Transcript Beyond Pathological Calcification

Beyond Pathological Calcification:
Strategies for Coping with the
Effects of Glycation, Oxidation and
Inflammation on Cellular Aging
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
Factors Affecting Aging
 Chronic Inflammation
 Excess or pathological Calcification
 Glycation
 Methylation Deficit
 Mitochondrial Energy Depletion
 Hormone Imbalance
 Fatty Acid Imbalance
 DNA Mutation
 Immune Dysfunction
 Non-Digestive Enzyme Imbalance (intracellular)
 Digestive Enzyme Deficit
 Excitotoxicity
 Circulatory Deficit
 Oxidative Stress
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 .
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
Glucose
+
Protein-NH2
Glycation
Rearrangement
Cross-linking
hours
days
weeks/months
Glycated
proteins
Amadori
Adducts
(Schiff Base)
Cell Activation
Tissue Structural Changes
AGES
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
Some outward examples of
AGEs
Negative Aspects of AGEs
Wrinkles
Cataracts
Arthritis
Erectile
Dysfunction
Chemokines,
Cytokines and
Adhesion
Molecoles toxic
to neurons
Key role in
development of
Cognitive
decline and
Alzheimer’s Dz
Oxidize Tau
proteins
Neurofibrillary
tangles assoc
w/Alzheimer’s
Collagen and Elastin
lose their suppleness
Trigger
Inflammatory
Reactions
Skeletal muscle
Carnosine
content ‘s 63%
from age 10 to
age 70
Good News! When added to living cell
cultures, carnosine extends their life span.
When added to decrepit aged cells, it
rejuvenates them.
AGEx
(Advanced Glycation Endproduct inhibitor)
Each 4 capsules contain:
L-Carnosine
Galega officinalis
(50% guanidine with negligible content of galegine)
L-Arginine
DMAE (dimethylaminoethanol)
Ascorbic acid
PABA (para aminobenzoic acid)
Vit E (d-alpha tocopheryl succinate)
Thiamine HCl
Alpha R Lipoic acid
Pyridoxal 5’ phosphate
1000mg
500mg
300mg
300mg
100mg
100mg
200IU
50mg
50mg
35 mg
Take 2 capsules two times per day without food or as directed.
Recommendation:Take AGEx with Glucostat multivitamin/mineral and a diet
made with low glycemic functional foods and dietary foods.
120ct
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

 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
L-Carnosine (B-alanyl-L-histidine)
 May protect against oxidative stress associated
w/Alzheimer’s Dz
 Protects neuronal and endothelial cells from damage
 Has anti-glycating properties
 Improves memory in Alzheimer’s
 Improves cognition in Alzheimer’s
 Protects against malondialdehyde toxicity
 Provides protection to cells and molecules from free
radical damage
 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, BAlanine, enhances collagen production)
 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 -
www.lef.org
Life Extension – Carnosine overview
Impaired
reverse
cholesterol
transport
Facilitation of
oxidation
Toxicity to
endothelium
Impaired
esterbation
of cholesterol
Calcification often accompanies
glycation!
L-Carnosine (B-alanyl-L-histidine)
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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 Feb;135(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 2001;2(1):19-34.
Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H, Sohal RS. Agerelated 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 14;93(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 3;852(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. 1999;94(2):571-7.
“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).”

 “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
Alzheimer’s disease.”
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 20;854:37-53.
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Sztanke K, Pasternak K. The Maillard reaction and its
consequences for a living body. Ann Univ Mariae Curie Sklodowska
[Med] 2003;58(2):159-162.
Wautier JL, Schmidt AM. Protein glycation:
a firm
link to endothelial
“Betty
Crocker
cell dysfunction. Circ Res. 2004 Aug 6;95(3):233-8.
Slow-Cook
Loeser RF, Jr. Aging cartilage and osteoarthritis
Oven”– what’s the link?
Sci Aging Knowledge Environ. 2004 Jul 21;2004(29):e31.
Seidler NW, Yeargans GS, Morgan TG. Carnosine disaggregates
glycated alpha-crystallin: an in vitro study. Arch Biochem Biophys.
2004 Jul 1;427(1):110-15.
Dukic-Stefanovic S, Schinzel R, Riederer P, Munch G. AGES in brain
ageing: AGE- inhibitors as neuroprotective and antidementia
drugs? Biogerontology. 2001;2(1):19-34.
Beyond Carnosine

Compounds that Inhibit Sugar attachment to Protein
(Glycation)
Pyridoxal 5’ phosphate
ASA (Aspirin)

Compounds that Inhibit or Block formation of Crosslinks
Guanidine (Goat’s Rue – Galega officinalis)
Aminoguanidine

Compounds that Trap reactive Carbonyl Intermediates
(C=O compounds lead to AGEs)
Guanidine(Galega)/Aminoguanidine, Carnosine, L-Arginine
 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
 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
EDTA
Galega
Penicillamine
Guanidine
Vit C, E, ARLA
Glucose
+
Glycated
proteins
Protein-NH2
(Schiff Base)
Amadori
Adducts
Aminoguanidine
Pyridoxal 5’
Phosphate
Reactive
Aspirin
Intermediates
C=O
AGES
Pyridoxal 5’ phosphate
 Bioactive form of Vitamin B6
 Significantly reduces non-enzymatic
glycation of proteins
 Inhibits AGE formation
 Exceeded only by aminoguanidine
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.
Galega officinalis (Goat’s 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.

Alpha R-Lipoic Acid
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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;
22:359-378.
Antioxidants and Neuroprotection
 Vitamin E
 Alpha R Lipoic Acid
 Coenzyme Co Q10
Antioxidants
reduce formation
of Amadori
adducts
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 Jul;59(7):1125-32
DMAE:
Dimethyl 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)
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 Down’s
syndrome children

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 DMAE’s
superior ability to cross the Blood-Brain Barrier

DMAE
References:
Coleman N, et al. DMAE in the treatment of hyperactive children.
Psychosomatics 17:68-72, 1976.
 Oettinger L. The use of DMAE in the treatment of disorders of
behavior in children. J Pediatrics. 53:671-675, 1958.
 Cedar G, et al. Effects of 2-Dimethylaminoethanol (DMAE) on the
metabolism of choline in plasma. J Neurochemistry. 30:12931296, 1978.

 Zs-Nagy, I, et al.
On the role of cross-linking of
cellular proteins in aging. Mech Agi Dev. 14:245251, 1980.
 Hochschile R. Effect of dimethylaminoethanol on
the life span of senile male A/J mice. Exp
Gerontol, 1973, 8: 4, 185-191.
Also present in:
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)
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
Some PABA references
Zarafonetis C. Darkening of gray hair during para-aminobenzoic acid therapy. J Invest Derm, 399-401.
 Allen JM. Rapid Reaction of Singlet Oxygen with PAminobenzoic 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, 248:550-561
 Dean W. DMAE and PABA, An Alternative to Gerovital
(GH3), the Romanian Youth Drug. Vit Res Prod. (vrp.com)

Additional References
Carpenter D. Correction of biological aging.
Rejuvenation, 1980,7:31-49
 Bjorksten J. Possibilities and limitations of chelation as
a means for life extension. Rejuvenation, 1980, 8:6772.
 Zinsser J, Butt EM, Leonard I. Metal content correlation
in aging aorta. J Am Geriatrics Soc, 1957, 5:20-26.
 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.

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
Contacts for Dr. David Wood
[email protected]
[email protected]
“May your practices and your
patients be blessed by your
care”