If you’ve dabbled in personalized medicine and nutrigenomics, odds are that you’ve come across the concept of methylation. While it's a real and vital pathway in many aspects of health, it’s both overhyped and widely misunderstood. Many people, including very seasoned practitioners, find terms like over- and undermethylation confusing. Partly, this is because genetic tests and homocysteine are woefully inadequate to diagnose over- or undermethylation. Also, both can have very similar presentations.
Worse yet, thousands of people every day incorrectly self-diagnose and introduce methylation supplements that either do nothing or cause adverse effects. This article will clarify methylation concepts and demonstrate why our Methylation Insights Report may help pinpoint the correct supplements and fine-tune the dosages.
What is methylation?
Methylation refers to the biochemical reaction that transfers a methyl group (-CH3) from a methyl donor to a methyl acceptor. The methyl acceptor could be DNA, neurotransmitters, proteins, waste substances like used hormones, homocysteine, or vitamins like folic acid.
The methylation cycle refers to a specific pathway that provides methyl groups for all the methylation reactions. These include the folate cycle (left-hand circle in the chart below) and the homocysteine-methionine cycle (right-hand circle in the chart below).
From “Epigenetic modulation of DNA methylation by nutrition and its mechanisms in animals” [1] Hcy = homocysteine. SAH = S-adenosylhomocysteine. SAM = S-adenosylmethionine
Methylation is crucial for numerous aspects of health, such as (not an exhaustive list):
- Cardiovascular health, especially as homocysteine affects blood vessel health
- Fertility and embryonic development
- Mental health and cognition
- Cellular energy production, such as through creatine production
- Liver and cellular detoxification
Methylation testing requires a whole-person systems-wide approach
Methylation influences every cell in your body. Although it’s one of the best-characterized pathways in nutrigenomics, it’s neither the only crucial pathway nor the most important.
Methylation is complex and tightly regulated. A person can have overmethylation of 3,000 genes and undermethylation of 2,000 others. More importantly, you have trillions of biochemical reactions happening every second, a large percentage of which involves methylation. This is why attempting to classify a person as over and undermethylation, or prescribing a supplement to treat either can backfire.
Most patients who Google methylation do so because they struggle with things like brain fog, chronic fatigue, mood issues, autism, fertility issues, or mold toxicity. If you help these patients in your practice, you will never find patients with only so-called methylation problems without ongoing inflammation, oxidative stress, gut dysbiosis, and mitochondrial dysfunction. To do no harm and deliver better outcomes, you’ll likely have to address these other issues first before treating methylation.
In the scientific literature, this pathway is called “One Carbon Metabolism.” Whereas in nutrigenomics, it’s often referred to as methylation pathways. Inevitably, searching for literature using the term “methylation” tends to turn up specific instances of methylation, not the methylation cycle as a whole. This can lead to further confusion, fear, and misinterpretations.
Current over and undermethylation tests and their shortcomings
In short, undermethylation refers to when your body has lower than optimal methylation, whether it’s neurotransmitters, detoxification pathways, or DNA. Whereas, overmethylation refers to when you have too much methylation on some or all of these pathways.
Sometimes, people who have adverse reactions to methylation supplements inaccurately say they have overmethylation. Sometimes, these reactions come from true overmethylation of their neurotransmitters or other molecules. Other times, these could be an inflammatory reaction to the supplement or due to inhibition of certain enzymes.
Canonically, there are two imperfect and inadequate ways to objectively estimate undermethylation.
- Elevated homocysteine. However, one can have undermethylation of other molecules in the body and still have normal homocysteine. Therefore, homocysteine is not the best marker for methylation. The good news is that elevated homocysteine typically responds well to a correction of vitamins B6, B9, and B12 deficiency.
- Methylenetetrahydrofolate reductase (MTHFR) genotype. The C677T variant of MTHFR gene weakens the enzyme function by about 35%. Whereas, the A1298C variant may reduce MTHFR function to a lesser extent [2].
The methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes a reaction that produces a methylated form of folate, 5-methylenetetrahydrofolate (5-MTHF) or methylfolate. Individuals can inherit risk variants in the MTHFR gene, thus predisposing them to dysfunction of methylation pathways and increased risk of heart disease, strokes, miscarriages, depression, anxiety and a variety of other diseases.[3, 4]
However, you can mitigate health risks due to MTHFR with adequate folate, choline, B12, riboflavin, creatine, and betaine intake as these nutrients are associated with the optimal methylation cycle functioning.[5], [6].
The MTHFR C677T variant can increase homocysteine for some people. However, most people with this variant have normal homocysteine and are healthy. Therefore, having MTHFR variants is not a disease on its own. This is because you can have the C677T variant but higher gene readouts (expression) than those with normal MTHFR. Nutrigenomic testing cannot determine your genetic readouts or how well your enzymes are functioning.
Crucially, you’d also need to consider symptoms, history, and other tests to estimate someone’s methylation status, especially if they don’t have an MTHFR variant or elevated homocysteine. This means it depends heavily on your clinical expertise or guesswork to deduce their methylation status.
More importantly, MTHFR is not the only gene involved in One Carbon Metabolism. There are at least 15 genes [7]. So, you can miss the forest for the trees if you only test and treat MTHFR.
For example, it’s still common to prescribe high-dose folic acid to treat MTHFR and elevated homocysteine, especially for fertility patients. However, folic acid is the synthetic form of folate (vitamin B9), which requires the enzyme dihydrofolate reductase (DHFR) to activate. DHFR is a very slow enzyme; very high doses of folic acid can block this enzyme altogether. Therefore, taking excessively high doses of folic acid rather than methylated folic acid can cause a build-up of unmetabolized folic acid [8]. Some, though conflicting, animal and clinical studies also suggest that long-term high doses of folic acid may contribute to cancer [9].
