Beyond Pathological Calcification

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Beyond Pathological Calcification

• Strategies for Coping with the Effects of
  Glycation, Oxidation and Inflammation on Cellular
  Aging

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David B. Wood, ND BSc. Univ of WA
(Microbiology) 1977 ND. Bastyr Univ.
1983 Cofounder, Vice President,
CMO BioGenesis Nutraceuticals, Inc.(2000 - )
Cofounder, President Trinity Family
Health Clinic, PS (1984 - ) Functional
Medicine Forum - 2006
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Factors Affecting Aging

• Chronic Inflammation
• Excess or pathological Calcification
• Glycation
• Methylation Deficit
• Mitochondrial Energy Depletion
• Hormone Imbalance
• Fatty Acid Imbalance

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• DNA Mutation
• Immune Dysfunction
• Non-Digestive Enzyme Imbalance (intracellular)
• Digestive Enzyme Deficit
• Excitotoxicity
• Circulatory Deficit
• Oxidative Stress

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In this lecture I will discuss how specific
nutraceutical interventions can help offset the
aging effects of glycation (AGEs) and its
concomitant effects on oxidation and inflammation
on our cellular structure, glands and
organs. Benefits positively affecting health,
vitality and longevity can be achieved with a
healthy lifestyle (diet, nutrition, exercise,
stress reduction) and specific nutraceutical
intervention .
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• Advanced Glycation Endproducts (AGE)
• When proteins are exposed to elevated levels of
  glucose the following series of non-enzymatic
  chemical reactions occur
• Glycation of proteins and formation of both
  Amadori adducts and AGE compounds can have
  biological consequences
• Glycation Rearrangement
  Cross-linking
• hours days
  weeks/months
• Glucose Glycated Amadori
  proteins
  Adducts AGES
• Protein-NH2 (Schiff Base)
• Cell Activation
• Tissue Structural Changes

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Glycation

• Occurs in everyone, but at a faster rate in
  diabetics
• Has devastating effects on the health of our
  tissues
• Most evident in
• Senile dementia
• Stiffening of the arterial system
• Degenerative diseases of the eye

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Some outward examples of AGEs
Not us!
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Negative Aspects of AGEs
Good News! When added to living cell cultures,
carnosine extends their life span. When added to
decrepit aged cells, it rejuvenates them.
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AGEx (Advanced Glycation Endproduct inhibitor)
Each 4 capsules contain L-Carnosine
1000mg Galega officinalis (50 guanidine with
negligible content of galegine) 500mg L-Arginine
300mg DMAE (dimethylaminoethanol) 300mg Ascor
bic acid 100mg PABA (para aminobenzoic
acid) 100mg Vit E (d-alpha tocopheryl
succinate) 200IU Thiamine HCl
50mg Alpha R Lipoic acid 50mg Pyridoxal 5
phosphate 35 mg Take 2 capsules two
times per day without food or as directed.
RecommendationTake AGEx with Glucostat
multivitamin/mineral and a diet made with low
glycemic functional foods and dietary
foods. 120ct
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L-Carnosine (B-alanyl-L-histidine)

• Naturally occurring di-peptide
• Found in muscle, brain, innervated tissues, lens
  and other tissues
• Powerful antioxidant
• Singlet oxygen, hydrogen peroxide, peroxyl and
  hydroxyl radicals
• Inhibits free radical induced damage from iron,
  copper and zinc
• Powerful anti-glycation agent
• Activates myofibillar ATPase enhancing muscle
  contractions

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• Increases cellular energy by enhancing
  mitochondrial oxidative energy production (ATP)
• Average dietary intake 50 250 mg from one
  serving of beef, pork or chicken (3-4 ounces)
• Therapeutic intake (supplemental)
• 1000 mg QD
• Protects SOD from oxidation
• Prevents accumulation of age-related free
  radicals

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L-Carnosine (B-alanyl-L-histidine)

• May protect against oxidative stress associated
  w/Alzheimers Dz
• Protects neuronal and endothelial cells from
  damage
• Has anti-glycating properties
• Improves memory in Alzheimers
• Improves cognition in Alzheimers
• Protects against malondialdehyde toxicity
• Provides protection to cells and molecules from
  free radical damage

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• Delays aging in human cells
• Protects against toxic aldehydes. Thus offers
  protection from diabetes complications,
  inflammatory ailments, and ETOH related liver
  disease
• Positive affect on healthy protein metabolism
• Positive affect on cellular homeostasis
• Prevents development of senility features
• Aids in wound healing (Its degradation product,
  B-Alanine, enhances collagen production)

