Your body relies on methylation. Methylation is a process that runs continuously, occurs in every cell, is important to our body functions, and is critical to how our genes are expressed. Methylation is an epigenetic process, meaning that it is very susceptible to diet and lifestyle changes. Aging and diseases of aging, including cancer and mental disorders, are often associated with methylation issues.
Epigenetics is the study of how our behaviors and environment can cause changes that affect the way our genes turn off and on. Unlike genetic changes, epigenetic changes are reversible and do not change your gene’s DNA sequence. However, they can change how your body reads a DNA sequence. DNA methylation is one of several epigenetic mechanisms that cells use to control gene expression.
DNA methylation is a biological process where methyl groups (CH3) comprised of one carbon and 3 hydrogen atoms are transferred to the DNA molecule and other substrates such as hormones, neurotransmitters, and immune cells. Methylation is involved in how your body manages heavy metals, regulates your gene expression, regulates protein function, and RNA processing (gene transcription and processing to maturity). Typically, methylation turns genes “off” and demethylation turns genes “on”.
S-adenosylmethionine (SAMe) is the methyl group donor for DNA methylation which requires key nutrients for its production. These methyl nutrients include vitamins (folate, riboflavin, vitamin B12, vitamin B6, choline) and amino acids (methionine, cysteine, serine, glycine). As such, imbalances in the metabolism of these nutrients have the potential to affect DNA methylation and have been implicated in the development of diseases such as cardiovascular disease.[i]
Why is methylation important and what is it used for? Methylation processes occur continuously in your body and are responsible for helping provide different chemicals to differentiate different organ systems. Your epigenetics change over time as you age and with exposure to diet and environment. When methylation is working well, it supports many functions such as:
- Energy production & mitochondrial function. Mitochondria may regulate methylation in DNA throughout the body [ii]
- Detoxification & Liver Health
- Estrogen Metabolism
- Eye Health
- DNA production, expression, and repair
- Fertility and fetal development: Methylation processes occur during gestation to help provide the right mix of chemicals for fetal development.
- Immune function
- Neurotransmitter production & function. Impaired methylation can decrease dopamine production which can lead to other issues such as inability to focus, concentration, short-term memory, organization, emotional stability, good sleep hygiene, and hormone regulation.
Methylation can result in biochemical alterations to DNA without changing the actual DNA gene sequence. DNA methylation plays a large role in metabolism and an unhealthy lifestyle can be attributed to changes in methylation. In the general population, 70% have normal methylation. 22% of people are undermethylated, and 8 % are overmethylated according to Bill Walsh, PhD.
Overmethylation enhances gene expression, while under-methylation does the opposite. An example is that many persons who suffer from anxiety and depression may be overmethylated which results in excessive activity at dopamine, norepinephrine, and serotonin receptors.
When the methylation switch is turned off, it is not producing enough SAMe, which leads to a lack of production of a number of important molecules, including Glutathione, Coenzyme Q10, Melatonin, Serotonin, Nitric Oxide, Norepinephrine, Epinephrine, L-Carnitine, Cysteine, or Taurine.
Potential signs/Symptoms/Pre-existing Conditions Methylation Issues:
- Nutrient deficiencies
- Mineral deficiencies
- Birth defects-As methylation issues can impact fetal development, it may be important to test prior to conception and to normalized. Deficiencies of folate can lead to Spina Bifida or Autism. While most pre-natal supplements contain folate or folic acid to avoid undermethylation issues, if a pregnant female is overmethylated, there could be concerns of providing additional supplements with folate.
- Ataxia or poor coordination
- Mental Disorders-Obsessive Compulsive Disorder (OCD), Perfectionism are intrinsic to people who are undermethylated. Bipolar disorders and schizophrenia have also been associated with methylation issues. Therefore, testing individuals’ methylation status is important.
- Behavior Disorders such as ADD, ADHD
- Sluggish metabolism
- Heart Disease, Stroke
Key factors that influence methylation:
- Genetics: Single Nucleotide Polymorphisms (SNPs) are gene alterations that result in a single nucleotide in a gene being altered in the sequence. While SNPs commonly occur in all individuals, and occur in populations, there are some that serve as biomarkers for disease.
