depression also results in a notable economic burden¹¹ as estimates suggest that the United States currently spends $210.5 billion on treatment of major depression¹²; a figure that exceeds expenditures on treatments for heart disease, stroke, cancer, obesity, Alzheimer’s disease, and arthritis.¹³

Most cases of depression are treated in the primary care setting through mainstream treatment modalities rooted in pharmacotherapy and psychotherapy. Nearly 60% of patients receive treatment for depression by a primary care provider; approximately 5% to 10% of all patients seen in primary care clinics.¹⁴ Almost 90% of health care providers recommend antidepressant medications either alone or in combination with psychotherapy to patients that have been identified as having depressive symptoms.⁷ In fact, antidepressants are currently the most prescribed class of medications in the United States.¹⁵ Antidepressants such as serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, and other atypical formulations target the neurotransmitter dysregulation found in depression.¹⁶ Current antidepressant treatment guidelines suggest that the clinical efficacy of these drugs be reassessed after at least 4 weeks of treatment.⁸ The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) randomized clinical trial found that approximately one-third of patients with depression achieved remission after 14 weeks of antidepressant treatment while 65% of patients achieved remission after 6 months.¹⁷ Notable limitations of antidepressants include their moderate efficacy relative to placebo, slow onset of action (typically weeks), potential withdrawal symptoms, problems with compliance, and adverse side effects.¹⁸

Psychotherapy, although less often utilized compared with medication, represents another treatment modality for depression.¹⁹ There are multiple forms of psychotherapy such as behavioral activation (positive reinforcement through increased participation in rewarding activities), cognitive behavioral therapy (coping strategies and restructuring of distorted beliefs), interpersonal therapy (understanding one’s relationships with others), and psychodynamic therapy (the role of unconscious thoughts in present behaviors).²⁰ Unfortunately, limited access to psychotherapy due to time restrictions, availability, and cost represent substantive impediments to their use in the primary care setting.²¹ However, when available, psychotherapy can be helpful in milder forms of depression, albeit its efficacy has often been overstated in the literature.²² Thus, psychotherapy has been paired with medication as the primary treatment for moderate to severe depression.²¹

Lifestyle Medicine as First-Line Therapy

Often unrecognized however is how lifestyle and environmental factors can significantly influence the development of chronic illness, including depression. For example, research suggests that approximately 80% of chronic diseases such as heart disease, stroke, and diabetes are affected, if not induced by, lifestyle choices and environmental factors.^23,24 Also, 60% to 70% of the variance in susceptibility to chronic diseases is due to individual-specific lifestyle and environmental factors.^25-27 Examples include poor nutrition, physical inactivity, poor sleep hygiene, unmanaged stress, social disconnectedness, lack of meaning and hope, and substance use.^25,28,29 These maladaptive lifestyle behaviors are the target of a new branch of medicine known as lifestyle medicine.

Lifestyle medicine is defined by the American College of Lifestyle Medicine as an evidence-based medical practice aimed at preventing, treating, and reversing disease as well as promoting health and well-being through the use of evidence-based therapeutic lifestyle modalities.³⁰ The American College of Lifestyle Medicine focuses on the following six lifestyle domains or pillars: diet/nutrition, exercise/physical activity, stress management, social relationships, sleep hygiene, and substance use.³⁰ Examples of lifestyle medicine interventions include eating a whole-food plant-based (WFPB) diet, increasing physical activity, sleeping in optimal conditions, integrating recreation and work-rest balance, connecting with others and maintaining supportive relationships, expressing positive emotions, practicing mindfulness, and avoiding illicit substances. There is evidence suggesting that some medical training programs are just beginning to train tomorrow’s providers in how to support their patients in recognizing both the lifestyle choices that contribute to their illness and how to adopt those positive lifestyle changes that can improve their health and wellness.^31-36

There are several benefits of positive lifestyle changes on depression. Whole foods and Mediterranean diets that incorporate greater intake of fruits and vegetables have been associated with a decreased risk of depression.³⁷ Moderate exercise of 20 minutes per day 3 times per week has been associated with decreased depression symptoms.³⁸ Nonpharmacological sleep hygiene interventions are effective in reducing the severity of depression symptoms.³⁹ Leisure activities, especially for those who are unemployed, have led to mental health benefits by increasing an individual’s perception of spending their time effectively and actively.⁴⁰ Mindfulness-based training can alleviate mood disorders such as anxiety and depression.⁴¹ Supportive and intimate relationships with family, friends, or significant others have been shown to have beneficial effects on psychological health.³⁷ Individuals developing a greater sense of meaning in their lives tend to manifest fewer depressive symptoms.⁴²

