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Methylation: The Fountain of Youth?

By Marsha McCulloch, MS, RD, In The Aisles | July 1, 2014

Although many factors impact disease risk, a growing body of research and clinical experience suggests genetically-targeted nutritional supplementation may have far-reaching health benefits.

Not so long ago it was almost unfathomable that we’d be able to peek at our genetics to determine what diseases we’re at risk for, let alone use nutrition to help bypass genetic mutations referred to as single nucleotide polymorphisms (SNPs). Since the completion of the Human Genome Project in 2003, this ability has been growing rapidly.

One area frequently impacted by genetic mutations that has received a great deal of attention is the methylation cycle. This biochemical process occurs in all cells of the body and is crucial for a variety of functions, including detoxification, energy production, immune function, maintaining and regulating genes, mood balancing and controlling inflammation, according to Amy Yasko, PhD, author of Feel Good Nutrigenomics: Your Roadmap to Health (NRI, LLC, 2014) and a leading expert in the methylation cycle.

The Impact of Methylation
“The methylation cycle is an ideal pathway to focus on for nutritional genetic analysis because the places where mutations occur are well-defined, so it’s clear where nutritional support can be used to bypass mutations,” said Dr. Yasko. “As its name suggests, one of the functions of this pathway is to generate methyl groups, chemically expressed as CH3. Your body moves these methyl groups around to turn genes on or off throughout the body.”

Genetic defects in methylation that cause a shortage of methyl groups can contribute to a wide range of health concerns. Perhaps the best known is the connection between methylation, homocysteine and cardiovascular disease. But methylation can impact many other conditions, such as Alzheimer’s disease, cancer, diabetes, neural tube defects, multiple chemical sensitivities, psychiatric conditions and even aging. “If the mythical fountain of youth did exist, my guess is it would be this pathway,” said Dr. Yasko.

Methylation defects can even contribute to addictions, as Cheryl Burdette, ND, at Progressive Medical Center in Atlanta, GA, and advisory board member for the nutraceutical company Xymogen, Orlando, FL, explained. “Because some methylation defects impact neurotransmitters such as serotonin, often people will find themselves using alcohol or medications to cope. It’s a vicious, feed-forward cycle though, because addictive substances like alcohol can create more methylation defects, so that makes it difficult for people to get out of the cycle. Although someone battling alcoholism may take a selective serotonin reuptake inhibitor or SSRI medication to increase serotonin, unless you correct the underlying issues—the methylation defects—the person will continue to need that outside support.” 

Consumers Driving Interest
This may be the first time you’ve heard of methylation, but countless consumers with complicated health issues who have witnessed conventional medicine fail them are well aware of it. Methylation is a complex topic to tackle, but consumers are poring through books, websites and online forums trying to understand how it applies to their specific health concerns. “I have more and more patients coming to me who have read about a series of symptoms they have that match these methylation defects,” said Dr. Burdette. She believes consumers are a major driving force prompting medical professionals to step up to the plate and learn the science.  

Ben Lynch, ND, is a leading educator on the methylation cycle, not only for consumers through www.mthfr.net, but also for health professionals, nationally and internationally. “I find great interest all across the board—including from traditional physicians, naturopaths, chiropractors, registered nurses and psychiatrists—and it’s growing on a weekly basis. My work is very well respected because what I’m teaching comes from scientific research and clinical experience. Practitioners are seeing big improvements, such as in psychiatric conditions including depression, anxiety, attention deficit disorder and autism, as well as in pregnancy care, such as reduction of miscarriages, so they’re very excited about it.”

Dr. Yasko has had a similar experience. She is increasingly invited to give seminars to conventional doctors with a variety of specialties. “These doctors are looking toward incorporating alternative approaches and are coming to recognize that these methylation pathways can’t be ignored,” she said. 

Methylation Genetic Testing
Consumers often start with a genetic test to determine if they may have methylation defects. Dr. Yasko explained that several genetic testing options are available, including saliva tests, pin prick blood spot tests and venous blood draws. “Although saliva tests are typically the least expensive and easiest to do, you do risk contamination from bacteria in the saliva, and the quality of the way the test is run probably leaves more room for error. The blood draw presents the least risk of sample contamination, but isn’t as accessible, so pin prick tests are a good alternative,” she said.