- MTHFR is an important gene for methylation. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme that breaks down the amino acid homocysteine recycling it into Methionine. The MTHFR gene that codes for this enzyme has the potential to mutate, causing a SNP, which can either interfere with or inactivate the enzyme. As we inherit one copy of MTHFR gene from each parent, when we are homozygous for a specific MTHFR SNP, that means we inherited the SNP from each parent. There are two common types, or variants, of MTHFR mutations: C677T and A1298C. Unfortunately, the variants cannot predict under or over methylation.
- COMT is another methylation gene which provides instructions for making an enzyme called catechol-O-methyltransferase. A specific COMT gene variation limits the body’s ability to remove catechols (a specific type of molecule that includes dopamine, norepinephrine, estrogen, etc.) by 3-4 times which is associated with greater levels of cortisol and inability for the body to de-stress.
- Diet: It has been suggested that diet is a key factor in methylation and that aberrant methylation is a direct result of diet. [iii]
- Chemical Exposure: Chemicals may alter biological processes, such as inflammation, hormonal disruption, oxidative stress, methyl group availability, resulting in epigenetic changes to DNA methylation, which can impact disease risk.[iv]
- Medications: Birth control pills, Dilantin, acid-blocking medications, Methotrexate, diuretics lower B vitamins.
- Smoking: Smoking has been shown to lead to extensive changes in methylation.[v]
How do I know if I have methylation issues? Finding out if you have over or under methylation may be important in terms of managing your health or treating your condition(s). Medications and supplements may work differently or make your condition worsen depending on this. Here are some tests that may be done to identify methylation issues:
- Measuring blood serum levels of Methylmalonic acid (MMA) and homocysteine: Homocysteine is an amino acid that the body produces from the breakdown of dietary proteins and testing levels is very reliable. Having high levels of homocysteine may be due to MTHFR or other enzymes which can damage blood vessels and lead to blood clots. People who have high homocysteine levels tend to have low levels of vitamin B12.
- Methylenetetrahydrofolate reductase (MTHFR) mutation test may be used to detect two relatively common mutations in the MTHFR gene that are associated with elevated levels of homocysteine in the blood. It is not routinely ordered due to expense and availability of less expensive testing.
- Testing methylation: There are a number of methylation panels available. Genova Diagnostics Methylation Panel as well as Doctor’s Data Methylation Panel are ways of finding out your methylation status. The DNA Methylation Pathway Profile allows clinicians to screen their patients for SNPs that may impact the function of important biochemical processes such as methionine metabolism, detoxification, hormone balance and Vitamin D function. DNA methylation testing is evolving to determine the best methods.[vi]
- Measuring serum histamine levels: High histamine is generally associated with undermethylation, while low histamine levels are associated with overmethylation.
- Measuring glucose levels: Individuals who have symptoms of drowsiness after meals, irritability, craving for sweets, trembling, anxiety, and intermittent poor concentration and focus may have low blood glucose issues.
- Testing for copper overload and other metal toxicity. Trace metals may be improper functioning of metallothionein proteins. Elevated copper may lead to changes in neurotransmitters such as dopamine and norepinephrine as well as hormonal imbalance.
- Measuring folate levels.
- Testing for Pyrrole Disorder: A urine test for pyrroles can identify an inborn error of pyrrole chemistry which results in significant zinc and Vitamin B-6 deficiencies. Common symptoms include explosive temper, emotional mood swings, poor short-term memory, and frequent infection. Features of individuals with pyrrole disorder include those with inability to tan, poor dream recall, abnormal fat distribution, and sensitivity to light and sound. This is common in autistic children.
- Infer your probable methylation status based on past reactions to medications. Overmethylated people often feel much worse taking an SSRI such as Paxil, Prozac, or Wellbutrin or other because these drugs tend to further lower an already low histamine.
What can I do if I have methylation issues? The Walsh Protocol is a method described by Dr. William Walsh which can help to identify biochemical imbalances that may contribute to mental disorders along with nutrient protocols to address these. Overall, as your body relies on methylation, issues can be addressed with diet and dietary nutrients with a trained provider.