The adoption of lifestyle interventions for other physical chronic diseases could also prevent, treat, and even reverse depression. For example, addition of walnuts to the diet have been found to reduce the risk of developing mild cognitive impairment and Alzheimer’s disease as well as depression and anxiety in both mice and human studies.⁴³ An 8-week mindfulness self-compassion program focused on kindness reduced depression symptoms and hemoglobin A1c in diabetic patients.⁴⁴ Another study found that a 7-day yoga program improves spinal mobility while reducing anxiety, depression and back discomfort in patients with chronic low back pain.⁴⁵ Furthermore, the application of exercise-based interventions can decrease the risk of depression in patients suffering from comorbidities such as coronary heart disease, stroke, dementia, metabolic syndromes, osteoporosis, and various cancers.⁴⁶ In patients with breast cancer, Pilates exercise reduced depressive symptoms and improved cardiopulmonary capacity.⁴⁷ Clearly, providers who prescribe lifestyle medicine interventions to patients with general medical conditions have an opportunity to simultaneously prevent and treat depression. The dual benefits of reductions in general medical and psychiatric disorders have led to a growing interest in both lifestyle medicine and the science of epigenetics, as described in the following section.

The Paradigm of Epigenetics in Health and Disease

Over the past several decades, medical researchers have been searching for a new biomedical paradigm to understand the influence of multiple lifestyle and environmental factors on health and disease. The field of epigenetics offers a scientific, evidence-based explanation for the interaction between genes, lifestyle, environment, and their collective impact on health and disease. Epigenetics refers to the study of any processes and structures that govern the way genes are packaged and read in the cell.^48-51 That is, how the epigenome or epigenetic information represented in the form of chemical markers attached to the gene act as a structural network that switches regions of DNA on and off, and thereby the activation of regional genetic information. These epigenetic actions determine the gene’s activation/expression or inactivation/silence in response to intrinsic and extrinsic environmental factors, such as lifestyle choices, without changing the DNA sequence.

Thus, epigenetic markers act as the means by which information is exchanged within cells.⁵² As cells are exposed to complex environmental factors and multicellular organismal factors, epigenetic-based messages (transmissions) are more likely to extend the process of information exchange, causing cells to generate epigenetically mediated responses to both extracellular and intracellular stimuli. In summary, epigenetic changes induce processes that alter and regulate epigenetic codes responsible for telling specific genes to read, and thereby activate/express or inactivate/silence processes leading to modifications of tRNA and mRNA, and subsequently protein-RNA interactions in the cell or phenotype. Two of the most common epigenetic mechanisms that influence changes in gene activation/expression or inactivation/silence are DNA methylation and histone modification (methylation or deacetylation and acetylation).⁵³ In general, methylation downregulates or represses/silences gene expression while acetylation upregulates or enhances gene activation/expression. These malleable epigenetic processes and their effects on gene expression determine phenotypic health characteristics and traits which contribute to one’s susceptibility to illness, state of health and well-being, and even longevity.^54-58

Growing evidence also reveals that a wide variety of illnesses, behaviors, and health indicators are linked to changes of epigenetic processes in a number of chronic diseases (eg, cancers of almost all types, cognitive dysfunction, mental illness, respiratory, cardiovascular, reproductive, autoimmune, and neurobehavioral disorders).^55,56,59-61 It has also been found that unhealthy lifestyle factors (ie, poor diet, physical inactivity, stress, social isolation, work shift, substance abuse, etc) play a role in the onset and progression of pathological processes through these epigenetically mediated alterations of gene expression. For example, a folate-deficient diet impairs biosynthesis of the active precursor for DNA methylation, and expedites the development of liver and colon cancer.^62,63 Also, chronic cigarette smoking can sensitize bronchial epithelial cells for transformation by an oncogene, mutated KRAS, via abnormal DNA methylation patterns that result in pathological pulmonary function and subsequently the development of lung cancer.^64,65 Conversely, healthy lifestyle choices (ie, plant-based nutrition, physical activity, social connectedness, smoking and substance cessation, meditation and relaxation, etc) can lead to health-promoting and disease-preventing gene expression and positive health outcomes. For example, tea and coffee have been suggested to play an important role in suppressing tumor progression, decreasing inflammation, and influencing estrogen metabolism through changes in DNA methylation of CpG sites in 28 regions of the human genome in women.⁶⁶ Another study found that a 6-month exercise intervention altered DNA methylation and splicing patterns of 18 genes associated with obesity, and 21 genes associated with type 2 diabetes mellitus.⁶⁷

The concept of interactions between genetics, epigenetics, phenotype, environment, and lifestyle is supported by monozygotic twin studies, which demonstrate how different environmental and lifestyle exposures can, over time, alter gene expression via epigenetic processes and thereby lead to discordance in the phenotypic traits, health status, and longevity of these twins.^68-70 Given evidence of the relationship between lifestyle choices and pathophysiologic processes leading to disease, the science of epigenetics serves as solid foundation for the practice of lifestyle medicine in its capacity to offer beneficial treatments and preventive measures to those individuals making maladaptive lifestyle choices associated with chronic disease, such as depression.

