When Methylation Goes Wrong Part 2

Dr. Alex Jimenez Explains Why Methylation Can Go Wrong

As previously discussed, many healthcare professionals have demonstrated potential concerns associated with folic acid and methyl-folate supplementation. Some risks of folic acid or other folate derivative supplements, such as commonly used alternatives like 5-mTHF and folinic acid, have become widely recognized and they aren’t frequently discussed. These diseases are described below.

Several of these diseases can usually be treated with vitamin B12 supplementation, respectively, and although fundamental, these are not the main focus of the article. However, we will continue to discuss whether or not the side-effects of folic acid supplementation, or aberrant DNA methylation activity, are a result of methylation gone wrong. Epidemiological data suggests an inverse association between folate status and risk of health issues. Research studies have demonstrated that excessive methylation may be harmful.

Diseases Caused by Aberrant Methylation

Aberrant methylation caused by folic acid supplementation is not explained by UMFA or DHF. Therefore, healthcare professionals cannot rule out the possibility of excessive or aberrant methylation as a contributing and/or underlying factor for health issues.

Cancer

Aberrant DNA methylation has been associated as a cause of a variety of cancers. Both loci-specific DNA hyper- and hypo-methylation has been demonstrated to occur in cancer cells, suggesting that both states can be distinguishing of tumorigenesis. Global DNA hypermethylation is also demonstrated in various cancer cells, as shown in Figure 2. The association between folic acid supplementation and colorectal cancer has been evaluated numerous times in research studies. A recent systematic review and meta-analysis demonstrated inconsistent and inconclusive evidence on the association between folic acid on colorectal cancer risk.

However, these research studies may oversee important details about the type, dose, and effect of supplementation as well as the folate, methylation, and disease status of the patient. By way of instance, specific DNA methylation in patients with stage II and III colon cancer has been considerably associated with the increased risk of developing future as well as predicting overall survival (hazard ratio 2.9, 95% CI 1.5-5.8, P=0.002) and disease-free survival (hazard ratio 4.0, 95% CI 1.6-10.2, P=0.003). In another research study, a randomized, controlled trial evaluating the potential benefits of 1 mg/d of folic acid supplementation for the prevention of colorectal adenomas, researchers found that folic acid failed to reduce the risk of the disease. As a matter of fact, researchers found that the risks of colorectal adenoma and noncolorectal cancers, especially prostate cancer, actually increased considerably.

Folic acid intake on breast cancer has also been evaluated in various research studies and is widely considered controversial. By way of instance, in one observational research study, dietary supplementation with folic acid greater or equal to 400 mcg/d was associated with a 20 percent increase in the risk of breast cancer compared with those reporting no supplement intake. In contrast, according to a 2014 Cochrane systematic review, food-sourced folate has protective properties against cancer. A recently published retrospective analysis gathered data from 367,993 women to demonstrate that higher food folate intake is associated with a lower risk of sex-hormone receptor-negative breast cancer in premenopausal women. However, further research studies are still required.

The connection between folate and cancer has also been tremendously analyzed. In a research study of women with breast cancer (n=204) compared with controls (n=408), participants with the highest tertile of plasma folate (median 17 nmol/L) had the highest risk of ERβ(-) breast cancer (odds ratio 2.67, CI 1.44–4.92, P=0.001). Several researchers had previously shown an increased risk in breast cancer specifically when the MTHFR C667T polymorphism was combined with high plasma folate levels, which may be a potential concern because patients who are diagnosed with this polymorphism are among the most frequent to take supplemental folates.

In another case-control research study of approximately 300 participants, it appeared that increased levels of serum folate promoted the progression of existing benign tumors, or polyps, into colorectal cancer, however, it also prevented carcinogenesis in healthy controls, leading researchers to determine that serum folate can have dual roles in the onset and progression of cancer. Additionally, recent research studies demonstrate potential dysregulation of one-carbon metabolism in cancer cells, specifically methionine uptake transporters, while increasing the serine-glycine biosynthesis pathway. These outcome measures may potentially explain the harmful effects of folic acid, as well as that of other forms of folate, where there is a prior history of cancer in participants.