Defects in one gene of the methylation cycle, MTHFR (methylene-tetrahydrofolate-reductase), are among the most well-known, including the C677T and A1298C mutations, which can be either heterozygous (affecting only one member of the gene pair) or homozygous (affecting both genes in the pair), but there are many others a skilled clinician should consider.

Mutations should be interpreted with caution, too. “Having a mutation doesn’t mean the activity of the gene is completely  ‘off.’  It may simply mean it functions at a lower efficiency or at an increased level that is undesirable or that the gene isn’t appropriately regulated,” said Dr. Yasko. For example, someone with a C677T mutation may have more difficulty ridding the body of environmental toxins, but that doesn’t mean the body isn’t detoxifying at all. Those with a homozygous mutation would generally be expected to have a greater impairment than with a heterozygous mutation, though.

Bypassing Methylation Defects
When supplementing for methylation defects, it’s important to understand the entire pathway, not just one imbalance in the pathway. “There’s too much misinformation out there, and I think people are jumping into supplementation without laying the proper groundwork,” said Dr. Yasko. “That approach can really backfire and make some sick people even sicker. Providing supplements to bypass defects in only one part of the methylation cycle could have downstream effects that make a person feel worse.

“Supplementation should be done in a staged and very careful manner,” she continued. “High doses of supplements aren’t necessarily better, either. Your body is in a very delicate balance.”

There are also different pathways you can support, and she finds it’s often best to support “short-cut” pathways first with smaller doses of several well-tolerated vitamins, minerals and phospholipids before tackling longer routes in the cycle.

Key Supplements
An integral part of supplementation for methylation support are the B vitamins, including vitamin B2 (riboflavin), B6, B12 and folate, which are all involved in methylation, said Dr. Burdette. The particular form of B vitamins used in supplements can make all the difference in their effectiveness for an individual person.

“For example, although folic acid, a synthetic form of folate, is the kind used to fortify foods, a different form called 5-methyl-tetrahydrofolate or 5-MTHF is the most active form of folate in the body, where it donates methyl groups needed for a variety of functions,” she said. “When you use the most active form of a vitamin, it reduces the amount of energy or ATP needed to convert the nutrient into the form used by the body, and it’s more likely to get to its target more quickly. That can be especially important as we age and our ability to produce ATP decreases.”

Supplementing with active forms is also key for people who have SNPs that impair their ability to convert nutrients to the form.

Folinic acid is another natural form of folate useful for certain methylation defects, said Dr. Lynch. As for B2 and B6, the most active forms are riboflavin 5-phosphate and pyridoxal 5-phosphate, respectively.

The best form of vitamin B12 can vary with a person’s specific combinations of certain SNPs. In her online support posted at www.knowyourgenetics.com, Dr. Yasko provides detailed charts helping consumers and their doctors navigate the decision tree of whether to use adenosyl B12, hydroxy B12 or methyl B12, as well as combinations of these different forms. Although methyl B12 is a widely touted active form, Dr. Yasko said adults who have trouble tolerating supplements that trigger detoxification and those who get jittery from caffeine may not respond as well to methyl B12.

A person’s lithium levels should also be evaluated before supplementing with B12, she added. “If someone has extremely low lithium levels, then I recommend first bringing lithium up into the normal range before adding B12 or you run the risk of lithium dropping even lower, which can happen because lithium is involved in transporting B12. Low lithium in the body has a whole host of psychological and physiological impacts.”

Many other supplements are typically used in bypassing methylation defects, depending on one’s specific SNPs and health concerns, including but certainly not limited to SAMe (S-adenosyl-methionine), reduced glutathione, DHA (docosahexaenoic acid) and zinc; and their use should be directed by a well-trained practitioner.

For example, not everyone tolerates SAMe well, but a skilled clinician can work around that. “SAMe is the primary methyl donor in the body,” said Dr. Lynch. “If people cannot tolerate SAMe, then providing phosphatidylcholine or creatine to the patient in supplement form spares SAMe. How? Over 70% of SAMe is utilized to produce phosphatidylcholine and creatine. By supplementing these two nutrients, SAMe is spared and supported indirectly.”

