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2
3. Dr. Russell Jaffe, MD, Ph.D., CCN
FASCP,
FACN,
FACAAI,
FOCIS,
FAMLI,
FRSM
Fellow,
Health Studies Collegium
Director,
PERQUE Integrative Health &
ELISA/ACT Biotechnologies, LLC
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4. What is Methylation?
Complex biological process: fuel for the body
Transfer or donation of one carbon methyl
group (-CH3) to other molecules
• Methyl donors
• Methyl acceptors
• Methyl carriers/factors
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5. What is Methylation?
Methylation acceptors need methyl carriers
and donors
Methyl acceptors: nucleic acids/DNA, RNA, Proteins,
Phospholipids, Bile salts, Biological amines
Methyl carriers: Vitamins B6, B12,folate, magnesium
ascorbate
Methyl donors: methionine, S-adenosylmethionine
(SAMe), betaine (trimethylglycine).
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7. Methylation deficits
Deficiency of methylation
factors and donors
Impaired protection
Reduced detoxification
Lack of mitochondrial
energy
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8. Clinical manifestations of hyperhomocysteinemia
• Cardiovascular health coronary artery
disease, renovascular hypertension,
thrombotic and embolic events (stroke).
• CNS effects: Vascular dementia, increased
risk of multiple brain infarcts and
Alzheimer’s senility.
• Bone Health: strong link with bone mineral
density, bone blood flow
Boers GHJ, et al. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. New Engl J Med 1985; 313:709-715.
Refsum H, Nurk E, etal The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J
Nutr. 2006 Jun; 136(6 Suppl): 1731S-1740S
Neetu Tyagi, Thomas P Vacek, John T Fleming, et al. Hyperhomocysteinemia decreases bone blood flow. Vascular Health and Risk Management,January 2011
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Volume 2011:7 Pg 31 – 35. (DOI: http://dx.doi.org/10.2147/VHRM.S15844)
9. Clinical manifestations of hyperhomocysteinemia
• Cancer: both increased and
decreased DNA methylation
involved
• Other
• Chronic Fatigue Syndrome/
Fibromyalgia/muscle pain
• PMS symptoms
Kim YI, et al. Global DNA Hypomethylation increases progressively in cervical dysplasia and carcinoma Cancer 1994; 74:893-899.
Regland B, et al. Homocysteinosis in the central nervous system in patients with fibromyalgia/chronic fatique syndrome. Abstr Intern Conf
Homocysteine Metabol 1995; Dromoland Castle, County Clare, Ireland, July 2-6.
Cooney C, et al. Methyl magic: maximum health through methylation. Andrew McMeel Publishing, Kansas City, Missouri, 1999.
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10. Cardiovascular Epigenetics
Andrea Baccarelli, Michiel Rienstra Emelia J. Benjamin. Cardiovascular Epigenetics Basic Concepts and Results From Animal
and Human Studies. Circulation: Cardiovascular Genetics. 2010; 3: 567-573. 10
11. Cardiovascular Epigenetics
DNA methylation
Primary regulator of inflammation
Homocysteine C-Reactive protein
atherosclerosis,
hypertension, and
diabetes
Andrea Baccarelli, Michiel Rienstra Emelia J. Benjamin.
Cardiovascular Epigenetics Basic Concepts and Results From Animal
and Human Studies. Circulation: Cardiovascular Genetics. 2010; 3:
567-573. 11
12. Effect of Homocysteine Levels on Survival in CHD
<6 mol/L
<9 mol/L
9-15 mol/L
16X
4X
15-20 mol/L
>20 mol/L
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13. Methyl Carriers
• Vitamin B6
• Vitamin B12: hydroxocobalamin : preferred form
• Folate: Natural folates, not synthetic folic acid
• Magnesium ascorbate
Adequate levels help keep
methyl donors at optimum levels
Methionine, SAMe, betaine (trimethylglycine)
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14. Healthy Methylation
B6, B12, folates
Difference in Five-Year Mortality Risk
1000%
R e la t iv e R is k (in % )
800%
The Difference in Senility Risk
600%
200%
S e n ility R is k (in % )
400%
100%
200%
0%
0%
<6.5 6.5-9 9. - 12. 12. - 15 >15 <6.5 >15
Relative Risk of Senility in Relation to
Relative Risk at Different Homocysteine Levels Homocysteine Levels
Arch Chem. 2004;50:3-32. and Arch Intern Med 2003;163:1933-1937. Schroecksnadel K, et. al. Hyperhomocysteinemia and immune activation.
Clin Chem Lab Med 2003; 41(11):1438-1443.
NEJM. 2002;346:476-483.
15. Methylation and autism
• Vitamin
insufficiency
• Increased
oxidative
stress
• Reduced
capacity for
energy
transport,
sulfation &
detoxification
Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, Geis E, Gehn E, Loresto M, Mitchell J, Atwood S, Barnhouse S, Lee W.
Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metab
(Lond). 2011 Jun 8;8(1):34.
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16. DNA methylation and immune system
DNA methylation patterns
have relevance in immune
function.
Restoring methylation can
strengthen immune
system-related therapies
Suarez-Alvarez B, Rodriguez RM, Fraga MF, López-Larrea C.DNA methylation: a promising landscape for immune
system-related diseases.Trends Genet. 2012 Oct;28(10):506-14. Epub 2012 Jul 21.
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17. Overloaded Immune System means:
• Chronic illness
• Inflammation = Repair deficits
• Increase in digestive remnants
• Chronic, degenerative,
autoimmune illness
Jaffe R. Immune Defense and Repair Systems in Biologic Medicine: Clinical Relevance of Biological Response Modifiers in
Autoimmunity: Diagnosis, Treatment, Tests, and Interpretation (Part I). Townsend Letter for Doctors and Patients 2009; Oct: 82-89.
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18. Healthy Immune Responses
• No allergies = tolerance
• Neutralizes infections & allergens
• Repairs us from daily damage
• Deletes cancer cells
White blood cell recycles pathogens
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19. Allergy Laboratory Tests
Type I Allergies
RAST or skin tests
Delayed Allergies
Lymphocyte response
assay needed to tell
‘good’ from ‘bad’
e.g. LRA by ELISA/ACT
covers all delayed
pathways
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20. Predictive Lab Tests
with Healthy Goal values
• Homocysteine <6 µmol/L for methylation, detox
• CRP <0.5 mg/dl for repair deficit inflammation
• Oxidative stress antioxidant sufficiency: Goal
Oxidized LDL/HDL & 8-oxo-guanine absent
• LRA by ELISA/ACT delayed allergy
functional tests and treatment plans
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21. Immune System: Enhance; Stop Burden
Hospitable host to pathogens = Tolerance lost
Allergens provoke symptoms:
Overload of Foreign Reactive Antigens
Repair deferred…defense 1st
Only Functional tests can identify
causes of immune overload…
go by results
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22. Physiology 1st approach
Immune System: Reset, Renew, Repair, & Restore Tolerance
Comprehensive Plan:
• Lower burden by substituting reactives
• Bioavailable nutritional supplements
• Life long health the Alkaline Way
Health Studies Collegium, The Joy of Food The Alkaline Way Guide, 18th ed. 2009-2010
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24. To Your Health
“Health is more than the absence of
disease. Health is the fullest physical,
mental, and spiritual expression attainable
by each individual."
Russ Jaffe paraphrasing
Hippocrates, Galen, Huang Ti, & WHO
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25. Health Studies Collegium
Questions Welcome
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