methylation: a key to optimizing health and longevity presenter: benjamin lynch, nd methylation...

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Methylation:A Key to Optimizing Health and Longevity

Presenter:Benjamin Lynch, ND

Methylation SummitDenver, CO

October 25, 2014

(c) 2014: Benjamin Lynch, ND

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Disclaimer & Disclosures

The information presented here is for informational and educational purposes only. Docere, Inc and Benjamin Lynch will not be liable for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any materials or information published.

President and CEO of SeekingHealth.com, SeekingHealth.org and founder of MTHFR.Net

(c) 2014: Benjamin Lynch, ND

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Why?

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Stress – likely worse with menses

Depression / Insomnia

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Folate

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Source: Big Stock Photo 10

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Functions of Folate

“The functions of folate in human physiology are relatively simple, but the implications of their activity (and dysfunction) can be profound and far reaching.”

Source: Herb, Nutrient and Drug Interactions by Stargrove et al

Functions:• synthesis of nucleic acids (for DNA production/repair and tRNA)• single carbon metabolism (methylation)• interconversion of amino acids (for neurotransmitter production

and detoxification)• formation and maturation of RBC, WBC and platelet production

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Does Folic Acid = Folate?

Folic acid does NOT equal Folate.

Folic Acid is only ONE type of Folate.

Folic acid is not found in nature. Folate is.

Folic acid must undergo numerous biochemical transformations prior to utilization.

Must be specific when discussing folate. Use the appropriate term and form.• Folic acid (unmetabolized folic acid)• Folinic acid (5-FormylTHF)• Methylfolate (5-MTHF)

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Comparing Folic Acid to 5-Methyltetrahydrofolate

CH3

FOLIC ACID

METHYLFOLATE

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MTHFR: Why now?

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Folic Acid

MTHFR increasing in the population.• Folic acid fortification, artificial insemination, steroids, hormones

• ↑ Full-Term Pregnancies• ↑ Folate SNPs• ↑ Methylation SNPs• ↑ Inferior SNPs• ↑ Metabolic Issues.

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↑ Susceptibility to Environmental Exposures

UnNatural DeSelection: Survival of the ‘Unfittest’

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“Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link.”

“It is hypothesized here that the enhancement of maternal folate status before and during pregnancy in the last 15 years has altered natural selection by increasing survival rates during pregnancy of infants possessing the MTHFR C677T polymorphism, via reduction in hyperhomocysteinemia associated with this genotype and thereby miscarriage rates.

This also points directly to an increased rate of births of infants with higher postnatal requirements for folic acid needed for normal methylation during this critical neurodevelopmental period.

If these numbers have increased then so have the absolute number of infants that after birth fail to maintain the higher folate status experienced in utero thus leading to an increased number of cases of developmental disorders such as Autism. Detection of the C677T polymorphism as well as other methionine cycle enzymes related to folate metabolism and methylation at birth as part of newborn screening programs could determine which newborns need be monitored and maintained on diets or supplements that ensure adequate folate status during this critical postnatal neurodevelopment period.”

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Epigenetics

“As an organism grows and develops, carefully orchestrated chemical reactions activate and deactivate parts of the genome at strategic times and in specific locations.

Epigenetics is the study of these chemical reactions and the factors that influence them.”

(c) 2014: Benjamin Lynch, NDhttp://learn.genetics.utah.edu/content/epigenetics/ and Epigenetics and the developmental origins of inflammatory bowel diseases.

“Epigenetic changes are environmentally responsive mechanisms that can modify gene expression independently of the genetic code.”

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Epigenetics and Methylation

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Methylation

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What is Methylation?

The addition of a single carbon group with three hydrogens onto a compound

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ARSENIC

URACIL

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Arsenic. Big Deal.

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Functions of Methylation

Several Functions of Methylation:1. Turn on and off genes (gene regulation)2. Process chemicals, endogenous and xenobiotic compounds (biotransformation –

histamine, arsenic)3. Build neurotransmitters (norepinephrine epinephrine, serotonin melatonin)4. Metabolize neurotransmitters (dopamine, epinephrine)5. Process hormones (estrogen)6. Build immune cells (T cells, NK cells)7. DNA and Histone Synthesis (Thymine aka 5-methyluracil)8. Produce energy (CoQ10, carnitine, creatine, ATP)9. Produce protective coating on nerves (myelination)10. Build and maintain cell membranes (phosphatidylcholine)

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SAM (s-adenosylmethionine) FACTS

1. After ATP, SAM is the most widely used enzymatic substrate in the body2. Primary methyl donor3. Requires methionine, ATP, magnesium for formation4. Requires zinc, betaine (or choline), methylcobalamin, methylfolate, FAD and NAD for

remethylating homocysteine back to SAM5. Strongly inhibited by its end product - SAH6. SAH conversion to homocysteine, and adenosine, requires NAD7. SAH can be elevated even if homocysteine is not!8. If SAM production is disrupted, a plethora of pathologies may occur.9. If SAM cannot be utilized, a plethora of pathologies may occur.10. SAM production/recycle back up systems:

• MTR blocked? BHMT. • BHMT blocked? MTR. • Both blocked?