Motivation and Purpose

Currently, no single study has reviewed the epigenetic processes, including the expression of genes and proteins associated with lifestyle medicine–based approaches, in managing depression. Nonetheless, the following represents an attempt to demonstrate how lifestyle factors and interventions can contribute to changes in gene expression associated with depression. In this concise review, we will (1) address the relationship between epigenetic changes and the multiple lifestyle and environmental factors contributing to depression, (2) highlight the effects of common therapeutic lifestyle factors and interventions on epigenetic changes in depression and health outcomes, and (3) discuss the implications of utilizing an epigenetics-driven lifestyle medicine approach to prevent, treat, and reverse depression. We will focus on the following lifestyle medicine pillars: diet, exercise, sleep, stress management, and social relationships.

Epigenetic Changes of Lifestyle Factors on Depression

Diet

As demonstrated in studies involving nutriepigenomics, the foods we ingest can influence epigenetic processes that lead to changes in phenotypic characteristics and traits. These changes can be either beneficial or detrimental. For example, a high-fat diet can affect brain homeostasis and biological processes, including change of intracellular signaling and gene expression contributing to the development of anxiety and depressive behaviors.⁷¹ More specifically, rats exposed to 16-week high-fat diet were found to have an increased expression of pro-inflammatory cytokines, including increases in levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNFα) mRNA; factors associated with increased anxiety and anhedonia commonly seen in depression. Furthermore, rats consuming a high-fat diet demonstrated an increased expression of ADAM1, a gene involved in regulating proteolytic release from cellular membranes of signaling proteins such as the cytokines TNFα and IL-6 in the hippocampus.

This research model also demonstrated that rats exposed to both a high-fat and high-fructose (HFHF) diet and stress showed depressive-like behaviors (eg, decreased preference in, and/or exploring for another rat) and increased anxiety-like behavior compared with controls. It was found that increased IL-4 and IL-5 mRNA expression, thought to be part of an adaptive anti-inflammatory profile within the hippocampus, were stimulated by acute stress but abolished with HFHF diet treatment.⁷² Furthermore, HFHF promoted increased hepatic LCN2 mRNA expression as well as increased LCN2 plasma levels, indicating increased hepatic inflammation. Thus, this study showed that an unhealthy dietary pattern can lead to epigenetic processes that disrupt metabolic and inflammatory gene networks in the brain, gut, and liver, and thereby may contribute to onset of depression and anxiety. It also indicated a complex interaction between psychological stress, diet, and mental health.

In mice, 20 weeks of a Western diet, or a diet high in fat, sugar, sodium, and energy-dense foods increased activation of the brain tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase, an enzyme associated with many inflammatory diseases, cancer, diabetes, and depression.⁷³ The Western diet also affected pro-inflammatory cytokines along with increased mRNA expression of IL-6 in the hypothalamus and TNFα and interferon-γ (IFNγ) in the hippocampus, which in turn was exacerbated by lipopolysaccharide (LPS); an endotoxin known to drive inflammatory reaction and the mediation of indoleamine 2,3-dioxygenase. The study also demonstrated increased neurobehavioral issues, including depressive behaviors in mice exposed to a controlled systemic immune challenge with LPS.

Additionally, LPS-induced depressive-like behavior was manifested in the LPS-fed obese mice, and not in the LPS-treated lean mice. Notably, maternal diets with palatable (high fat, high sugar) and energy-dense foods can leave long-lasting epigenetic marks via changes in both DNA methylation and histone modifications in the genetic makeup of their progeny.⁷⁴ For instance, in a mouse model, the maternal consumption of high fat during pregnancy and lactation changed gene expression involving DNA hypomethylation in the DAT, MOR, and PENK promoters of dopamine and opioids in their offspring. Thus, this may serve as an explanation for why and how maternal dietary behaviors involving a preference for palatable foods were carried over in their offspring.

There is epigenetic evidence supporting a reduction in depression symptoms with diets that are primarily plant based. Polyphenols, a component of phytochemicals, are enriched in plant foods (eg, fruits, vegetables, olives, soybeans, cocoa beans) and are found to be effective in promoting resilience during stress and reducing depression. One experimental mouse study found that the administration of grape-derived polyphenols known as dihydrocaffeic acid (DHCA) and malvidin-3′-O-glucoside (Mal-gluc) reduced stress and depression via epigenetic factors modulating inflammatory responses and synaptic plasticity in the brains of mice with depression.⁷⁵ Furthermore, Mal-gluc significantly promoted RAC1 expression by reducing HDAC2 expression, while DHCA significantly inhibits PBMC (peripheral blood mononuclear cells) IL-6 expression by inhibiting DNA methylation of the IL-6 genes. DHCA also regulates other inflammatory cytokines including IL-1β and IL-12, both of which have been shown to be increased in individuals suffering from a mild depressive disorder. Another experimental mouse study reported polyphenol resveratrol’s efficacy as an antidepressant agent by affecting gene expression in several brain regions.⁷⁶ More specifically, 2 groups of mice were subjected to 2 stressful tests, including a forced swim test and a tail suspension test; stresses known to induce depression-related behaviors. Mice treated with resveratrol upregulated the BDNF (brain-derived neurotrophic factor) mRNA levels in the prefrontal cortex and hippocampus; regulatory changes also observed with use of the antidepressant fluoxetine.

