Step 6: What the Heck is Methylation, and Why Should I Care?

Ten Steps Program to Boost Brain Health Step 6:

What the Heck is Methylation, and Why Should I Care?

 Dear Readers,

I watched a viral 1967 old movie last week, ‘The Graduate.’ In it, 21-year-old Benjamin, played by Dustin Hoffman, is told at his college graduation party about a future commodity he should pursue as a career.

“I have one word for you,” says Mr. McGuire, a wealthy friend of Benjamin’s parents. “Plastics. The future is plastic.”

And I, dear reader, for you, also have one word:

“Methylation.”

Go ahead, try to pronounce it. “ Meth-el-ay-shun.”

It was one of those complex scientific terms my mother loved to hear me say.

“Oh, my son, the doctor! He uses such fancy, schmancy words. I don’t understand half of them, but listen to him talk! Did I get my money’s worth or what?”

“Yes, Mom,” I said.

Every mother’s dream. With less than an estimated 0.2% of the United States adult population having even heard of this term, why should you, dear reader, know or care about such an esoteric concept?

You don’t care? I’ll tell you why. You will be glad you asked.

What is Methylation?

Methylation is the biochemical process where a molecule called a methyl group, composed of one carbon atom bound to three hydrogen atoms (-CH3), is added to another molecule. ⁽²⁾

Ugh. But remember, Mom. So proud to hear that or any explanation. “My son, the docta!”

Adequate methylation is necessary to counter the aging process and is crucial for maintaining DNA integrity and repair mechanisms. As one matures (Mom would never say ages; a-g-e and o-l-d are four-letter words in her book), DNA damage accumulates, leading to cellular dysfunction and disease.

Adequate methylation contributes to the repair and maintenance of DNA, influencing how genes are turned on or off and slowing down age-related changes. Methylation reduces the risk of age-related diseases such as cardiovascular disease, neurodegenerative deterioration, and cancers. ⁽³⁾

Your liver, the body’s primary detoxification mechanism, uses a methylation pathway, specifically B6, B12, folate, and SAMe, to “conjugate,” i.e., attach various molecules to toxins to make them water-soluble to be excreted from the body. ⁽⁴⁾

During methylation, liver cells add a methyl group to a toxin. The methylation process makes the toxin less harmful to the body and easier to eliminate. The nutrients required for this process include vitamins B6, B12, folate, and SAMe. ⁽⁵⁾

Not to be overlooked, methylation is necessary to produce glutathione, our most potent protector from damage caused by free radicals and toxins. ⁽⁶⁾

Methylation regulates gene expression. With aging, oops, there is that word again: changes in the methylation patterns of genes occur, leading to altered gene function. Proper methylation helps maintain regular gene activity, essential for healthy aging. Oncogenes silencing and stimulation of tumor suppressor genes through methylation prevent tumor cell growth, i.e., cancer, which is more common in older age. ⁽⁷⁾

Cellular senescence, a cell’s cessation of division, is a crucial indicator of aging. Methylation plays a pivotal role in cellular senescence by providing a shield to telomeres, the protective caps at the ends of chromosomes. Telomeres serve as “buffers” against the wear and tear associated with aging. ⁽⁸⁾

Methylation plays a role in converting homocysteine into methionine, mitigating age-related health risks. High levels of homocysteine, due to poor methylation, are

associated with cardiovascular diseases, cognitive decline, and bone health issues. ⁽⁹⁾

Critical for preserving brain function, methylation is involved in synthesizing neurotransmitters serotonin and dopamine and neurotransmitter metabolism. Poorly methylated patients easily succumb to neurological disorders such as Alzheimer’s,

Parkinson’s, and Huntington’s Disease, autism spectrum disorders, cognitive decline, mood disorders, depression, and anxiety. Adequate methylation is critical for

age-defying brain function and overall health. ^(10-11)

Balanced methylation is a fundamental building block of the immune system.

Sufficient methylation prevents autoimmune conditions. ⁽¹²⁾

Proper methylation regulates the expression of genes involved in and reduces chronic inflammatory responses. ⁽¹³⁾

Lifestyle changes you can undertake to improve methylation include:

8. Balanced Diet: Your diet should be rich in natural, whole foods, particularly folate and B vitamins, such as leafy greens, legumes, nuts, and whole ⁽¹⁴⁾
9. Reduced Alcohol Consumption: Excessive alcohol interferes with absorbing B vitamins, nutrients necessary for proper methylation. ⁽¹⁵⁾
10. Stress Reduction: Chronic stress has a variety of negative impacts on Incorporate a stress-management technique like mindfulness, yoga, or meditation. Make these techniques compatible with your personality so that it is a joy and not a chore. ⁽¹⁶⁾
11. Regular Exercise: Physical activity supports healthy methylation. ⁽¹⁷⁾
12. Sleep: Good sleep hygiene, thus ensuring sufficient rest, is essential for maintaining adequate methylation processes and optimal health. ⁽¹⁸⁾
13. Environmental Toxins: Avoiding exposure to pollutants, heavy metals, and chemicals, easier said than done these days, improves methylation ⁽¹⁹⁾
14. Smoking: Smoking’s adverse health effects interfere with Stop it.(20)
15. Weight: No matter the political climate, obesity hinders ⁽²¹⁾

