Methylation takes place approximately one billion times per second and affects nearly every essential process in the body, according to functional medicine physician Robert Rountree, M.D. But when this vital process is not optimized—which can happen as a result of a variety of dietary, lifestyle, and genetic factors—your physical and mental well-being, from a cellular to whole-body level, will be suboptimal or worse. For example, methylation is essential for the production of certain bioactive vitamins (e.g., folate and vitamin B12), amino acids, neurotransmitters, hormones, red blood cells, DNA, RNA, and antioxidants that directly impact cardiovascular, neurological, reproductive health, energy production, detoxification pathways, and more. Typically, DNA methylation turns genes off, while demethylation turns genes on. DNA methylation is an example of epigenetics2—that is, changes in the physical structure of DNA caused by your behaviors (including nutrition, lifestyle, etc.) or environment, which can be passed down from parent to child. The pivotal and fascinating process of DNA methylation is relevant to life and health—from early development to immunity, memory formation, and more. The methyl groups that participate in methylation come from a variety of micronutrients in your diet collectively dubbed “methyl donors3,” which include folate (B9), vitamin B12, vitamin B6, riboflavin (B2), betaine, choline, and several others.* You’ll notice the prominence of essential B vitamins in this lineup. Folate is probably the most well-known methyl donor in the B vitamin family, so we’ll use it as an example to highlight exactly how methylation works. Once you consume folate from food or folic acid (found in fortified foods and certain supplements), the enzyme methylenetetrahydrofolate reductase (MTHFR) theoretically (the MTHFR gene codes for the MTHFR enzyme, more on that later) converts vitamin B9 into its bioactive form called methylfolate or 5-methyltetrahydrofolate (5-MTHF), which is fully activated and can now serve as a methyl donor for those widespread health functions mentioned earlier (think heart, brain, detox, energy, immunity, etc.).* Specifically, this bioactive folate (5-MTHF) donates a methyl group4 to the amino acid homocysteine to convert it to the amino acid methionine. Not only does this directly support healthy homocysteine levels (i.e., helps them from getting too high) in the body, but also methionine can then be utilized to form S-adenosylmethionine (SAM-e). SAM-e is incredibly important because it functions as a “universal methyl donor3” for all biological methylation processes in the body, including DNA methylation, which means it donates methyl groups to all sorts of acceptor molecules to support optimal physiological functioning globally in the body. After SAM-e has donated its methyl groups, it’s converted back to homocysteine, which can go on to produce cysteine (another amino acid) and then master antioxidant glutathione, or to accept another methyl group from 5-MTHF and repeat the cycle. Taken together, the activation of folate (aka, the “folate cycle”) and the homocysteine conversion onto methionine and ultimately SAM-e (dubbed the “methionine cycle”) enable and fuel methylation. The methylation cycle, that is. Ferira goes on to say, “Achieving and maintaining healthy homocysteine levels is required for the optimal production of numerous amino acids, neurotransmitters, hormones, and antioxidants, which participate in processes throughout the body and mind.”* Indeed, this biomarker has massive implications for our overall health, but especially for cardioprotective blood vessel functioning and neuroprotective actions for thriving brain function. Some important compounds (i.e., hormones, neurotransmitters, coenzymes, and other bioactives) that require methylation to be manufactured include the following: Finally, as mentioned above, DNA methylation can help silence genes that might otherwise up your risk for unruly processes in the body that can lead to suboptimal organ functions and worse. While individual responses vary, this suboptimal methylation can manifest on a spectrum in terms of its health impact. And as Ferira points out, “Interestingly, the MTHFR genetic variant is not rare but rather widespread, with some estimates indicating that approximately 40% or more of the population could be impacted. That’s over a hundred million Americans alone.” Certain diet and lifestyle habits can also interfere with optimal methylation. In addition to inadequate consumption of folate-rich nutrition and failing to take in bioactive forms of B vitamins and other methyl-donor nutrients, “too much alcohol or coffee consumption, smoking cigarettes, and high exposures to arsenic in food and water can all deplete the body of methyl groups needed for optimal methylation—unless you’re taking steps to replace them with food or supplements,”* says Rountree. So what happens when methylation isn’t top notch? “Methylation affects all physiological processes, so we see a wide range of problems when it’s compromised,” says functional medicine physician Karyn Shanks, M.D. Shanks goes on to share that these