(c) 2014: Benjamin Lynch, ND S-adenosyl-L-homocysteine hydrolase and methylation disorders: Yeast as a model system

MTHF’R

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Main Pathway(Low protein)

Backup(High protein)

SAMe Excess(High protein)

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How is Methylation Disturbed?

Methylation is often disturbed by various mechanisms1. Lack of cofactors supporting methylation (Zinc, B2, Mg, Choline, B6, B12)2. Lack of substrate driving methylation forward (Methionine, Hcy)3. Medications (antacids, methotrexate, metformin, nitrous oxide)4. Specific nutrients depleting methyl groups (high dose Niacin)5. Environmental toxicity, heavy metals, chemicals (acetylaldehyde, mercury)6. Excessive end product (feedback inhibition – DMG, SAM, SAH, Hcy)7. Genetic mutations/polymorphisms (MTHFR, GSTM1, PEMT, MAT, GAMT, SOD)

8. Mental state (stress, anxiety, lack of sleep)9. Receptor site blocking (folic acid, antibodies)10.Carrier protein deficiency (transcobalamin, folate binding proteins)11. Inflammation (TNF-alpha)12.Hormones (estrogen, cortisol)

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Clinical Look

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Promoters of Mast Cell Release• Adenosine• Cortisol• Pathogens - LPS

Conditions?

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What should you be asking??

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Stress

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“PET scans (show) diminished serotonin synthesis in children with ASD between the age of 2 - 5 years. The short-term depletion of L- tryptophan exacerbate(s) repetitive behaviour and elevate(s) anxiety in autistic individuals.” Rose’Meyer Molecular Autism 2013

Stress

Immune escape

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Autism – Prenatal Associated Risks

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Methylation and detoxification systems are poorer in mothers of Autistic children• SAH > 30 umol/L = 7.3 fold increased risk• SAM:SAH ratio < 2.5 = 10.7 fold increased risk• GSH:GSSG ratio < 20 = 15.2 fold increased risk• Both SAM:SAH and GSH:GSSG ratios off = 46 fold increased risk

Medications• Corticosteroids• Valproic acid• SSRI

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Patient Evaluation

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Methylation Dysfunction

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Conditions/History (some)• Bile stagnation• IBD, Constipation• Diabetes• Obesity• Fatty Liver (NASH)• Allergies / Asthma• Mental dysfunction• Cancer• Hispanic, Chinese, Italian descent• Reflux• Dental issues / Amalgams / Root Canals• Lyme, H pylori, Candida, EBV, Hep, Strep• Autoimmune• Eating disorders• Neurological disorders• Cardiovascular disorders

Lifestyle• Type A• Vegan• Vegetarian• Addictions• Hobbies• Commuter• Couch Potato• Premier Athlete• Occupational Exposures

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At-Risk Populations for Methylation Dysfunction

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Environment• Zipcode (www.scorecard.org)• New construction• Remodeling• Office/Employment• Mold• Gas/Propane/Exhaust• Cleaning supplies• Gardening supplies• Food• Water• Bedroom location• House orientation

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Screening

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Team Care – Request Charts Prior to Treatment• One Page Summary• History - thorough• Current Medications and Supplements (including OTC)• Diagnoses• Recent Lab Findings• Status of Children (autistic? DS? NTD?)

Labs (some)• 23andMe MTHFRSupport.com / Genetic Genie• CBC• Full thyroid with antibodies• CDSA (Doctors Data)• Urinary OAT (Great Plains)• Serum ferritin, vitamin D, fasting insulin, DHEA-S• RBC Fatty Acids and Plasma Amino Acids (Doctors Data)• Methylation Profile (Doctors Data)• ION Panel (Genova)

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Take Caution with MTHFR (you already know to avoid Folic Acid)

• Antacids (deplete B12)• Cholestyramine (deplete cobalamin and folate absorption)• Colestipol (decrease cobalamin and folate absorption)• Methotrexate (inhibits DHFR)• Nitrous Oxide (inactivates MS)• High Dose Niacin (depletes SAMe and limits pyridoxal kinase = active B6) • Theophylline (limits pyridoxal kinase = active B6)• Cyclosporin A (decreases renal function and increases Hcy)• Metformin (decreases cobalamin absorption)• Phenytoin / Valproic acid (folate antagonist)• Carbamazepine (folate antagonist)• Oral Contraceptives (deplete folate)• Antimalarials JPC-2056, Pyrimethamine, Proguanil (inhibits DHFR)• Antibiotic Trimethoprim (inhibits DHFR)• Ethanol• Bactrim (inhibits DHFR)• Sulfasalazine (inhibits DHFR)• Triamterene (inhibits DHFR)

Source: Fischbach, Laboratory Diagnosis and BMJ http://heart.bmj.com/content/83/2/127/T1.expansion.html and Herb, Nutrient and Drug Interactions by Stargrove

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Support Pathways!