Nutraceutical interventions to improve methylation include:

1.     Vitamin B12, Folate (B9), and Vitamin B6

1. Vitamins B6, B12, and folate produce S-adenosylmethionine (SAMe). SAMe is involved in immune function and mood. ⁽²²⁾
2. Vitamin B12 and folate deficiencies lead to peripheral neuropathy, cognitive and mood disorders, depression, megaloblastic anemia, and spinal degeneration. ⁽²³⁾
3.  Vitamin B6 Vitamin B6 (P-5-P) is needed to produce the active form of Folic acid (5-MTHF)
4. Dose: B12 500 mcg minimum per day to protect cardiac function Folate 400 mcg/day ⁽²⁴⁾
   B 6 in its active form; pyridoxal 5′-phosphate (PLP): 1-2 mg/d ⁽²⁵⁾

2.     Betaine (Trimethylglycine) ⁽²⁶⁾

1. Provides methyl groups for homocysteine, creatine, and

b.    Balances fluids

1. Has positive effects on fatty infiltration of the liver (NAFL)
2. Dose: 5-3 mg/day; For exercise performance, 1.25 mg 2x/d; Fatty liver- 10 mg 2x/d

3.     Choline ⁽²⁷⁾

1. Supports cognitive function, fetal neural development, and
2. Betaine precursor
3. Dose: Adult female 425 mg/d; Adult male 550 mg/d

4.     Magnesium ⁽²⁸⁾

1. Acts as a cofactor in the methylation pathway
2. Aids in DNA synthesis and repair
3. Supports SAMe production
4. Supports ATP (energy) production,
5. Metabolizes homocysteine
6. Is essential for the formation of neurotransmitters
7. Dose: 300-400 mg/day

5.     Zinc ⁽²⁹⁾

1. Methyl donor
2. Stabilizes DNA, RNA
3. Deficiency leads to cell death (apoptosis)
4. Dose: Minimum Females 8 mg/day, Males 11 mg/day

6.     Milk Thistle ⁽³⁰⁾

1. Liver detox agent
2. Acts as an antioxidant and anti-inflammatory agent
3. Dose: 140-210 mg 2-3x/day

7.     Green tea extract ⁽³¹⁾

1. Reduces the effect of DNA methyltransferase 1 (DNMT1), a suppressor of tumor genes.
2. Neuroprotective and Cardioprotective
3. Antioxidant
4. Dose: 1-2 grams of tea per cup, 2-3 times daily

8.     SAMe ⁽³²⁾

1. Provides leading methyl donor for
   1. Acetyl-L-Carnitine: Neuronutrient and membrane-transporting agent

1. Epinephrine & adrenaline: Endogenous catecholamine, stress hormone, and neurotransmitter

• Phosphatidylcholine: an essential component of biological membranes

1. Carnitine: Transporter of fatty acids into mitochondria
2. Phosphocreatine: ATP (energy) reservoir
3. Melatonin: Circadian rhythm modulator

1. Dose: Mood support: 400-1600 mg in 2-4 doses Joint support: 600-1200 mg/d

Liver dysfunction: 600-1200 mg/d

9.     Methylation adaptogens:

1. Curcumin ⁽³³⁾
   1. Reduces the effect of DNA methyltransferase 1 (DNMT1), a suppressor of tumor genes. (anti-neoplastic effect)
   2. Anti-inflammatory and antioxidant effects

• Neuroprotective

1. Dose: 500-2000 mg/d in divided doses

b.    Anthocyanins ⁽³⁴⁾

1. Reduces the effect of DNA methyltransferase 1 (DNMT1), a suppressor of tumor genes. (anti-neoplastic effect)
2. Anti-inflammatory and antioxidant effects

• Neuroprotective

1. Dose: The best way to consume anthocyanins is through a diet rich in colorful fruits and vegetables. Foods high in anthocyanins include berries (like blueberries, blackberries, and raspberries), red grapes, cherries, red onions, and purple cabbage.

c.     Quercetin ⁽³⁵⁾

1. Upregulates DNA methyltransferase 1 (DNMT1) in both mRNA and protein expressions.
2. Antiinflammatory, antioxidant

• Can increase risk of bleeding-Do not use with blood thinning agents

1. Dose:400-600 mg 1-3x/d

d.    Rorsmarinic acid ^(36-37)

1. Anti-inflammatory, antioxidant
2. Supports healthy probiotic bacteria levels in the GI

• Neuroprotective
  1. Supports a calming immune response to microglial (inflammatory brain cell) activation