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• Enhances the immune system
• Reduces lactic acid accumulation
• Promotes muscle recovery, enhancing athletic
  performance
• Anti-hypertensive effects
• Reduces lipid peroxide production and inhibits
  LDL C oxidation
• Source - Life Extension Carnosine overview
• www.lef.org

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Impaired reverse cholesterol transport
Facilitation of oxidation
Toxicity to endothelium
Impaired esterbation of cholesterol
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Calcification often accompanies glycation!
Nanobacteria, C. Pneumoniae
Chicken or Egg?
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L-Carnosine (B-alanyl-L-histidine)

• Stvolinskii SL, Fedorova TN, Yuneva MO, Boldyrev
  AA. Protective effect of carnosine on Cu,
  Zn-superoxide dismutase during impaired oxidative
  metabolism in the brain in vivo. Institute of
  Neurology, Russian Academy of Medical Sciences,
  Moscow. Bull Exp Biol Med. 2003
  Feb135(2)130-2.
• Dukic-Stefanovic S, Schinzel R, Riederer P, Munch
  G. AGES in brain aging AGE-inhibitors as
  neuroprotective and anti-dementia drugs?
  Pysiological Chemistry 1, Biocenter, Univ of
  Wurzberg, Germany. Biogerontology
  20012(1)19-34.
• Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H,
  Sohal RS. Age-related losses of cognitive
  function and motor skills in mice are associated
  with oxidative protein damage in the brain.
  Dept. of Pharmacology, Univ. of N. Texas Health
  Science Center, Fort Worth, TX. Proc Natl Acad
  Scid. 1996 May 1493(10)4765-9.

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• Gulyaeva NV, Dupin AM, Levshina IP. Carnosine
  prevents activation of free-radical lipid
  peroxidation during stress. Bull Exp Biol Med.
  1989 107(2)148-152.
• Horning MS, Blakemore LJ, Trombley PQ.
  Endogenous mechanisms of neuroprotection role of
  zinc, copper, and carnosine. Brain Res 2000 Jan
  3852(1)56-61.
• Our results demonstrate that carnosine can
  rescue neurons from zinc- and copper-medicated
  neurotoxicity and suggest that one function of
  carnosine may be as an endogenous neuroprotective
  agent
• Boldyrev A, Song R, Lawrence D, Carpenter DO.
  Carnosine protects against excitotoxic cell death
  independently of effects on reactive oxygen
  species. Neuroscience. 199994(2)571-7.

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Pluripotent protective effects of carnosine, a
naturally occurring dipeptide

• Selected quotes from this study
• Evidence will be presented to suggest that
  carnosine, in addition to antioxidant and oxygen
  free-radical scavenging activities, also reacts
  with deleterious aldehydes to protect susceptible
  macromolecules. Our studies show that, in vitro,
  carnosine inhibits nonenzymic glycosylation and
  cross-linking of proteins induced by reactive
  aldehydes (aldose and ketose sugars, certain
  triose glycolytic intermediates and
  malondialdehyde (MDA), a lipid peroxidation
  product).

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Hipkiss AR, Preston JE, Himsworth DT, Worthington
VC, Keown M, Michaelis J, Lawrence J, Mateen A,
Allende L, Eagles PA, Abbott NJ. Pluripotent
protective effects of carnosine, a naturally
occurring dipeptide. Ann NY Acad Sci. 1998 Nov
2085437-53.

• We propose that carnosine (which is remarkably
  nontoxic) or related structures should be
  explored for possible intervention in pathologies
  that involve deleterious aldehydes, for example
  secondary diabetic complications, inflammatory
  phenomena, alcoholic liver disease, and possibly
  Alzheimers disease.

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• Sztanke K, Pasternak K. The Maillard reaction
  and its consequences for a living body. Ann Univ
  Mariae Curie Sklodowska Med 200358(2)159-162.
• Wautier JL, Schmidt AM. Protein glycation a
  firm link to endothelial cell dysfunction. Circ
  Res. 2004 Aug 695(3)233-8.
• Loeser RF, Jr. Aging cartilage and
  osteoarthritis whats the link? Sci Aging
  Knowledge Environ. 2004 Jul 212004(29)e31.
• Seidler NW, Yeargans GS, Morgan TG. Carnosine
  disaggregates glycated alpha-crystallin an in
  vitro study. Arch Biochem Biophys. 2004 Jul
  1427(1)110-15.
• Dukic-Stefanovic S, Schinzel R, Riederer P, Munch
  G. AGES in brain ageing AGE- inhibitors as
  neuroprotective and antidementia drugs?
  Biogerontology. 20012(1)19-34.

