Epigenetic Modulation (Diet, Exercise, Methylene Blue, Sleep, and More)

Our ability to adapt to changes in the environment and "learn" from our experiences is made possible by a flexible epigenome.

While this adaptability promotes advantageous adaptation to environmental factors, it also permits flaws to combine and have detrimental effects on both individual and evolutionary levels [1]. 

Our growth and maturation are controlled by specific gene sets that are choreographed events in conjunction with environmental cues, depending on the period of life at which they are triggered or suppressed. Any type of epigenetic factor that affects genes or gene expression networks during a person's life can lead to an imbalance in the regulatory process and may have a lasting impact [1].

Our previous articles discussed a brief overview of epigenetics and the most common modifications. In this article, we will share various interventions which modulate epigenetic regulation.

Put away the cigarettes, alcohol, lazy boy, and let's go! 

Diet

There is great interest by the scientific community to understand how dietary habits impact genes associated with various diseases. However, the molecular mechanisms by which nutritional components or dietary habits alter the expression of genes is still not fully understood; it is proposed that these processes are caused by epigenetic control [2,3]. The phrase "epigenetics diet" was first used in 2011 by Tollefsbol's laboratory [4]. It refers to a group of bioactive dietary substances that alter the epigenome and provide favorable health effects. Examples include broccoli's isothiocyanates, soybeans' genistein, red grapes' resveratrol, and others. 

One of the key components of the “epigenetic diet” are polyphenols, a compound widely present in tea, fruits, and vegetables. Polyphenols suppress oncogenic microRNA (miRNA) and promote tumor suppressor miRNA. They also inhibit the activity of DNA methyltransferase (DNMT) and hence may reduce the risk of cancer. 

Dietary Restriction (DR) [2,3]

DR is defined as reducing particular or total nutrient intake without causing malnutrition. DR includes calorie restriction (CR), intermittent fasting (IF), and a fasting-mimicking diet (FMD). 

Several studies have found that DR-induced weight reduction is associated with the hypomethylation of genes responsible for weight gain [3,5,6]. Additionally, substantial changes in DNA methylation were observed at WT1, CD44, and ATPase phospholipid transporter in obese or overweight males after DR intervention. There was also an increase in IL-6 DNA methylation in obese women on a Mediterranean diet with DR [3,5].

DR also downregulated the expression of miR-125a-5p; this miRNA has a positive correlation with obesity and a negative correlation with insulin sensitivity [9]. BMI, adiposity, and insulin response are also linked with other DR-induced changes in circulating miRNAs [3,7].

DNA methylation is linked with aging, and to understand whether CR affects slowing down aging, a multi-center clinical trial, “Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE),” was designed [8,9].

This clinical trial found that individuals on the CR regimen had larger percentages of fat-free mass compared to total body mass due to CR-induced weight loss and decreased adiposity. Greater insulin sensitivity, reduced cardiovascular disease risk scores, and improved indicators of liver function were also linked to CR [8,9]. A DNA methylation clock was used to confirm that the speed of aging is slowed based on clinical and plasma biomarker analysis [9-11].

In addition, miRNAs regulate genes involved in insulin signaling, mitochondrial respiration, protein homeostasis, and aging-related processes, including metabolism and longevity. A study found that CR induced the expression of miR-71 and miR-228, which repressed the gene associated with aging [12].

IF also slows down aging and induces longevity. The molecular mechanism for IF-induced longevity is via the regulation of fasting-induced changes in gene expression, where components of miRNA machinery play a vital role [2,3]. 

Exercise

Physical activity and exercise play an important role in regulating epigenetic modifications [6]. DNA methylation was considerably lower in 714 promoters in physically active men than in inactive men [6]. The lifelong physically active group of men was found to have hypomethylated genes associated with metabolism myogenesis, contractile function, and oxidative stress resistance. While the methylation of introns, exons, and CpG islands was identical in the two groups. 

Exercise and Cancer

Physical activity is associated with reducing the risk of various cancers by impacting global epigenetic modifications. A clinical trial investigated the effect of moderate exercise (150 min/week) on DNA methylation in breast cancer patients. The trial found that exercise reduced the methylation level of lethal genes and was associated with better overall patient survival. 

Exercise and Type 2 Diabetes

Endurance training and aerobic exercise have been associated with affecting not only levels of global methylation but also the level of gene-specific promoter methylation. This impacted global methylation improves the expression of genes involved in metabolic diseases, especially those related to type 2 diabetes. Exercise elevates the skeletal muscle H3 serine phosphorylation, thus regulating signaling pathways like AMPK, PKA, and PKC, which regulate glucose metabolism.