1. Inhibits DNMT1 activity in breast cancer cells
2. Exerts an anticancer effect on osteosarcoma cells

1. Sources: Herbal extracts of lemon balm, rosemary, oregano, sage, thyme, and peppermint.

• Dose: 50% Extract 500 mg and

e.     Lycopene ⁽³⁸⁾

1. Antioxidant function
2. Liver detox agent

• Reduces methylation of oncogenic gene expression
  1. Protects prostate in androgen-dependent cancers

1. Found in tomatoes and other red fruits and
2. Dose: 6-30 mg/day

f.      Sulforaphane ^(39-40)

1. Improves blood pressure
2. Normalizes kidney methylation

• Changes DNMT1 expression

1. Reactivates methylation-silenced genes
2. Induces methylation changes in cancer cells
3. Anti-proliferative (Protects against growth) in prostate cancer cell lines

• Found in broccoli, cauliflower, and other cruciferous vegetables
• Dose: 20-60 mg/day

One Last Wrinkle in the Pie: The (MTHFR) Methylation Genetic Defect

With our newfound understanding of the pivotal role of the methylation pathway in maintaining well-being, we would be remiss not to mention the genetic defect of MTHFR (methylenetetrahydrofolate reductase).

The MTHFR gene encodes an enzyme essential for converting a form of folic acid (Vitamin B9) into another, which is necessary for converting homocysteine into methionine. There are at least 40 MTHFR genetic defect variations with symptoms ranging from ocular issues, abnormal blood clotting, skeletal abnormalities, and cognitive deficits. ⁽⁴¹⁾

The most common MTHFR variants, 677C>T and 1298A>C, are linked to increased homocysteine levels in the blood. High homocysteine indicates an increased risk of high blood pressure, blood clots, pregnancy loss, psychiatric disorders, and certain cancers. ⁽⁴²⁾

Associated medical syndromes with MTHFR defects include ⁽⁴³⁾

• ADHD (attention deficit hyperactivity disorder)
• Autism
• Autoimmune disease and thyroid issues
• Cardiovascular disease
• Chronic fatigue
• Colon cancer
• Digestive issues, including IBS (irritable bowel syndrome)
• Hormonal issues, including PCOS (polycystic ovary syndrome)
• Migraines
• Schizophrenia

Diagnosis of MTHFR defects involves measuring homocysteine levels in the blood and testing for MTHFR variants. Tests for folic acid, B6, and B12 levels may hint at an MTHFR defect. ⁽⁴⁴⁾

Treatment:

Treating MTHFR genetic defects involves a multifaceted approach, as the condition affects how the body processes folate and folic acid.

1. Dietary Changes: Increase the intake of natural folate-rich foods such as leafy greens, legumes, nuts, and certain Unlike synthetic folic acid, natural folate is more easily processed by those with MTHFR mutations. ⁽⁴⁵⁾
2. Supplementation: ⁽⁴⁶⁾
   • Use Methylfolate (the active form of folate) instead of folic
   • Add B vitamins, especially vitamin B12, which works closely with folate in methylation processes.
   • Add Omega 3 Fatty Acids, which are anti-inflammatory and affect methylated gene expression.
3. Lifestyle Modifications: Reducing alcohol intake, avoiding smoking, and minimizing exposure to toxins improve methylation efficiency. ⁽⁴⁷⁾
4. Regular Exercise: Regular physical activity improves overall health and aids the body’s methylation processes. ⁽⁴⁸⁾
5. Homocysteine Levels: Elevated homocysteine levels are associated with MTHFR “Normal Levels” < 11 umol/L, ”Optimal Levels” < 10 umol/L

(49)

6. Medication Review: Medications and supplements that may interfere with folate metabolism: ⁽⁵⁰⁾

• Procainamide, Hydralazine, EGCG, Azacytidine,
• Cholestyramine, BCP
• Betaine, Methotrexatee, Carbamazepine
• Phenytoin, Valproic Acid, Levodopa
• Estrogen, Phenothiazines, Cholestyramine

7. Genetic Counseling: Genetic counseling might benefit those considering starting a family, as MTHFR mutations can impact pregnancy and fetal development. ⁽⁵¹⁾

Conclusion

Ensuring optimal methylation levels plays a key role in slowing or reversing the impact of age-related illnesses. It contributes significantly towards promoting healthy aging by

• Sustaining DNA integrity
• Regulating gene expression
• Affecting cellular senescence and telomere length
• Regulating homocysteine levels
• Bolstering neurological health
• Mitigating chronic inflammation

Knowledge is indeed power. We here at the Clearfield Medical Group, as part of our central mission, are committed to making you and Mom proud by providing you with this type of valuable information. Our goal is to preserve and enhance your health and

well-being!

Thanks for the great head start, Mom! Sincerely,

Dr. Bill Clearfield

xxxxxx

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