Kara Fitzgerald, ND

Tolle Totum

Up until now, we’ve been putting a heavy emphasis on supplementation with B vitamins, betaine, choline and other substrates and cofactors for methylation support. However, there are a number of other and perhaps unexpected ways in which we can balance methylation expression (both metabolically and genetically). This includes preventing hypermethylation of the epigenome.

Hypermethylation

Is too much methylation a real problem? Unfortunately, yes. Although for the last 10-15 years we have been focused on restoring methylation capacity where deficits exist, perhaps most successfully through the fortification of foods with folic acid (a measure that has significantly reduced the number of neural tube defects in newborns¹), the reality is that abundant (and growing) research also indicates associations between inappropriate excessive methylation within the epigenome and various disease states.

Let’s take cancer as an example. Excessive methylation (termed “hypermethylation”) is commonly found in cancer cell lines.² Specifically, hypermethylation appears in the promoter regions of cancer-protective tumor suppressor genes.³ Higher levels of methylation in promoter regions typically act to repress gene expression (turn the gene off), which is clearly undesirable for these genes. Dual roles are suspected for folate in the onset and progression of cancer; ie, folate protects against cancer initiation, but also potentially supports tumor growth where cancers are already established.⁴

Beyond cancer, research also tells us that disturbed epigenetic methylation patterns, including hypermethylation, have been found in other diseases including autoimmunity, allergy, and Down syndrome.^5-12

Methylation Balance & Adaptogens

There is no doubt that methylation deficiency is also a problem. Poor methylation status and folate deficits have been linked with a wide variety of conditions, including ADHD, autism, allergies, anxiety, diabetes, heart disease, insomnia, depression, and even aging.^13-15 But the reality is that we don’t want to blindly push methylation too far. Instead, our goal should be that “sweet spot” of methylation balance, which we can best achieve by taking steps to enable the body to do the right thing at the right time.

This is where methylation “adaptogens” come in. We are all familiar with the concept of adaptogens as balancing agents, most commonly discussed in relation to hypothalamic-pituitary-adrenal (HPA) axis support. Of course, the adaptogen concept can be applied to any bodily system that is in homeodynamic balance, and methylation is no exception.

There are several dietary and lifestyle interventions that have been shown to have an adaptogenic effect on methylation, including active demethylation of areas of the epigenome that are aberrantly hypermethylated. In this article, we will shine a light on one of those adaptogens: exercise.

Exercise & Methylation Metabolism

Homocysteine (Hcy) is one metabolic biomarker for methylation status, since one of its pathways of metabolism is the conversion of Hcy to methionine by either methionine synthase (requiring folate – as 5-methyl-THF – and vitamin B12) or betaine-homocysteine S-methyltransferase (BHMT) (supported by zinc, choline, and betaine). Elevated Hcy suggests methylation deficits.

Exercise appears to increase levels of BHMT expression and can thereby reduce folate deficiency-induced hyperhomocysteinemia.¹⁶ A systematic review published in 2014 also reported that daily physical activity is consistently associated with lower Hcy levels in a dose-dependent manner.¹⁷

However, it is important to tailor physical activity to each individual. Acute exercise has been associated with a temporary increase in Hcy levels,¹⁷ and this effect is exacerbated in untrained individuals or if methylation nutrient deficits are present (eg, low folate and/or vitamin B12).¹⁸ Gradual build-up of exercise tolerance via regular practice can shift the tolerance curve to the right and improve long-term homocysteine status.

Exercise & DNA Methylation

Both acute and chronic exercise alter epigenetic methylation, directly influencing how our genes get expressed. Favorable global and site-specific increased and decreased methylation marks are possible with physical activity, illustrating its adaptogenic properties.^19-21

For instance, aging itself is associated with a global depletion of DNA methylation. Regular activity over a lifetime (childhood, adolescence, and adulthood) can be partially protective of DNA methylation losses.²² For example, regular tai chi practice (at least 1 hour per week for 3 years or more) by females over age 50 has been shown to slow age-related methylation decline.²³

On the other hand, regular exercise supports selective demethylation of specific gene promoter regions, which has the net effect of increasing their expression. In a study of breast cancer patients, a 6-month moderate-intensity aerobic exercise program was shown to reduce the promoter methylation of DNA suppressor genes.²⁴ This favorable epigenetic shift allows for increased expression of those anti-cancer genes that have been associated with improved overall survival. In fact, demethylating agents are currently being researched and used in conventional cancer care,²⁵ highlighting the importance of this biological activity.

Additional Methylation Support

Exercise is one way in which we can support patients with methylation imbalances, but it’s not the only factor we can consider. There is a broad range of methylation modifiers that are worthy of consideration , including food-based nutrients, dietary patterns, stress, sleep, detoxification, the microbiome, and mitochondria. In my practice, I also review and address potential sources of methyl donor drain that can deplete endogenous reserves. This kind of support is both effective and safe over the long term, since it is based on supporting healthy bodily processes rather than forcing reaction rates forward.²⁶

A final note: I do use supplemental folate and other methylation-supportive nutrients in my practice as therapeutic probes, paying close attention to correlation with clinical symptoms. However, dietary and lifestyle practices play a tremendous role in supporting my patients that need methylation balancing, enabling me to keep supplement dosing lower and for shorter durations. These tools also allow us to support those patients who can’t tolerate the supplements – a scenario that many practitioners have encountered. Now we have effective tools to offer that group as well.