Exercise and Cardiovascular Disease

There are various studies showing the indirect effect of exercise regulating epigenetic modification in cardiovascular physiology. A study was conducted on 12 healthy individuals before and after four weeks of sprint exercise. The analysis revealed that specific changes in DNA methylation and expression of miRNAs are associated with cardiovascular physiology. Animal studies have shown that exercise could potentially prevent hypertension by regulating the expression of miRNA associated with the disease.

Stress Mitigation

Studies have reported that global DNA methylation is affected by stress exposure in early childhood [18,19]. One study showed hypermethylation of the glucocorticoid receptor gene in suicide victims who had a history of abuse as children, but not in controls or suicide victims who had no history of abuse as children [18,19]. 

Stress mitigation leads to a better lifestyle by regulating epigenetic modification [20]. Yoga, meditation, and mindful activities have been associated with decreased DNA methylation of glucocorticoid receptors in the brain. An epigenetic study found that mindfulness-based stress reduction (MBSR) altered levels of global histone H4 acetylation and reduced expression of the HDAC 2, 3, and 9 in PBMCs in patients with depression [21,22]. The positive outcome led to the hypothesis that MBSR may have a therapeutic impact on depression by reducing HDAC expression [20,22].

Alternative Medicine

Another potential strategy for enhancing human health and lifestyle is provided by alternative medicine, which can mediate advantageous environment-epigenome interactions [1]. These include Ayurveda, acupuncture, naturopathy, and body massage. A study was conducted in a cohort of 11 burnout patients to find the effect of acupuncture on the level of DNA methylation [23]. In this study, a genome-wide analysis of epigenetic alterations in blood DNA was done before and after acupuncture treatment. The authors found that acupuncture significantly reduced burnout in patients and affected the level of DNA methylation [23]. Ayurveda uses herbs and natural products for the treatment of diseases [24]. Commonly used herbs in Ayurveda are turmeric, cinnamon, and basil. Studies have shown how these common herbs regulate histone modifications and reduce cancer risk [1,24,25]. 

Methylene Blue

Methylene blue plays a vital role in combating the reactive oxygen species and, thus, oxidative stress [26]. Oxidative stress in cells leads to an expression imbalance of global epigenetic modification at the histone modifications and DNA methylation [27-29]. This results in an increased risk of cancer [28]. Oxidative stress is also associated with aging. With its antioxidant role, methylene blue may help reverse oxidative stress and hallmarks of an aging epigenome [30].

Sleep

Sleep deprivation and shift work have been associated with alterations in the epigenome [31]. Researchers have found that just one night of sleep loss can trigger tissue-specific epigenetics, gene expression, and metabolic changes that are associated with the loss of lean muscle mass and an increase in fat [32]. A detailed role of sleep deprivation and epigenetic alteration is reviewed in this article [33]. To learn more about this, read our blog article about the importance of sleep here.

Lifestyle Changes

Smoking tobacco is known to cause alteration in the DNA methylation of genes associated with lung cancer [1,19]. Smoking is a trigger for carcinogenesis as it affects the DNA methylation of tumor suppression genes like p16 and p53 [19]. Alcohol consumption is known to cause site-selective methylation, acetylation, and phosphorylation of histones and DNA hypomethylation in hepatic and neurological tissue [34].

As we said in the beginning of this article, time to put down (and throw out) your cigarettes and alcohol!

Conclusion

Epigenetic modifications are reversible in nature, and these changes cause many diseases, including cancer, metabolic disease, and cardiovascular disease.

Many of the interventions discussed in this article are easy to implement such as increasing the consumption of polyphenols in the diet, getting regular exercise, and making sure to get good sleep. Doing so can reverse the markers of epigenetic modification, slow down aging, and reduce the risk of disease.

If you are a practitioner and would like to dive deeper into the clinical practice of epigenetics, see homehope.org and the epigenetics module. 