Changes in gene expression induced by early life stress in mice were found to be at least partially ameliorated by high-fat diet. This possibly indicates a positive, albeit limited, therapeutic impact of “comfort food” through reduction in overall stress response via increased expression of hippocampal GR (glucocorticoid receptor) mRNA and hypothalamic CRF (corticotrophic-releasing factor).⁷⁷ In a randomized, double-blinded, placebo-controlled clinical trial with women aged 18 to 40 years with polycystic ovary syndrome (PCOS), coadministration of vitamins D and E, and omega-3 fatty acid for 12 weeks demonstrated beneficial effects on Beck Depression Inventory scores as well as anxiety and stress scale scores.^78,79 It was reported that PCOS patients suffered from impaired emotional well-being, including anxiety and depression.⁸⁰ Compared with the placebo, vitamin D and omega-3 fatty acid cosupplementation significantly decreased gene expression of IL-1 and increased expression of vascular endothelial growth factor (VEGF) in the subjects’ circulating mononuclear cells.⁷⁸ Also, coadministration of vitamin E and omega-3 fatty acid upregulated expression of peroxisome proliferator-activated receptor gamma (PPARG), a known co-activator-1 alpha in depressive behavior and glucose promoting anti-inflammatory, while downregulating IL-8 and TNF-alpha expression in PCOS subjects’ circulating mononuclear cells.⁷⁹

Exercise

An animal model study has revealed that exercise cessation induces depression-like, anxiety-like, and impaired cognitive-like behaviors.⁸¹ More specifically, 12-week-old mice were randomized to an exercise-based treatment group (6 months duration), an exercise cessation group (4 months exercise followed by 2 months pause), and a control group (no exercise). The findings demonstrated that 10 of 75 genes in the hippocampus were differentially expressed in the exercise cessation group; findings demonstrating an increased expression of neurogenesis-associated genes (Ntrk1), reduced expression of immune (ll10, Gfap), and monoamine-related genes (Htr1a), compared with control mice. Also, changes in the expression of 9 genes, including increased Slc6a4 and reduced Sirt1 were shown in the exercise cessation group, compared with the exercise group. The increased depression and anxiety as well as impaired cognition with exercise cessation are associated with altered neurogenic, monoaminergic, and immune hippocampal gene expression; findings consistent with the pathogenesis of depression and related anxiety.

Late adulthood in humans is associated with hippocampal deterioration and dysfunction due to age-related downregulated expressions in BDNF genes. However, one study has demonstrated that aerobic exercise ameliorated hippocampal atrophy, improved memory function, and reduced depression by increasing expression of BDNF genes.⁸² Furthermore, physical activity increased hippocampal neuropeptide Y (NPY) mRNA and H3K18 acetylation, leading to reduction in the mRNA levels of a histone modifying enzyme called HDAC5. The decreased levels of HDAC5 mRNA in FSL (Flinders sensitive line) rats (selectively bred for increased anticholinesterase DFP for the study) led to an increase in H3 acetylation and BDNF expression; findings suggesting their role as resilience-mediating genes similar to NPY. This physical activity intervention served as a means of exploring how genes like NPY and BDNF might play a role as a novel nonpharmacological antidepressant. Another study demonstrated that swimming could reverse chronic unpredictable mild stress, including depression-like behaviors.⁸³ The positive effect of exercise on depression-like behavioral changes induced by chronic unpredictable mild stress was correlated with hippocampal plasticity-related proteins and expression of growth-associated protein-43 (GAP-43) and synaptophysin (SYN).

Sleep

Patients with major depressive disorder have abnormal circadian rhythms, including temperature, hormonal secretion, mood, and particularly sleep;^84-86 rhythms that are modulated by clock gene machinery and its byproducts.^87,88 With an approximately 2-hour reduction in sleep duration in modern urban settings, an array of health issues, including depression, was demonstrated via varied regulation of the silent mating-type information regulation 2 homolog 1 (SIRT1). More specifically, inhibition of SIRT1 expression caused disruptions to the circadian cycles.⁸⁹ It was also found that abnormalities in a circadian clock gene (BMAL1/CLOCK [NPAS2]) (ie, abnormalities that contribute to depression), were reset with chronotherapies involving sleep deprivation therapy (SDT) and sleep phase advance.⁹⁰ Studies also demonstrated that repeated and single nights experience of SDT were efficacious in treating depression.^91-94 Those who responded well to SDT in this study consistently saw significant expression of circadian clock genes (RORA, DEC2, and PER1).⁹⁰ But, while SDT demonstrates a fast-acting recovery effect, it has a limitation in terms of high rates of relapse. Chronotherapies involving sleep phase advance along with bright light treatment were found to sustain these beneficial effects longer. Sleep phase advance therapy initially helped shift bedtimes to much earlier (6 hours earlier), then, progressively set later bedtimes (4 hours and 2 hours, respectively). While the timing of sleep is associated with shifting internal circadian rhythms, morning bright light induces phase advances related to internal circadian rhythms.^95,96

A crossover study demonstrated that 1 week of sleep-restricted condition (5.7 hours, SEM = 0.03 per 24 hours) and circadian rhythms disruption (8.50 hours, SEM = 0.03 per 24 hours) reduced the number of genes with a circadian expression profile (from 1855 to 1481), compared to the control condition.⁹⁷ It was found that 711 gene expressions were regulated following the insufficient sleep condition; gene expressions that were associated with circadian rhythms, sleep homeostasis, oxidative stress, and metabolism. For example, the genes related to circadian rhythms and sleep (eg, PER2, PER3, and RORA) were downregulated while the genes (PRDX2, PRDX5) associated with oxidative stress were upregulated.