Betty Crocker Slow-Cook Oven
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Beyond Carnosine

• Compounds that Inhibit Sugar attachment to
  Protein (Glycation)
• Pyridoxal 5 phosphate
• ASA (Aspirin)
• Compounds that Inhibit or Block formation of
  Crosslinks
• Guanidine (Goats Rue Galega officinalis)
• Aminoguanidine
• Compounds that Trap reactive Carbonyl
  Intermediates
• (CO compounds lead to AGEs)
• Guanidine(Galega)/Aminoguanidine, Carnosine,
  L-Arginine

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• Chelating Agents that inhibit conversion of
  Schiff Bases to Amadori Products
• EDTA (Liposomal oral EDTA, rectal suppository or
  IV)
• Penicillamine
• Antioxidant Agents that inhibit conversion of
  Schiff Bases to Amadori Products
• Vitamin C
• Vitamin E
• Lipoic Acid

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• Botanical Antioxidants that may inhibit
  conversion of Schiff Bases to Amadori products
• Green Tea, Hawthorn, Grape Seed, Milk Thistle,
  Ginger Root, Ginkgo
• Aboca provides these botanicals as organic cold
  processed, freeze-dried whole phytocomplex
  concentrates!
• Compounds that Inhibit formation of Amadori
  Products
• Guanidine (Galega)/Aminoguanidine

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EDTA Penicillamine Vit C, E, ARLA
Galega Guanidine Aminoguanidine
Glucose Glycated Amadori
proteins
Adducts AGES Protein-NH2 (Schiff Base)
Pyridoxal 5 Phosphate Aspirin
Reactive Intermediates CO
Galega Guanidine Aminoguanidine Carnosine L-Argini
ne
Galega Guanidine Aminoguanidine
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Pyridoxal 5 phosphate

• Bioactive form of Vitamin B6
• Significantly reduces non-enzymatic glycation of
  proteins
• Inhibits AGE formation
• Exceeded only by aminoguanidine

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Thiamine

• Vitamin B1 or thiamine is the parent compound for
  the development of a promising new compound
  ALT-711.
• This compound shows promise in being able to
  UNDUE existing crosslinked proteins.
• Thiamine is an effective crosslink breaker
  (Pearson and Shaw)
• Breaking existing crosslinks has been shown to
  improve arterial elasticity.

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Galega officinalis (Goats Rue)

• Historical use for Diabetic treatment for
  centuries
• Contains Guanidine which results in its
  glucose/insulin regulating properties
• Insulin sensitizing, glucose lowering
• Safe Galega should have negligible content of
  galegine. Galegine may cause nasal discharge and
  blood pressure lowering.
• Metformin (Glucophage) antidiabetic biguanide
  derived from Galega officinalis.

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Alpha R-Lipoic Acid

• Strong antioxidant protection and enhanced
  antioxidant recycling
• Enhanced biological energy production
• Fat and water soluble
• Natural form
• Claims that lipoic acid slows aging of the brain
  and has anti-aging benefits seem to be related to
  is potent antioxidant properties
• Reduces production of Amadori adducts

• Packer L, Tritschler HJ, Wessel K.
  Neuroprotection by the metabolic antioxidant
  alpha-lipoic acid. Free Rad Biol Med. 1997
  22359-378.

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Antioxidants and Neuroprotection

• Vitamin E
• Alpha R Lipoic Acid
• Coenzyme Co Q10

Antioxidants reduce formation of Amadori adducts
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Vitamin E and Cognitive Decline in Older Persons

• There was a 36 reduction in the rate of decline
  among persons in the highest quintile of total
  vitamin E intake (-4.3 x 10(-2) standardized
  units per year) compared with those in the lowest
  quintile (-6.7 x 10(-2) standardized units per
  year) (P .05), in a model adjusted for age,
  race, sex, educational level, current smoking,
  alcohol consumption, total calorie (energy)
  intake, and total intakes of vitamin C, carotene,
  and vitamin A. We also observed a reduced decline
  with higher vitamin E intake from foods (P .03
  for trend). There was little evidence of
  association with vitamin C or carotene intake.
• CONCLUSION Vitamin E intake, from foods or
  supplements, is associated with less cognitive
  decline with age.
• Arch Neurol 2002 Jul59(7)1125-32