- For over-methylated individuals, support with already methylated forms of supplements such as methylated B12, methylcobalamin versus cyanocobalamin or B9, methylfolate versus folic acid is often indicated. Histamine is important to be balanced and giving methlyfolate can reduce methyl which in turn increases histamine which is an important neurotransmitter and messenger. Too many methyl compounds result in high levels of dopamine, serotonin, and epinephrine neurotransmitters which can result in anxiety, sleep disorders, psychosis, or even suicide can result. Many people can receive therapy which may after several months resolve the condition through the Walsh protocol.
- For undermethylated individuals, L-Methionine and/or SAM-e may be used. Zinc, Vitamin C, Calcium/Magnesium, and Vitamin B-6 also may help. Inositol sometimes helps with sleep problems. These individuals often have seasonal allergies, perfectionism, competitiveness, and other distinctive tendencies. A high percentage have an inborn tendency to be depressed in calcium, magnesium, methionine, and Vitamin B-6. Note that individuals who have obsessive-compulsive tendencies, oppositional-defiant disorder, or seasonal depression are often undermethylated which is associated with low serotonin neurotransmission; these individual may not react well to folate if they have MTHFR according to Dr. Bill Walsh. This is because folate tends to enhance gene expression. Low serotonin individuals who do well on SSRI medications need to enhance serotonin enhanced and folate decreases this. SAM-e supplementation works similarly to SSRIs to enhance serotonin.
- Diet: High homocysteine levels can be addressed with diet. Eating leafy greens, beans, nuts, fruit, whole grains to get B6, B12, and folate. Also meat, liver, eggs, oily fish are good sources of B12.
- Dietary Restrictions: Limit sugar, coffee, alcohol, saturated fat, and animal protein.
- Digestive Function: Identify digestive issues such as dysbiosis, leaky gut, and lack of digestive enzymes. Improve digestive function by addressing issues such as high or low stomach acid, need for supplemental digestive enzymes, and dietary modification.
- Exercise: Get regular exercise.
- Stabilize blood glucose: If an individual has chronically low glucose blood sugar stabilizing nutrients such as chromium, CoQ-10, may be indicated.
- Medications: Avoid if possible, medications that interfere with methylation or work with a provider to find the medications best suited for your specific methylation issues.
Summary: Your body relies on methylation processes to provide balanced biochemical functions and support gene expression. SNPs are common to all people and just because you have SNPs does not mean you have a health problem or you will develop a disease. When methylation processes are not working appropriately, signs, symptoms, and disease may result. Exploring methylation issues with a functional practitioner can help, as proper methylation can be addressed with appropriate nutrient support.
[i] Glier, M.B., Green, T.J. and Devlin, A.M. (2014), Methyl nutrients, DNA methylation, and cardiovascular disease. Mol. Nutr. Food Res., 58: 172-182. https://doi.org/10.1002/mnfr.201200636
[ii] D’Aquila, Patrizia & Giordano, Marco & Montesanto, Alberto & Passarino, Giuseppe. (2012). Global DNA methylation levels are modulated by mitochondrial DNA variants. Epigenomics. 4. 17-27. 10.2217/epi.11.109.
[iii] Morgan, A., Davies, T., & Mc Auley, M. (2018). The role of DNA methylation in ageing and cancer. Proceedings of the Nutrition Society, 77(4), 412-422. doi:10.1017/S0029665118000150
[iv] Baccarelli A, Bollati V. Epigenetics and environmental chemicals. Curr Opin Pediatr. 2009;21(2):243-251. doi:10.1097/mop.0b013e32832925cc
[v] Zeilinger S., Kuhnel B., Klopp N., Baurecht H., Kleinschmidt A., Gieger C., Weidinger S., Lattka E., Adamski J., Peters A., et al. Tobacco smoking leads to extensive genome-wide changes in DNA methylation, PLoS ONE, 2013, vol. 8 pg. e63812 10.1371/journal.pone.0063812
[vi] Kurdyukov S, Bullock M. DNA Methylation Analysis: Choosing the Right Method. Biology (Basel). 2016;5(1):3. Published 2016 Jan 6. doi:10.3390/biology5010003
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