References:

1. Cordero AM, Crider KS, Rogers LM, et al. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines. MMWR Morb Mortal Wkly Rep.2015;64(15):421-423.
2. Varley KE, Gertz J, Bowling KM, et al. Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res.2013;23(3):555-567.
3. Rengucci C, De Maio G, Casadei Gardini A, et al. Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence. J Exp Clin Cancer Res. 2014;33:65.
4. Chiang FF, Huang SC, Wang HM, et al. High serum folate might have a potential dual effect on risk of colorectal cancer. Clin Nutr.2015;34(5):986-990.
5. Hong X, Wang X. Epigenetics and development of food allergy (FA) in early childhood. Curr Allergy Asthma Rep. 2014;14(9):460.
6. Sordillo JE, Lange NE, Tarantini L, et al. Allergen sensitization is associated with increased DNA methylation in older men. Int Arch Allergy Immunol. 2013;161(1):37-43.
7. Hollingsworth JW, Maruoka S, Boon K, et al. In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest. 2008;118(10):3462-3469.
8. Martino D, Dang T, Sexton-Oates A, et al. Blood DNA methylation biomarkers predict clinical reactivity in food-sensitized infants. J Allergy Clin Immunol. 2015;135(5):1319-1328.e1-12.
9. Luo Y, Wang Y, Shu Y, et al. Epigenetic mechanisms: An emerging role in pathogenesis and its therapeutic potential in systemic sclerosis. Int J Biochem Cell Biol. 2015;67:92-100.
10. Fukuhara T, Tomiyama T, Yasuda K, et al. Hypermethylation of MST1 in IgG4-related autoimmune pancreatitis and rheumatoid arthritis. Biochem Biophys Res Commun. 2015;463(4):968-974.
11. Nakano K, Whitaker JW, Boyle DL, et al. DNA methylome signature in rheumatoid arthritis. Ann Rheum Dis. 2013;72(1):110-117.
12. Jin S, Lee YK, Lim YC, et al. Global DNA hypermethylation in down syndrome placenta. PLoS Genet. 2013;9(6):e1003515.
13. Greißel A, Culmes M, Napieralski R, et al. Alternation of histone and DNA methylation in human atherosclerotic carotid plaques. Thromb Haemost. 2015;114(2):390-402.
14. Skinner MK. Environmental epigenomics and disease susceptibility. EMBO Rep. 2011;12(7):620-622.
15. Wu YL, Hu CY, Lu SS, et al. Association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and essential hypertension: a systematic review and meta-analysis. Metabolism. 2014;63(12):1503-1511.
16. Neuman JC, Albright KA, Schalinske KL. Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model. Nutr Res.2013;33(6):487-493.
17. e Silva Ade S, da Mota MP. Effects of physical activity and training programs on plasma homocysteine levels: a systematic review. Amino Acids.2014;46(8):1795-1804.
18. Herrmann M, Schorr H, Obeid R, et al. Homocysteine increases during endurance exercise. Clin Chem Lab Med.2003;41(11):1518-1524.
19. Voisin S, Eynon N, Yan X, Bishop DJ. Exercise training and DNA methylation in humans. Acta Physiol (Oxf). 2015;213(1):39-59.
20. White AJ, Sandler DP, Bolick SC, et al. Recreational and household physical activity at different time points and DNA global methylation. Eur J Cancer. 2013;49(9):2199-2206.
21. 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.
22. White AJ, Sandler DP, Bolick SC, et al. Recreational and household physical activity at different time points and DNA global methylation. Eur J Cancer.2013;49(9):2199-2206.
23. 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.
24. Zeng H, Irwin ML, Lu L, et al. Physical activity and breast cancer survival: an epigenetic link through reduced methylation of a tumor suppressor gene L3MBTL1. Breast Cancer Res Treat.2012;133(1):127-135.
25. Howell PM, Liu Z, Khong HT. Demethylating Agents in the Treatment of Cancer. Pharmaceuticals (Basel).2010;3(7):2022-2044.
26. Fitzgerald KN, Hodges RE. Methylation Diet and Lifestyle. 2016. (n.p.) eBook available at http://www.drkarafitzgerald.com/professionals/methylation-diet-lifestyle/

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Kara Fitzgerald, ND, completed post-doctorate training in nutritional biochemistry and laboratory science under the direction of Richard Lord, PhD, at Metametrix Laboratory (now Genova Diagnostics). She completed her residency at Progressive Medical Center in Atlanta, GA. Fitzgerald co-authored and edited Case Studies in Integrative and Functional Medicine and was a contributing author for Laboratory Evaluations for Integrative and Functional Medicine and The Institute for Functional Medicine (IFM)’s Textbook of Functional Medicine. She has been published in numerous peer-reviewed journals and blogs regularly for professionals and consumers at www.drkarafitzgerald.com. Dr Fitzgerald is on the faculty at IFM and maintains a functional medicine practice in Sandy Hook, CT.