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DMAEDimethyl amino ethinol

• Alleviates behavioral problems and hyperactivity
  associated with Attention Deficit Disorder (ADD)
• Made naturally in the brain
• Increases attention span
• Decreases aggression
• Improves learning ability
• Occassionally shows increase in IQ (70 of ADD
  patients)

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DMAE

• Inhibits and reverses cross-linking of proteins
• Facilitates removal of lipofuscin from neurons
  and skin (age spots)
• Increases alertness
• Alleviates anxiety
• Reduces apathy and increases motivation
• Improves interhemispheric flow of information in
  the corpus callosum thereby improving creativity
  and verbal fluency
• Improves behavior and mental function in Downs
  syndrome children

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DMAE

• Improves memory and learning
• Elevates mood
• Reduces sleep need by 1 hour after 6 weeks of
  use
• Dreams become more lucid (vivid)
• Sleep is sounder with clearer head on waking and
  more refreshed
• Enhances Acetylcholine levels within the brain
• Increases RNA in the brain (rat research)
• Increases Choline levels within the brain due to
  DMAEs superior ability to cross the Blood-Brain
  Barrier

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DMAE

• References
• Coleman N, et al. DMAE in the treatment of
  hyperactive children. Psychosomatics 1768-72,
  1976.
• Oettinger L. The use of DMAE in the treatment of
  disorders of behavior in children. J Pediatrics.
  53671-675, 1958.
• Cedar G, et al. Effects of 2-Dimethylaminoethanol
  (DMAE) on the metabolism of choline in plasma.
  J Neurochemistry. 301293-1296, 1978.
• Zs-Nagy, I, et al. On the role of cross-linking
  of cellular proteins in aging. Mech Agi Dev.
  14245-251, 1980.
• Hochschile R. Effect of dimethylaminoethanol on
  the life span of senile male A/J mice. Exp
  Gerontol, 1973, 8 4, 185-191.

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• Also present in

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PABA (para amino benzoic acid)

• Antioxidant
• Quenches singlet oxygen
• Provides protection against
• Ozone
• Smoking
• Other air pollutants
• Anti-Crosslinking Agent
• Appears to slow or reverse crosslinking in
  protein connective tissue structures (ie.
  Collagen)

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PABA

• Anti-Aging
• Promotes greater flexibility
• Useful in Tx of vitiligo (a depigmenting disease)
• Helps prevent graying of hair or restore normal
  hair color in 10-25 of patients
• Reduces fibrotic processes
• Peyronnies disease
• Dupuytrens contracture
• Scleroderma

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Some PABA references

• Zarafonetis C. Darkening of gray hair during
  para-amino-benzoic acid therapy. J Invest Derm,
  399-401.
• Allen JM. Rapid Reaction of Singlet Oxygen with
  P-Aminobenzoic Acid (PABA) in Aqueous Solution.
  Biochem Biophys Res Commun, July 1995.
• Bjorksten J. Crosslinkage and the aging process,
  in Theoretical Aspects of Aging, by Morris
  Rockstein (ed), Academic Press, NY, 1974.
• Zarafonetis C. Antifibrotic Therapy with POTABA.
  Am J of Med Sci, 1964, 248550-561
• Dean W. DMAE and PABA, An Alternative to
  Gerovital (GH3), the Romanian Youth Drug. Vit
  Res Prod. (vrp.com)

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Additional References

• Carpenter D. Correction of biological aging.
  Rejuvenation, 1980,731-49
• Bjorksten J. Possibilities and limitations of
  chelation as a means for life extension.
  Rejuvenation, 1980, 867-72.
• Zinsser J, Butt EM, Leonard I. Metal content
  correlation in aging aorta. J Am Geriatrics Soc,
  1957, 520-26.
• Chappell LT, Stahl JP, Evans R. EDTA Chelation
  treatment for vascular disease A Meta-Analysis
  using unpublished data. J Adv Med, 1994, 7 3,
  131-142.

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BioGenesis products to consider for Anti-Aging

• AGEx
• Liposomal EDTA
• CogniFactors
• Aboca botanicals Green Tea, Hawthorn, Grape
  Seed, Milk Thistle, Ginger Root, Ginkgo
• Vitamin E, Alpha R Lipoic Acid, Coenzyme CoQ10,
  Seleno ExCell, Oxy ATP, Cardio Complete, High
  ORAC Berry Blend

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Contacts for Dr. David Wood dwoodnd_at_bio-genesis.co
m dwoodnd_at_trinityclinic.com
May your practices and your patients be blessed
by your care