Methylation: A Key to Optimizing Health and Longevity Presenter: Benjamin Lynch, ND Methylation Summit Denver, CO October 25, 2014 (c) 2014: Benjamin Lynch, ND

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

Why? (c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

Stress – likely worse with menses Depression / Insomnia (c) 2014: Benjamin Lynch, ND

Folate (c) 2014: Benjamin Lynch, ND

Source: Big Stock Photo

synthesis of nucleic acids (for DNA production/repair and tRNA) 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.” 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 (c) 2013: Benjamin Lynch, ND Source: Herb, Nutrient and Drug Interactions by Stargrove et al

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) (c) 2013: Benjamin Lynch, ND

Comparing Folic Acid to 5-Methyltetrahydrofolate CH3 METHYLFOLATE  (c) 2013: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

MTHFR: Why now? (c) 2014: Benjamin Lynch, ND

Survival of the ‘Unfittest’ 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. ↑ Susceptibility to Environmental Exposures UnNatural DeSelection: Survival of the ‘Unfittest’ (c) 2014: Benjamin Lynch, ND

“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.” (c) 2014: Benjamin Lynch, ND

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.” “Epigenetic changes are environmentally responsive mechanisms that can modify gene expression independently of the genetic code.” http://learn.genetics.utah.edu/content/epigenetics/ and Epigenetics and the developmental origins of inflammatory bowel diseases. (c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

Epigenetics and Methylation (c) 2014: Benjamin Lynch, ND

Methylation (c) 2014: Benjamin Lynch, ND

What is Methylation? The addition of a single carbon group with three hydrogens onto a compound (c) 2014: Benjamin Lynch, ND

URACIL ARSENIC

Arsenic. Big Deal. (c) 2014: Benjamin Lynch, ND

Several Functions of Methylation: Turn on and off genes (gene regulation) Process chemicals, endogenous and xenobiotic compounds (biotransformation – histamine, arsenic) Build neurotransmitters (norepinephrine  epinephrine, serotonin  melatonin) Metabolize neurotransmitters (dopamine, epinephrine) Process hormones (estrogen) Build immune cells (T cells, NK cells) DNA and Histone Synthesis (Thymine aka 5-methyluracil) Produce energy (CoQ10, carnitine, creatine, ATP) Produce protective coating on nerves (myelination) Build and maintain cell membranes (phosphatidylcholine) (c) 2013: Benjamin Lynch, ND

MTHF’R SAM (s-adenosylmethionine) FACTS After ATP, SAM is the most widely used enzymatic substrate in the body Primary methyl donor Requires methionine, ATP, magnesium for formation Requires zinc, betaine (or choline), methylcobalamin, methylfolate, FAD and NAD for remethylating homocysteine back to SAM Strongly inhibited by its end product - SAH SAH conversion to homocysteine, and adenosine, requires NAD SAH can be elevated even if homocysteine is not! If SAM production is disrupted, a plethora of pathologies may occur. If SAM cannot be utilized, a plethora of pathologies may occur. SAM production/recycle back up systems: MTR blocked? BHMT. BHMT blocked? MTR. Both blocked? MTHF’R (c) 2014: Benjamin Lynch, ND S-adenosyl-L-homocysteine hydrolase and methylation disorders: Yeast as a model system

Main Pathway Backup SAMe Excess (Low protein) (High protein) (c) 2014: Benjamin Lynch, ND

Methylation is often disturbed by various mechanisms How is Methylation Disturbed? Methylation is often disturbed by various mechanisms Lack of cofactors supporting methylation (Zinc, B2, Mg, Choline, B6, B12) Lack of substrate driving methylation forward (Methionine, Hcy) Medications (antacids, methotrexate, metformin, nitrous oxide) Specific nutrients depleting methyl groups (high dose Niacin) Environmental toxicity, heavy metals, chemicals (acetylaldehyde, mercury) Excessive end product (feedback inhibition – DMG, SAM, SAH, Hcy) Genetic mutations/polymorphisms (MTHFR, GSTM1, PEMT, MAT, GAMT, SOD) Mental state (stress, anxiety, lack of sleep) Receptor site blocking (folic acid, antibodies) Carrier protein deficiency (transcobalamin, folate binding proteins) Inflammation (TNF-alpha) Hormones (estrogen, cortisol) (c) 2013: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

Clinical Look (c) 2014: Benjamin Lynch, ND

Conditions? Promoters of Mast Cell Release Adenosine Cortisol Pathogens - LPS (c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

What should you be asking??