We can’t know from these research studies what folate derivative plays the biggest role in these outcome measures, because serum folate demonstrates various folate vitamers, however, we do know that serum folate is largely made up of 5-MTHF, about 86.7% percent, with UMFA typically making up a much smaller amount, about 4.0 percent. Whether the effect of the smaller amount of UMFA is enough to cause the progression of pre-cancerous lesions or whether increased levels of 5-MTHF are also implicated, healthcare professionals have to determine which intervention to choose to present the least risk to the patient’s overall health and wellness.

Autoimmunity

Systemic sclerosis is a misunderstood autoimmune health issue characterized by endothelial injury, immune abnormalities, and fibrosis. It is believed to develop from epigenetic dysfunction in immune cells which trigger immune cell activation and proliferation. Variations in several epigenetic mechanisms are involved in the pathogenesis of the disease. Hypermethylation of specific genes, Fli-1, KLF5, and BMPRII, can ultimately reduce their anti-fibrotic effects. Conversely, the overexpression of immune cells CD40L, CD70, and CD11a, are also involved and have been associated with hypomethylation of their corresponding genes, among other functions.

The pathogenesis of other autoimmune conditions may also be influenced through methylation. IgG4-related autoimmune pancreatitis, or AIP, and other autoimmune-like phenotypes are associated with MST1, a serine/threonine kinase, deficiency in humans, which leads to T-cell immunodeficiency and hypergammaglobulinemia with autoantibody production. IgG4-related AIP patients who also exhibit extrapancreatic lesions demonstrate a considerable increase in the methylation of MST1 and decreased protein development, suggesting that this gene is regulated through methylation and may be associated to the underlying disease. Aberrant methylation, both hypo- and hyper, have also been shown in rheumatoid arthritis and autoimmune thyroid diseases.

Allergy

We also found that researchers believe that environmental exposures which increased DNA methylation may also increase the risk for allergic disease by suppressing Th1 and T regulatory cell differentiation which would otherwise prevent the differentiation of allergy-promoting Th2 cells. In a research study of elderly men (n=704), minor increases, about 0.31 percent, in methylation at gene Alu repeat sequences have been considerably associated with prior sensitization to at least one allergen, raising the possibility that even small changes in epigenetic regulators might have considerable clinical effects. Hypermethylation at specific CpG sites is believed to be useful for differentiating clinically non-reactive and clinically reactive food-allergic phenotypes than serum IgE and skin prick testing.

Down Syndrome

In Down Syndrome, early-life downregulation of the TET family genes involved in DNA demethylation and downregulation of REST transcription factor expression and subsequent methylation of REST-vacant sites, are believed to be potential pathways leading to the global DNA hypermethylation associated with Down Syndrome. More details can be found in Figure 3 below.

Reasons to be Cautious

While the effects of methylated folate or folic acid cannot be conclusively determined from the research studies discussed above, there are enough unknowns to justify potential concerns. Research studies are ongoing and it is not yet clear how aggressive 5- MTHF, or other methylation supplementation, affects well-being or the progression of diseases. Data suggest that we should be cautious and focus on supporting the body’s own health and wellness for methylation balance rather than attempting to override them.

Metabolic and DNA methylation are complex in their regulation of gene expression. Epigenomic regulation also depends on many environmental inputs, including both nutritional and lifestyle modifications, which make up methylation activity regulation. A safer way to support methylation activity, especially over the longer term, is through food-based nutrients as well as food and lifestyle practices which have been demonstrated to promote favorable methylation activity and epigenetic imprints in patients with these diseases.

DNA methylation is a fundamental epigenetic mechanism which regulates gene expression, cell energy production, detoxification, and many other functions. Unfortunately, some people may experience methylation health issues which can affect overall health and wellness. Many health professionals may help treat these methylation problems with supplementation, however, research studies have demonstrated that supplementation can sometimes cause methylation to go wrong. Aberrant methylation can cause a variety of diseases, including cancer, autoimmunity, allergy, and down syndrome.

Dr. Alex Jimenez D.C., C.C.S.T. Insight

Smoothies and Juices for Methylation Support

While many healthcare professionals can recommend nutritional guidelines and lifestyle modifications to improve methylation support, there are several options you can try yourself at home. As described above, methylation support supplementation should be determined by a healthcare professional. Smoothies and juices are a fast and easy way to include all the necessary nutrients you need for methylation support without any side-effects. The smoothies and juices below are part of the Methylation Diet Food Plan.