Comparison between Methylation Genetic Test and Metabolomic Testing
|
Methylation Genetic Testing |
Methylation Metabolomic Testing |
|
|
Genes tested |
MTHFR, MTR, MTRR, AHCY, GNMT, CBS, MAT1A, BHMT, SHMT1 |
Gene function inferred but not tested |
|
Metabolites tested |
No |
Homocysteine, methionine, cystathionine, glycine, serine, sarcosine, methylmalonic acid, adenine, adenosine |
|
Assesses health risks |
Yes |
Yes |
|
Actions based on test results |
Test for metabolites to establish the functioning of methylation pathways. Consider lifestyle, dietary and supplement changes to compensate for theoretical impairments in gene function. |
Make necessary lifestyle, dietary and supplemental changes to address metabolite pathways, if necessary. Retest metabolites to assess response to treatment |
|
Test results will change in response to treatments |
No |
Yes |
Metabolomic testing, on the other hand, eliminates the guesswork from genetic testing. You can directly measure how the One Carbon Metabolism pathway and downstream methylation processes are working. It’s the most direct test for under and overmethylation.
Theriome Aristotle - the Best Methylation Test
Theriome’s Aristotle measures metabolites that are directly and indirectly part of the methylation cycle, including homocysteine, sarcosine, cystathionine, methionine, and cysteine. This provides a more accurate assessment of the functioning of the methylation cycle, rather than just looking for the presence or absence of genetic variants in the methylation cycle.
In addition, Aristotle covers 68% of other metabolic pathways and provides health scores in categories that tend to be dysfunctional in patients interested in methylation.
While measuring genetic risks can correlate with health outcomes, diet, lifestyle and environmental exposures play a larger role in the impact of chronic disease risk. [10]
Metabolites provide the measurable outputs of these genetic pathways in the context of all these environmental factors. Hence, metabolomics objectively and directly measures your methylation and can tell whether you’re over or under-methylation. Aside from telling whether someone is over or under-methylated as a whole, the test also indicates if downstream pathways are running smoothly as a result of methylation.
The Methylation Insights Report is included as part of the Theriome Aristotle Test for no extra charge. By taking the Theriome Aristotle test, one can more accurately assess whether their diet and lifestyle choices are sufficient for their methylation pathways and all downstream pathways, regardless of genetic variant status.
Additionally, our Digital Twinning algorithm helps identify recommendations to optimize all metabolic pathways, including methylation pathways and pathways that affect methylation. You can also retest later to ensure the recommended diet, lifestyle and supplement interventions have made a favorable impact on their methylation pathways.
1 Zhang, N. (2015) Epigenetic modulation of DNA methylation by nutrition and its mechanisms in animals. Anim. Nutr. 1, 144–151 https://doi.org/10.1016/j.aninu.2015.09.002
2 Friedman, G., Goldschmidt, N., Friedlander, Y., Ben-Yehuda, A., Selhub, J., Babaey, S., et al. (1999) A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J. Nutr. 129, 1656–1661 https://doi.org/10.1093/jn/129.9.1656
3 Raghubeer, S. and Matsha, T. E. (2021) Methylenetetrahydrofolate (MTHFR), the one-carbon cycle, and cardiovascular risks. Nutrients, MDPI AG 13, 4562 https://doi.org/10.3390/nu13124562
4 Wan, L., Li, Y., Zhang, Z., Sun, Z., He, Y. and Li, R. (2018) Methylenetetrahydrofolate reductase and psychiatric diseases. Transl. Psychiatry, Springer Science and Business Media LLC 8, 242 https://doi.org/10.1038/s41398-018-0276-6
5 Anderson, S., Panka, J., Rakobitsch, R., Tyre, K. and Pulliam, K. (2016) Anxiety and methylenetetrahydrofolate reductase mutation treated with S-adenosyl methionine and methylated B vitamins. Integr. Med. 15, 48–52
6 Arnold W. Mech, MD, and Andrew Farah, MD, DFAPA. (2016, May 25) Correlation of Clinical Response With Homocysteine Reduction During Therapy With Reduced B Vitamins in Patients With MDD Who Are Positive for MTHFR C677T or A1298C Polymorphism: A Randomized, Double-Blind, Placebo-Controlled Study. Psychiatrist.com https://www.psychiatrist.com/jcp/correlation-clinical-response-homocysteine-reduction/
7 Lee, Y. L., Xu, X., Wallenstein, S. and Chen, J. (2009) Gene expression profiles of the one-carbon metabolism pathway. J. Genet. Genomics, Elsevier BV 36, 277–282 https://doi.org/10.1016/S1673-8527(08)60115-0
8 Bailey, S. W. and Ayling, J. E. (2009) The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc. Natl. Acad. Sci. U. S. A., Proceedings of the National Academy of Sciences 106, 15424–15429 https://doi.org/10.1073/pnas.0902072106
9 Ebbing, M., Bønaa, K. H., Nygård, O., Arnesen, E., Ueland, P. M., Nordrehaug, J. E., et al. (2009) Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA, American Medical Association (AMA) 302, 2119–2126 https://doi.org/10.1001/jama.2009.1622
10 Rappaport, S. M. (2016) Genetic factors are not the major causes of chronic diseases. PLoS One 11, e0154387 https://doi.org/10.1371/journal.pone.0154387