Stress (c) 2014: Benjamin Lynch, ND

Stress Immune escape (c) 2014: Benjamin Lynch, ND “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 (c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

Autism – Prenatal Associated Risks 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 (c) 2014: Benjamin Lynch, ND

Patient Evaluation (c) 2014: Benjamin Lynch, ND

Methylation Dysfunction 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 (c) 2014: Benjamin Lynch, ND

At-Risk Populations for Methylation Dysfunction Environment Zipcode (www.scorecard.org) New construction Remodeling Office/Employment Mold Gas/Propane/Exhaust Cleaning supplies Gardening supplies Food Water Bedroom location House orientation (c) 2014: Benjamin Lynch, ND

Team Care – Request Charts Prior to Treatment Screening 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) (c) 2014: Benjamin Lynch, ND

Cholestyramine (deplete cobalamin and folate absorption) 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 (c) 2014: Benjamin Lynch, ND

“Geez. Now what?” Support Pathways! (c) 2014: Benjamin Lynch, ND

Contribution from Adam Rinde, ND

Should we use folic acid?! NTD Associated Genes: MTHFR MTR MTRR CBS MTHFD1 RFC1 SLC19A1 DHFR SHMT1 TCN2 TYMS FOLH1 FOLR2 BHMT2 FOLR1 (c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

Test available through Doctors Data Oxidative Stress & Mitochondrial Screening Glutathione Levels Enzyme Upregulation Ammonia Levels Vitamin Levels Test available through Doctors Data (c) 2013: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

What did the doctor do? What happened here? (c) 2014: Benjamin Lynch, ND

Here is the consequence. What happened? How to restore? (c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

(c) 2013: Benjamin Lynch, ND

Folates: Which are off? (c) 2014: Benjamin Lynch, ND

http://www.hdri-usa.com/tests/methylation/ mislabeled (c) 2014: Benjamin Lynch, ND http://www.hdri-usa.com/tests/methylation/

Systems Approach Have to do it ALL. Cannot cherry pick. (c) 2014: Benjamin Lynch, ND

Remove Reduce Restore Support Pathways (c) 2014: Benjamin Lynch, ND

Interventions Prior to Pregnancy 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 (c) 2014: Benjamin Lynch, ND

Steps of Treatment 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 (c) 2014: Benjamin Lynch, ND

Reduces Catabolism & Burden Supports many Pathways Immediate Support (commonly) Diet / Lifestyle / Environment (low histamine) Adaptogens Adrenal Electrolytes Liver (castor oil, milk thistle, enema) Thyroid (indirect ideally – iodine?) B vitamins (no folate/B12 initially) Trace Minerals (watch Fe, Cu) Glutathione (start low dose) Reduces Catabolism & Burden Supports many Pathways http://booksite.elsevier.com/brochures/conap2/PDFs/Vol7Flavin-DependentEnzymes.pdf and http://lpi.oregonstate.edu/infocenter/vitamins/riboflavin/ (c) 2014: Benjamin Lynch, ND

Key Points to Take to the Clinic Identify Obstacles and Remove Foundation / Basics Inform Prepare Team care Test – RBC Fatty Acids, Methylation Profile, 23andMe, MTHFR Support, ION Panel Adrenals / Adapt Glutathione GI Pathogens Inflammation Mitochondrial support Sulfur tolerance (SUOX blocked?) Pathways and Systems – NOT Protocols or SNPs (c) 2014: Benjamin Lynch, ND

Three Points to Take to the Clinic Balance Methylation Remove blockages Reduce workload Restore nutritionally Screen for SNPs Test Methylation and restore balance – after Foundation (c) 2014: Benjamin Lynch, ND

Key Treatments to Recommend Castor oil packs Sauna Coffee enemas / Colonics Breathing Meditation Earthing Chewing NADH Test 80% Satiety (c) 2014: Benjamin Lynch, ND

Key Supplements to Use at the Clinic Adaptogens Liposomal Glutathione (start low) Phosphatidylcholine Electrolytes (w/ Ribose/Creatine/Taurine) Fatty acids Multivitamin/mineral (to start - no folate, B12, Cu, Ca, Fe) Methylfolate w/ methyl/adenosylcobalamin (after foundation) Throw away Folic Acid (c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

(c) 2014: Benjamin Lynch, ND

Thank you 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 If our environment and diet are healthy – then the MTHFR SNP is not so significant.