Important Supplement Considerations
Not only must manufacturers understand how to formulate supplements with the best forms of nutrients, the purity of the supplements is also a key concern. “A lot of people with methylation defects have a life-long accumulation of garbage due to impaired detoxification. If they can take supplements that are free of fillers, artificial flavorings and so on, that’s the best way to go,” said Dr. Lynch. “It’s ironic that some companies are making products that support methylation, yet they contain various other ingredients requiring methylation for the body to get rid of them.”

Dr. Lynch also emphasized that supplementation should be used to enhance something that is deficient for that moment. “Doctors should teach patients that before they reach for the supplement bottle, they should evaluate how they’re feeling and what the function of the supplement is. In other words, assess whether they need it or not.”

He continued, “For example, if a doctor prescribes 1 milligram of methyl folate twice a day, which is a nutrient that can be stored in the bile, and the patient takes it every day, plus one day eats a huge leafy green salad, then they’ve got all of this folate in addition to the 2 milligrams they’re supplementing with, and that might increase side effects in that individual for that particular day.

Whereas the next day, they may be under tremendous stress and get a big dose of environmental contaminants, so they might need 4 milligrams of methyl folate instead of just 2 milligrams. Recommendations have to be continually reevaluated and adjusted as needed.”

The Bigger Picture
Although methylation defects are common, not every person with mutations in this pathway will develop health complications, Dr. Yasko noted. “There is a complex interplay of infectious and environmental factors with genetics. For example, when you have bacterial or viral infections in your system, it increases inflammation, which in turn worsens existing genetic mutations. A certain threshold or body burden needs to be met for each of these factors in order for disease to occur.”

Dr. Burdette agreed. “The lower a person’s toxic body burden, the better biochemical pathways such as methylation work in the body. So, a big lifestyle piece is not consuming toxins in the first place, such as by eating organic foods and limiting exposure to environmental pollutants such as methyl-mercury.”

Infrared sauna can be a key strategy in toxin elimination, as can exercise. “The more you exercise, the more you sweat, which releases toxins. And the more you exercise, the higher your metabolism, which not only impacts the rate you burn calories, but it also impacts the amount of toxins excreted from the body,” she added.

Over the next decade and beyond, Dr. Lynch anticipates preventive medicine will be at the forefront. “Identifying, treating and supporting methylation defects must be a foundational part of all patient care. Given the importance of methylation, I believe it can have either a direct or indirect effect on basically any health condition.”

Dr. Yasko added, “If everyone would run methylation genetic testing and supplement to bypass where the problems are, I think we’d have a lot less chronic disease. Ideally, it would become common practice for everyone to be tested at birth. The more you know, the more control you have over your health.”   


Marsha McCulloch, MS, is a registered dietitian and a frequent contributor to several national nutrition and health magazines. She can be reached at marsha@intheaisles.com; Website: www.intheaisles.com.

Health Concerns Related to Methylation Defects
This is a snapshot of the ever-growing list of conditions that research suggests may be impacted by methylation defects.

• Addictions (smoking, drugs, alcohol)
• Allergies
• Alzheimer’s disease
• Anxiety
• Atherosclerosis
• Attention deficit disorder
• Atrial fibrillation
• Autism
• Bipolar disorder
• Cancer
• Chemical sensitivity
• Chronic bacterial and viral infections
• Chronic fatigue syndrome
• Depression
• Diabetes
• Down syndrome
• Endometriosis
• Epilepsy
• Fibromyalgia
• Heart attack
• High homocysteine
• Hypertension
• Huntington’s disease
• Infertility
• Irritable bowel syndrome
• Metal toxicity
• Methotrexate and other drug toxicities
• Migraine
• Miscarriages
• Mitochondrial disease
• Multiple sclerosis
• Neural tube defects
• Parkinson’s disease
• Pre-eclampsia
• Renal failure
• Rett syndrome
• Rheumatoid arthritis
• Turner syndrome
• Schizophrenia
• Seizures
• Sleep disorders
• Stroke
• Sulfite sensitivity
• Systemic lupus erythematosus (SLE)
• Thyroid dysfunction

Sources: www.mthfr.net, www.knowyourgenetics.com and Feel Good Nutrigenomics: Your Roadmap to Health by Dr. Amy Yasko (NRI, LLC, 2014)