Sea Green Smoothie
Servings: 1
Cook time: 5-10 minutes
• 1/2 cup cantaloupe, cubed
• 1/2 banana
• 1 handful of kale or spinach
• 1 handful of Swiss chard
• 1/4 avocado
• 2 teaspoons spirulina powder
• 1 cup water
• 3 or more ice cubes
Blend all ingredients in a high-speed blender until completely smooth and enjoy!

Berry Bliss Smoothie
Servings: 1
Cook time: 5-10 minutes
• 1/2 cup blueberries (fresh or frozen, preferably wild)
• 1 medium carrot, roughly chopped
• 1 tablespoon ground flaxseed or chia seed
• 1 tablespoons almonds
• Water (to desired consistency)
• Ice cubes (optional, may omit if using frozen blueberries)
Blend all ingredients in a high-speed blender until smooth and creamy. Best served immediately!

Sweet and Spicy Juice
Servings: 1
Cook time: 5-10 minutes
• 1 cup honeydew melons
• 3 cups spinach, rinsed
• 3 cups Swiss chard, rinsed
• 1 bunch cilantro (leaves and stems), rinsed
• 1-inch knob of ginger, rinsed, peeled and chopped
• 2-3 knobs whole turmeric root (optional), rinsed, peeled and chopped
Juice all ingredients in a high-quality juicer. Best served immediately!

Ginger Greens Juice
Servings: 1
Cook time: 5-10 minutes
• 1 cup pineapple cubes
• 1 apple, sliced
• 1-inch knob of ginger, rinsed, peeled and chopped
• 3 cups kale, rinsed and roughly chopped or ripped
• 5 cups Swiss chard, rinsed and roughly chopped or ripped
Juice all ingredients in a high-quality juicer. Best served immediately!

Zesty Beet Juice
Servings: 1
Cook time: 5-10 minutes
• 1 grapefruit, peeled and sliced
• 1 apple, washed and sliced
• 1 whole beet, and leaves if you have them, washed and sliced
• 1-inch knob of ginger, rinsed, peeled and chopped
Juice all ingredients in a high-quality juicer. Best served immediately!

Protein Power Smoothie
Serving: 1
Cook time: 5 minutes
• 1 scoop protein powder
• 1 tablespoon ground flaxseed
• 1/2 banana
• 1 kiwi, peeled
• 1/2 teaspoon cinnamon
• Pinch of cardamom
• Non-dairy milk or water, enough to achieve desired consistency
Blend all ingredients in a high-powered blender until completely smooth. Best served immediately!

ProLon® Fasting Mimicking Diet

Balanced methylation support can be achieved through proper nutrition. The ProLon® fasting mimicking diet offers a 5-day meal program which has been individually packed and labeled to serve the foods you need for the FMD in precise quantities and combinations. The meal program is made up of ready-to-eat or easy-to-prepare, plant-based foods, including bars, soups, snacks, supplements, a drink concentrate, and teas. The products are scientifically formulated and great tasting. Before starting the ProLon® fasting mimicking diet, 5-day meal program, please make sure to talk to a healthcare professional to find out if the FMD is right for you. The ProLon® fasting mimicking diet can help promote methylation support, among a variety of other healthy benefits.

Many doctors and functional medicine practitioners may recommend higher doses of methyl donors in several patients, however, further research studies are needed to determine the proper amount of methylation supplementation. The scope of our information is limited to chiropractic, musculoskeletal and nervous health issues as well as functional medicine articles, topics, and discussions. To further discuss the subject matter above, please feel free to ask Dr. Alex Jimenez or contact us at 915-850-0900 .

Curated by Dr. Alex Jimenez

Additional Topic Discussion: Acute Back Pain

Back pain is one of the most prevalent causes of disability and missed days at work worldwide. Back pain attributes to the second most common reason for doctor office visits, outnumbered only by upper-respiratory infections. Approximately 80 percent of the population will experience back pain at least once throughout their life. Your spine is a complex structure made up of bones, joints, ligaments, and muscles, among other soft tissues. Injuries and/or aggravated conditions, such as herniated discs, can eventually lead to symptoms of back pain. Sports injuries or automobile accident injuries are often the most frequent cause of back pain, however, sometimes the simplest of movements can have painful results. Fortunately, alternative treatment options, such as chiropractic care, can help ease back pain through the use of spinal adjustments and manual manipulations, ultimately improving pain relief.

Formulas for Methylation Support

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