References

1. Kanherkar, R. R., Bhatia-Dey, N. & Csoka, A. B. Epigenetics across the human lifespan. Front Cell Dev Biol 2, 49 (2014).
2. Ng, G. Y.-Q., Fann, D. Y.-W., Jo, D.-G., Sobey, C. G. & Arumugam, T. V. Dietary restriction and epigenetics: part I. Cond Med 2, 284 (2019).
3. Ng, G. Y.-Q., Fann, D. Y.-W., Jo, D.-G., Sobey, C. G. & Arumugam, T. V. Epigenetic regulation by dietary restriction: part II. Cond Med 2, 300 (2019).
4. Hardy, T. M. & Tollefsbol, T. O. Epigenetic diet: impact on the epigenome and cancer. Epigenomics 3, 503–518 (2011).
5. Na, Y. K., Hong, H. S., Lee, W. K., Kim, Y. H. & Kim, D. S. Increased methylation of interleukin 6 gene is associated with obesity in Korean women. Mol Cells 38, 452 (2015).
6. Abraham, M. J., El Sherbini, A., El-Diasty, M., Askari, S. & Szewczuk, M. R. Restoring Epigenetic Reprogramming with Diet and Exercise to Improve Health-Related Metabolic Diseases. Biomolecules 13, 318 (2023).
7. Makwana, K. et al. Aging and calorie restriction regulate the expression of miR-125a-5p and its target genes Stat3, Casp2 and Stard13. Aging (Albany NY) 9, 1825 (2017).
8. Ramaker, M. E. et al. Epigenome-wide Association Study Analysis of Calorie Restriction in Humans, CALERIETM Trial Analysis. The Journals of Gerontology: Series A 77, 2395–2401 (2022).
9. Waziry, R. et al. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nat Aging 3, 248–257 (2023).
10. Kraus, W. E. et al. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol 7, 673–683 (2019).
11. Longo, V. D. & Anderson, R. M. Nutrition, longevity and disease: From molecular mechanisms to interventions. Cell 185, 1455–1470 (2022).
12. Smith-Vikos, T. et al. MicroRNAs mediate dietary-restriction-induced longevity through PHA-4/FOXA and SKN-1/Nrf transcription factors. Current Biology 24, 2238–2246 (2014).
13. Zeng, H. et al. Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1. Breast Cancer Res Treat 133, 127–135 (2012).
14. Sailani, M. R. et al. Lifelong physical activity is associated with promoter hypomethylation of genes involved in metabolism, myogenesis, contractile properties and oxidative stress resistance in aged human skeletal muscle. Sci Rep 9, 3272 (2019).
15. Sailani, M. R. et al. Lifelong physical activity is associated with promoter hypomethylation of genes involved in metabolism, myogenesis, contractile properties and oxidative stress resistance in aged human skeletal muscle. Sci Rep 9, 3272 (2019).
16. Fernandes, T. et al. Exercise training restores the endothelial progenitor cells number and function in hypertension: implications for angiogenesis. J Hypertens 30, 2133–2143 (2012).
17. Denham, J., O’Brien, B. J., Marques, F. Z. & Charchar, F. J. Changes in the leukocyte methylome and its effect on cardiovascular-related genes after exercise. J Appl Physiol 118, 475–488 (2015).
18. McGowan, P. O. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12, 342–348 (2009).
19. Alegría-Torres, J. A., Baccarelli, A. & Bollati, V. Epigenetics and lifestyle. Epigenomics 3, 267–277 (2011).
20. Venditti, S. et al. Molecules of silence: Effects of meditation on gene expression and epigenetics. Front Psychol 11, 1767 (2020).
21. Kaliman, P. et al. Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators. Psychoneuroendocrinology 40, 96–107 (2014).
22. Kaliman, P. Epigenetics and meditation. Curr Opin Psychol 28, 76–80 (2019).
23. Petitpierre, M., Stenz, L. & Paoloni-Giacobino, A. Epigenomic changes after acupuncture treatment in patients suffering from burnout. Complement Med Res 29, 109–119 (2022).
24. Sharma, H. & Keith Wallace, R. Ayurveda and epigenetics. Medicina (B Aires) 56, 687 (2020).
25. Kanherkar, R. R. et al. Epigenetic mechanisms of integrative medicine. Evidence-Based Complementary and Alternative Medicine 2017, (2017).
26. Yang, L., Youngblood, H., Wu, C. & Zhang, Q. Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation. Transl Neurodegener 9, 1–22 (2020).
27. Yi, X., Zhu, Q.-X., Wu, X.-L., Tan, T.-T. & Jiang, X.-J. Histone methylation and oxidative stress in cardiovascular diseases. Oxid Med Cell Longev 2022, (2022).
28. García-Guede, Á., Vera, O. & Ibáñez-de-Caceres, I. When oxidative stress meets epigenetics: implications in cancer development. Antioxidants 9, 468 (2020).
29. Selman, C., Blount, J. D., Nussey, D. H. & Speakman, J. R. Oxidative damage, ageing, and life-history evolution: Where now? Trends Ecol Evol 27, 570–577 (2012).
30. Xue, H., Thaivalappil, A. & Cao, K. The Potentials of Methylene Blue as an Anti-Aging Drug. Cells 10, 3379 (2021).
31. Gaine, M. E., Chatterjee, S. & Abel, T. Sleep deprivation and the epigenome. Front Neural Circuits 12, 14 (2018).
32. Cedernaes, J. et al. Acute sleep loss results in tissue-specific alterations in genome-wide DNA methylation state and metabolic fuel utilization in humans. Sci Adv 4, eaar8590 (2018).
33. Gaine, M. E., Chatterjee, S. & Abel, T. Sleep deprivation and the epigenome. Front Neural Circuits 12, 14 (2018).
34. Shukla, S. D. et al. Emerging role of epigenetics in the actions of alcohol. Alcohol Clin Exp Res 32, 1525–1534 (2008).