Social Relationships

Childhood social adversity, including parental death, low levels of parental care, or episodes of bullying before 16 to 18 years old have been linked to psychiatric disorders and cognitive impairment in adulthoold.^98-103 Early life adversities and maltreatments were associated with NR3C1 gene methylation processes in adulthood. NR3C1 is close to an NGFI-A binding site known to encode for the GR gene, a key element involved in modulation of hypothalamic-pituitary-adrenal axis. More specifically, early life stress induced hypermethylation of NR3C, and subsequently, psychopathology, including depression while hypomethylation of NR3C1 was associated with posttraumatic stress disorder (PTSD).^99,100,104 Sexual abuse or early life stress is associated with increased expression of hippocampal NOTCH1 gene; a gene that may influence long-term susceptibility to depression and other mood disorders.¹⁰⁵ Adolescents who carry the A118G polymorphism in the μ-opioid receptor gene (OPRI, rs1799971) were more severely depressed than A/A homozygotes after social rejection (eg, a relationship breakup or loss of employment).¹⁰⁶ Furthermore, research has demonstrated that reductions in opioid receptor expression along with reductions in signaling efficiency leads to increased susceptibility to major depressive disorders. These findings occur in adolescents who were G allele carriers of μ-opioid receptor and appear to represent a protective process to blunt negative affective responses such as painful life events following social rejection.

One prospective longitudinal epigenetic study demonstrated changes in gene methylation associated with lower socioeconomic status in adolescents and also found changes in brain function associated with risk for mental illness. The investigators discovered differential methylation of the SLC6A4 serotonin transporter gene promoter that elevated amygdala function and symptoms of depression.¹⁰⁷ The differential methylation of SLC6A4 was independently associated with child abuse, stress-related depression, and an increased reactivity of the amygdala to fearful stimuli. It was also found that mental health problems, including depression are worsened when people experienced social inequalities including low socioeconomic status.¹⁰⁸ Another study examined the effects of social adversity on gene expression in the endogenous opioid system.¹⁰⁹ Perceived social isolation or feelings of loneliness in depression was found to lead to an upregulation of pro-inflammatory transcription factor, nuclear factor-kappa B (NF-κB) and downregulation of GR gene.^110,111 Chronic social adversity in a mouse model showed reduced expression of endothelial cell tight junction protein Claudin-5 (CLDN5).¹¹² The CLDN5 downregulation leads to a more permeable blood-brain barrier and thereby increased passage of peripheral IL-6, a known promoter of depression into the brain parenchyma. The decreased CLDN5 expression may induce depression-like behaviors following subthreshold social stress.

Another study investigated the epigenetic effects of hurricane exposure and social support on mental health in adults.¹¹³ In this study, hurricane exposure included 5 aspects (ie, level of loss, lack of access, no reimbursement by insurance, displacement from home, and experience of hurricane-force winds or flooding), while social support factors included emotional, instrumental, and appraisal support. The outcome measures included information of posthurricane PTSD and depression obtained from structured interviews. Interestingly, participants with high hurricane exposure and low social support showed low expression of serotonin transporter gene of 5-HTTLPR variant. Such high-risk individuals were 4.5 times more at risk of developing PTSD and major depression compared with low-risk individuals who received high social support.

Furthermore, a study of women following surgery for breast cancer showed that greater social well-being (SWB) was associated with low levels of pro-inflammatory and pro-metastatic leukocyte gene expression.¹¹⁴ The primary assessment of SWB included estimates of the level of support from family and friends as well as subjective feelings of being close to them, based on the FACT-B social/family well-being subscale (The Functional Assessment of Cancer Therapy–Breast; version 4). It was observed that the cancer patients who reported high social support or social integration had less expression of pro-inflammatory (cytokines, chemokines, and COX-2) and pro-metastatic genes (eg, MMP9). Interestingly, when SWB variables were controlled, there was no significant association between leukocyte gene expression and depression. SWB appeared to mediate a biobehavioral pathway between depression and gene expression. This study demonstrated a possible mechanism linking social resources and survival time with therapeutic processes in breast cancer patients who recently underwent surgery.