potential issues can truly span the entire body, possibly manifesting as suboptimal energy levels and cognitive function, or mood challenges and subpar detoxification abilities. More specifically, interference with neurotransmitters may contribute to low mood and feelings of anxiousness, lack of focus, difficulty sleeping, and more; while an inability to adequately excrete toxins can drive inflammatory processes and negatively affect skin and energy, as well as gut, musculoskeletal, and reproductive health, according to Ali Miller, R.D., L.D., CDE, registered dietitian. Ferira adds that elevated homocysteine levels resulting from poor methylation “is not only a lab test result you’ll want to avoid, but more importantly, over time, this imbalance can contribute to vascular issues that are directly pertinent to your heart and brain.” She underscores this further, explaining that, “normal methylation and healthy homocysteine levels are inextricable and pivotal to optimize for cardioprotective and neuroprotective benefits throughout life.” Because methylation is essential for homocysteine processing and recycling, elevated homocysteine levels could be a clinical biomarker indicator of suboptimal methylation. Ferira shares that, “depending on the practitioner, they may consider age- and gender-specific homocysteine ranges to test for normalcy.” For example, for ages 18 to 60, a homocysteine result of less than 14.5 µmol/L is considered in the normal range. But in functional and integrative medicine, a more conservative homocysteine level (less than 7 μmol/L7) may be considered optimal. In cases of elevated homocysteine, supplementing and eating more foods that are rich in methyl-donors in their bioactive formats can support methylation and bring homocysteine levels back to a healthier range.* Although quite common in integrative, functional, and precision medicine settings, genetic testing to determine if you have the MTHFR variant isn’t necessary to assess your methylation status. It’s definitely informative but typically not even recommended unless you have elevated homocysteine and specifically want to know if your genes are part of the equation. If you’re interested in genetic testing, consider working with an integrative or functional medicine practitioner who can run a comprehensive panel and make targeted, personalized recommendations for lifestyle changes and nutrition protocols based on those results. In addition to those key players, Ferira adds an oft-forgotten B vitamin into the methylation mix: “Riboflavin, aka vitamin B2, is a required cofactor for the MTHFR enzyme, required for folate recycling8, so it can be the amazing methyl donor it’s designed to be,”* she explains. Talk about B vitamin synergy. Here’s how you can get your fill of each methyl donor from food: Smart supplements with methyl donors woven into the very fabric of their formulation (like mbg’s methylation support+, which features a specific combination of bioactive B vitamins and betaine to optimize methylation function and status) can come in handy, too.* For example, if you’re seeking to support healthy homocysteine levels, or you know you have the MTHFR gene variant, taking a supplement that already contains the bioactive form of folate (methylfolate, aka 5-MTHF) plus the fully activated forms of other B vitamins can help you absorb and utilize these methylation-essential nutrients most efficiently.* While there’s still some debate on the best interventions and approach, Rountree has been using and recommending methylfolate in his clinical practice for the past 20 years. Ferira concurs, adding, “This precision approach of delivering bioactive methyl donors and other key methylation cofactors is shared by most practitioners in the integrative medicine and nutrition sectors.”* We hope more methylation health discussions will go mainstream, because, “the methylation cycle and DNA methylation are probably some of the most underdiscussed, yet wide-reaching and essential, physiological processes in the body. I’m ready for their prime time because so many people would benefit from methylation optimization,” says Ferira. She goes onto say that, “The right combo of bioactive B vitamins and bioactives are a gene-focused and biohacking nutrition approach to maximize your methylation potential."* Finally, try to prioritize high-quality sleep and stress management practices, says Shanks, as both stress and inadequate sleep9 have been shown to negatively affect DNA methylation. Boosting your daily physical activity levels can help with both, as well as promote detoxification and possibly even lower homocysteine levels10. But when this vital process is compromised (which can happen as a result of a variety of dietary, lifestyle, and genetic factors) your physical and mental well-being, from a cellular to whole-body level, will pay the price. The good news: A simple homocysteine test can help you get a glimpse of your own methylation cycle health and help determine whether you need to make any dietary or lifestyle changes—such as supplementing with a precision nutrition solution like mbg’s methylation support+—to promote healthy methylation every day.*