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“Geez. Now what?”

48Contribution from Adam Rinde, ND

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Should we use folic acid?!NTD Associated Genes:1. MTHFR2. MTR3. MTRR4. CBS5. MTHFD16. RFC17. SLC19A18. DHFR9. SHMT110. TCN211. TYMS12. FOLH113. FOLR214. BHMT215. FOLR1

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Oxidative Stress & Mitochondrial Screening Glutathione Levels Enzyme Upregulation Ammonia Levels Vitamin Levels

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What did the doctor do? What happened here?

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Here is the consequence. What happened? How to restore?

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Folates: Which are off?

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61http://www.hdri-usa.com/tests/methylation/

mislabeled

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Systems Approach

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Have to do it ALL. Cannot cherry pick.

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Support Pathways

1. Remove2. Reduce3. Restore

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Interventions Prior to Pregnancy

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Implement on all patients• Breathing• Sleep schedule• Filtered water• Caffeine free or greatly reduce• Whole food meals: healthy fat, grass-fed meats, protein, veggies, few good carbs• Gluten and dairy free three week trial then challenge one at a time• Chewing• Read: The Metabolic Makeover• CoQ10• Liposomal Glutathione• Choline• Prenatal• Probiotic• D3• Adaptogens• Adrenal cortex• Exercise – rebounder, weights, resistance, yoga, Zumba• Sauna• Potassium• Magnesium

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Steps of Treatment

(c) 2014: Benjamin Lynch, ND

No Protocol – Think Systems – Do NOT Treat the SNP• Remove causes and exposures

• Food, Lifestyle, Environment, Social, Hobby, Employment, Meds, Supplements• Basic Foundational Support

• Food, Sleep, Hydration, Breathing, Exercise, Social, Nutritional• Identify all areas of dysfunction

• GI, adrenals, mitochondria, liver, cell membranes• Pathogens

• CDSA, OAT, Total IgG, IgM, IgE• Labs

• CBC w chem panel• Urinary hormones, (Precision Analytical)• Serum ferritin, TNFa• Methylation Profile• RBC Fatty acids• RBC Essential and Toxic Elements• Fasting insulin• DHEA-S• 24 hr Iodine and Spot

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Immediate Support (commonly)

1. Diet / Lifestyle / Environment (low histamine)

2. Adaptogens3. Adrenal4. Electrolytes5. Liver (castor oil, milk thistle, enema)

6. Thyroid (indirect ideally – iodine?)

7. B vitamins (no folate/B12 initially)

8. Trace Minerals (watch Fe, Cu)

9. Glutathione (start low dose)

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Reduces Catabolism & BurdenSupports many Pathways

http://booksite.elsevier.com/brochures/conap2/PDFs/Vol7Flavin-DependentEnzymes.pdf and http://lpi.oregonstate.edu/infocenter/vitamins/riboflavin/

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Key Points to Take to the Clinic

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1. Identify Obstacles and Remove2. Foundation / Basics3. Inform4. Prepare5. Team care6. Test – RBC Fatty Acids, Methylation Profile, 23andMe, MTHFR

Support, ION Panel7. Adrenals / Adapt8. Glutathione9. GI10. Pathogens11. Inflammation12. Mitochondrial support13. Sulfur tolerance (SUOX blocked?)14. Pathways and Systems – NOT Protocols or SNPs

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Three Points to Take to the Clinic

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1. Balance Methylation• Remove blockages• Reduce workload• Restore nutritionally

2. Screen for SNPs3. Test Methylation and restore balance – after Foundation

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Key Treatments to Recommend

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1. Castor oil packs2. Sauna3. Coffee enemas / Colonics4. Breathing5. Meditation6. Earthing7. Chewing8. NADH Test9. 80% Satiety

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Key Supplements to Use at the Clinic

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1. Adaptogens2. Liposomal Glutathione (start low)3. Phosphatidylcholine4. Electrolytes (w/ Ribose/Creatine/Taurine)

5. Fatty acids6. Multivitamin/mineral (to start - no folate, B12, Cu, Ca, Fe)7. Methylfolate w/ methyl/adenosylcobalamin (after foundation)

Throw away Folic Acid

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Great ways to stay informed:• Newsletter Available at www.MTHFR.net• Facebook: https://www.facebook.com/drbenjaminlynch• October 2013 Nutrigenomics Conference www.SeekingHealth.org • March 2014 Nutrigenomics Conference – www.SeekingHealth.org• Pathway Planner Poster and Set – www.SeekingHealth.org • Physician’s Forum for Collaboration – www.SeekingHealth.org

(c) 2014: Benjamin Lynch, ND

Thank you