Stress

Several studies revealed that psychosocial stress, burnout, and adverse environments were associated with changes of methylation patterns in glucocorticoid receptor gene NR3C1,¹¹⁵ serotonin transporter gene SLC6A4,¹¹⁶ and brain-derived neurotrophic factor gene BDNF.¹¹⁷ Such findings indicate that experience-dependent DNA methylation may be a potential biomarker of stress-related mental disorders such as depression. For instance, downregulation in the serotonin transporter gene SLC6A4 have been reported with both adverse environmental factors and depression in DNA derived from peripheral tissue (blood or epithelial cells) as well as in brain neuronal cells. A study involving the enrollment of shift-work nurses found that environmental stress is concurrent with increased methylation of the serotonin transporter gene (SLC6A4) promoter. In contrast, after adjustment for stress and symptom severity, environmental stress as well as job-related exhaustion/burnout in a nurse cohort, SLC6A4 methylation levels were significantly lowered.¹¹⁶ However, in another study, the direction of this epigenetic response of DNA methylation to adversity in the SLC6A4 transporter was incongruent with prior findings.¹¹⁸ In a sample of depressed patients, increased methylation levels of the promoter of gene encoding serotonin transporter (SLC6A4) was associated with childhood adversities and worsened clinical symptoms, but not with treatment response.

BDNF has been consistently associated with depression and its treatment with antidepressants. In fact, it was observed that reduced BDNF mRNA expression in peripheral tissue of acutely depressed patients was reversed by successful antidepressant treatment.¹¹⁹ While the hippocampus is one of several brain regions implicated in the pathophysiology of depression, increased histone acetylation observed at specific promotor regions of BDNF in the hippocampus contributed to a stress-regulated process by inducing a reversal of depressive-like behavior.¹²⁰ Also, decreased transcription of BDNF was observed in patients with major depression disorder where decreased expression led to reduced hippocampal volume.¹²¹ In another study with depressed patients, an increased level of BDNF promoter methylation was associated with a history of suicidal attempts and suicidal ideation during treatment.¹²² Another review found that both caretakers of dementia patients and couples dealing with marital stress have elevated IL-6 and C-reactive protein (CRP); inflammatory factors associated with the development of depression.¹²³ These proinflammatory reactions trigger CRF and hypothalamic-pituitary-adrenal axis activation, which in turn negatively affects neurotransmitter metabolism. Such reactions may also involve increased methylation of the promoter region of the GR gene, resulting in decreased GR expression involving the binding of cortisol and glucocorticoids. This gene increases stress response and has a potential role in psychological disorders including depression. In addition, investigators have identified that increased histone deacetylation in HDAC4 and HDAC5 in several hippocampus subregions plays an adaptive role in decreased memory formation and stress-induced pathology such as depression after exposure to a variety of acute stressor such as predator stress, social defeat stress, or forced swim stress in animal models.¹²⁴

A randomized trial demonstrated that retreat and relaxation for 1 week led to positive impacts on disease-associated molecular phenotypes, including changes in gene expressions.¹²⁵ The research was conducted at a retreat center where 2 treatment cohorts (one representing novice meditators, and the other representing experienced meditators) received a program consisting of mantra meditation (4 hours per day), yoga (3 hours per day), lecture, and self-reflective exercises. An active control group consisting of the residents living at the same location for the same amount of time (but no treatment program) was labeled as having “the vacation effect.” Interestingly, both treatment and control groups showed positive psychological outcomes related to depression, stress, vitality, and mindfulness. Also observed was an increase in the expression of 390 relaxation effect genes; an increase correlated with the suppression of both stress response and inflammation. Furthermore, analysis of regulatory meditators demonstrated a reduction in the expression of genes involved in protein synthesis, viral expression, and viral infectious cycles.

Among the genes that were downregulated in both the treatment and control (vacation) participants were MME and FOXO3, both known stress-related genes. Low levels of FOXO3 were found to serve an antidepressant effect in the mice study, thereby preventing the behavioral stress response in the mice.¹²⁶ This study demonstrated, for the first time, a stress reduction intervention through meditation and relaxation, including vacation effects, can reduce FOXO3 gene expression related to depression. A 30-year study of familial risk for depression identified four single genes implicated in both depression and spirituality.¹²⁷ These findings demonstrated that increased expression of dopamine (DRD2), serotonin (5-HT1B), monoamine vesicular transporter (VMAT1), and oxytocin (OXTR) related genes were positively associated with the participants’ sense of spirituality or religion. In the high-risk group of depressed participants, phenotypic expression of spirituality or religion was suppressed. Promotion of spirituality in childhood may protect those at higher genetic risk for depression.

Discussion

The current narrative review describes how negative lifestyle behaviors can induce epigenetically mediated effects likely to cause and/or worsen depression, and how positive lifestyle interventions can induce beneficial epigenetic alterations likely to alleviate and/or prevent the worsening of depression. To the best of our knowledge, this is the first scientific review providing epigenetic evidence for the management of depression by lifestyle medicine–based approaches to care. Further research directed at lifestyle-mediated factors (eg, diet, exercise, sleep, stress, social relationship, and spirituality) on the development of depression will more deeply elucidate its pathogenesis and potential targets for a therapeutic effect. This is especially important as while contemporary treatment regimens such as antidepressant medications and psychotherapy are helpful, such therapies do not optimally alleviate depression in patients. Therefore, epigenetic research conducted in the context of depression can be used to develop lifestyle interventions as well as novel antidepressant drugs targeting selective epigenetic mechanisms associated with depression.

This report highlights how negative lifestyle factors can induce epigenetic changes of gene expression that lead to depression. Socially negative lifestyle factors, such as childhood adversity, childhood sexual abuse, and social rejection were found to be associated with genetic hypermethylation and single-nucleotide polymorphism patterns that increase production of pro-inflammatory mediators, downregulate anti-inflammatory markers, and alter the expression of opioid and glucocorticoid receptors involved in the stress response. Disrupted sleep was found to be associated with increased inflammatory mediators and varied regulation of genes associated with the circadian rhythm as well as development of anxiety and depression. It was also found that certain genotypes have greater predisposition to developing depression when exposed to reduced sleep duration. High-fat “Western diets” were found to be associated with increased gene expression of pro-inflammatory mediators, and thereby lead to an increased risk of depression. Exercise cessation was found to be associated with altered neurogenic, monoaminergic, and immune hippocampal gene expression; findings also consistent with the pathogenesis of depression and anxiety. Evidence highlighting those negative lifestyle factors that contribute to disease-exacerbating pathophysiology provide an encouraging rationale for implementing lifestyle-based interventions and behavioral change.

Our review also demonstrates how positive lifestyle interventions can induce epigenetic changes that alleviate and/or prevent the worsening of depression. For instance, social connectivity and integration was found to be associated with decreased expression of pro-inflammatory mediators in the blood plasma; findings that have been implicated in the development of depression. Sleep-focused cognitive behavioral therapy was found to downregulate pro-inflammatory cytokines tied to depression while sleep deprivation therapy has the ability to reset abnormal circadian clock genes that contribute to depression. Stress reduction interventions through meditation, relaxation, and vacation exhibited suppression of the stress response, inflammation, and depression-related gene expression. Spirituality was found to be associated with increased gene expression of neurotransmitter activity such as dopamine (DRD2) and serotonin (5-HT1B) and decreased risk of depression. Plant-based diets with polyunsaturated fatty acids and polyphenols were found to decrease depression risk by modulating gene expression associated inflammatory processes and neuronal plasticity. Moderate-intensity exercise was associated with decreased inflammation and improved hippocampal plasticity, and thereby alleviate the risk of depression. Collectively, these findings suggest that positive lifestyle interventions across these multiple, lifestyle domains/pillars, lead to beneficial modifications at the epigenetic level; modifications that improve the clinical outcomes in patients suffering from depression.

While epigenetic research provides growing evidence of the benefits associated with a lifestyle medicine–based approach to the management of depression, it is important to recognize that there are many gaps in this evolving body of literature. To begin, studies regarding lifestyle interventions’ effects on epigenetic mechanisms associated with depression are limited. Some studies included in this review incorporated animal models since there are few studies identifying changes in gene expression related to lifestyle factors that are associated with depression in human participants. Also, the investigation of optimal lifestyles serving as a therapeutic intermediary between depression and epigenetic changes was not as prominent in studies involving the effect of adverse lifestyle factors. Of the previously mentioned lifestyle medicine domains/pillars, diet and exercise have been those most studied in depression.³³ This is to be expected as both domains have been strongly associated and well-studied with other chronic health conditions. Furthermore, diet and exercise have been shown to moderate a range of biological pathways, including inflammatory cytokines, oxidative stress, neurotrophins, and the stress-response system.³³ The evidence regarding the effects of stress management, social relationships, and sleep hygiene are still growing. It is also important to recognize that some intervention studies utilize multiple concurrent domains of lifestyle, such as diet and exercise. However, their epigenetic influence has not been well elucidated when used in combination. Recognition of these gaps in the literature can lead to the formulation of more focused research regarding the influence of lifestyle medicine on epigenetics in depression. Increasing research and evidence of epigenetic based benefits of lifestyle medicine derived treatments for depression is likely to produce more cost-effective, safe, and clinically efficacious nonpharmacological treatment options for primary care practitioners who care for patients suffering from depression.

Implications for Primary Care Practice

We hope that health care providers will both consider and utilize the concepts discussed in this manuscript as the basis for adopting a holistic, epigenetics-supported lifestyle medicine–based approach to the prevention, treatment, and even reversal of chronic disease, such as depression. If healthcare providers can adopt the knowledge and skills of lifestyle medicine and the evidence of a lifestyle-epigenetic connection, they can (1) systematically assess both their patients’ lifestyle and environmental risk factors that induce or worsen depression and (2) develop and implement lifestyle interventions that mitigate these risk factors, positively alter gene expression to prevent and reduce depression, and thereby lead to improved mental and physical health.

However, in order to achieve these benefits, providers will need to develop the behavioral, motivational, and environmental skills of lifestyle medicine; skills insufficiently developed and applied in conventional medical practice.¹²⁸ Current practice will need to shift toward the inclusion of deeper discussions with patients about how their current lifestyle factors are distal, medial, or proximal causes of their chronic disease, such as depression. The epigenetic findings related to lifestyle factors in the context of depression can serve as an opportunity to educate patients on its pathophysiology, and thereby better explain treatment choices.¹²⁹

In order to effectively incorporate lifestyle medicine practice for managing depression, there are some important considerations with regard to treatment guidelines, health coaching training, and practice models. First, a lifestyle medicine approach to specific illnesses, such as depression, can be advanced via a protocol whereby lifestyle medicine practitioners both assess their patients’ lifestyle choices and offer them therapeutic lifestyle interventions. Second, providers must be trained in health coaching techniques to help patients initiate healthful lifestyle behavioral changes. Some key themes associated with health coaching include trust and collaboration, agenda-setting, engaging and readiness, values and strengths, action and accountability, the relation between small successful steps and confidence, resistance and motivation, and support and resources.¹³⁰

For example, providers can utilize motivational interviewing skills to help patients recognize lifestyle habits that may induce depression or depressive behavior, develop the belief that depression-alleviating/preventing lifestyle change is possible, and establish goals for change.¹³¹ Providers can also utilize positive psychology and hope-based strategies to better understand their patient’s perceived capacity to change through agency thinking and expressing their perceived obstacles to change through pathways thinking.¹³² Utilizing these approaches may be especially helpful for patients who struggle with depression’s subclinical symptoms of anhedonia as well as decreased hope.³ Third, providers will need to identify sustainable lifestyle medicine practice models. Motley¹³³ proposes a model for building a lifestyle medicine practice within a primary care clinic that involves community participation, focus on teaching simple lifestyle concepts and at-home learning activities, as well as referral to allied health professionals and health coaches. Lifestyle Medicine Solutions has also developed a primary care lifestyle medicine practice with innovative reimbursement strategies that allow for sustainability so that it can continue to serve patients with chronic disease.¹³⁴

Strengths and Limitations

We discussed a novel epigenetic perspective to lifestyle medicine in the context of prevention and treatment of depression. Although the evidence favors the use of lifestyle medicine for depression, there are some considerations that must be made with regard to the study’s limitations. Weaknesses in the evidence include the fact that depression has not been uniformly defined across these studies. Many of these studies refer to depression as a measure of depressed mood but do not specifically determine severity of depression, or whether they are managing patients formally diagnosed with a major depressive disorder. Therapies such as psychotherapy alone may not be effective treatment for moderate and severe depression. Thus, it would be important to determine the severity of depressive symptoms in the studies featured in this review to help identify the lifestyle intervention that would be most effective in treating any given level of depressive severity.²²

Another important factor to highlight is that depression consists of individual subsymptoms, such as depressed mood, anhedonia, feelings of guilt or hopelessness/helplessness, changes in energy, sleep disturbances, appetite disturbances, and psychomotor changes.³ For some individuals, one or some of these symptoms may be more pronounced than others, and it is unknown which were more pronounced in the study samples. Moreover, it is unclear if certain lifestyle interventions are more effective in treating these subsymptoms, which then contribute to a greater overall improvement in depression reports by patients. Further investigation of lifestyle interventions targeting these specific subsymptoms and their effect on overall depression reports are warranted. Last, it is important to recognize that there is a risk for publication bias regarding lifestyle intervention studies as many of the published articles are based on favorable outcomes. The evidence regarding healthful lifestyle interventions reviewed in this study have all shown favorable outcomes as expressed in terms of reductions in depression. Another area for potential research would also be to compare the effects of various lifestyle interventions in different domains, such as a sleep intervention versus a mindfulness intervention.

Conclusion

The rising global burden of depression and its associated life-altering complications warrants substantial discussion about how to improve upon current treatment approaches for depression.^5,135 Optimizing treatment of an illness requires an address of as many of the given disease’s modifiable risk factors as possible; risk factors such as those negative lifestyle behaviors that lead to disease-exacerbating epigenetic processes. Lifestyle medicine addresses such factors and has the potential to alleviate the burden of depression by promoting healthful depression-reducing epigenetic changes. Medical training programs must prepare tomorrow’s health care providers, especially primary care providers, in how to apply an epigenetics-evidenced lifestyle medicine approach to prevent, treat, and reverse depression and its associated disorders.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval

Not applicable, because this article does not contain any studies with human or animal subjects.

Informed Consent

Not applicable, because this article does not contain any studies with human or animal subjects.

Trial Registration

Not applicable, because this article does not contain any clinical trials.

ORCID iDs

Jenny Sunghyun Lee

Frank Papa

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An Epigenetic Perspective on Lifestyle Medicine for Depression: Implications for Primary Care Practice

Abstract

Keywords

Lifestyle Medicine as First-Line Therapy

The Paradigm of Epigenetics in Health and Disease

Motivation and Purpose

Epigenetic Changes of Lifestyle Factors on Depression

Diet

Exercise

Sleep

Social Relationships

Stress

Discussion

Implications for Primary Care Practice

Strengths and Limitations

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

Ethical Approval

Informed Consent

Trial Registration

ORCID iDs

References