beyond pathological calcification: strategies for coping with the effects of glycation, oxidation...
TRANSCRIPT
Beyond Pathological Calcification:
Beyond Pathological Calcification:
Strategies for Coping with the Effects of Glycation, Oxidation and Inflammation on Cellular
Aging
David B. Wood, NDDavid B. Wood, ND
BSc. Univ of WA (Microbiology) 1977BSc. Univ of WA (Microbiology) 1977
ND. Bastyr Univ. 1983ND. Bastyr Univ. 1983
Cofounder, Vice President, CMO:Cofounder, Vice President, CMO:
BioGenesis Nutraceuticals, Inc.(2000 BioGenesis Nutraceuticals, Inc.(2000 - )- )
Cofounder, President:Cofounder, President:
Trinity Family Health Clinic, PS (1984 - Trinity Family Health Clinic, PS (1984 - ))
Functional Medicine Forum - 2006Functional Medicine Forum - 2006
Factors Affecting AgingFactors 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 In this lecture I will discuss how specific nutraceutical specific nutraceutical interventions can help offset the interventions can help offset the aging effects of glycation (AGEs) aging effects of glycation (AGEs) and its concomitant effects on and its concomitant effects on oxidation and inflammation on oxidation and inflammation on our cellular structure, glands our cellular structure, glands and organs.and organs.
Benefits positively affecting health, Benefits positively affecting health, vitality and longevity can be vitality and longevity can be achieved with a healthy lifestyle achieved with a healthy lifestyle (diet, nutrition, exercise, stress (diet, nutrition, exercise, stress reduction) and specific nutraceutical reduction) and specific nutraceutical interventionintervention . .
Advanced Glycation Endproducts (AGE)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
GlycationGlycation Occurs in everyone, but at a faster rate in
diabetics Has devastating effects on the health of our
tissues Most evident in:
Senile dementiaStiffening of the arterial systemDegenerative diseases of the eye
Some outward examples of AGEs
Some outward examples of AGEs
Not us!
Negative Aspects of AGEsNegative Aspects of AGEsWrinklesCollagen and Elastin lose their suppleness
Cataracts Arthritis Erectile Dysfunction
Trigger Inflammatory Reactions
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
Skeletal muscle
Carnosine content ‘s 63% from age 10 to age 70
Good News!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 1000mgGalega officinalis (50% guanidine with negligible content of galegine) 500mgL-Arginine 300mgDMAE (dimethylaminoethanol) 300mgAscorbic acid 100mgPABA (para aminobenzoic acid) 100mgVit E (d-alpha tocopheryl succinate) 200IUThiamine HCl 50mgAlpha R Lipoic acid 50mgPyridoxal 5’ phosphate 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)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 radicalsInhibits 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)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, B-
Alanine, 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 - Life Extension – Carnosine overviewwww.lef.org
Impaired reverse cholesterol transport
Impaired esterbation of cholesterol
Toxicity to endothelium
Facilitation of oxidation
Calcification often accompanies glycation!
Calcification often accompanies glycation!
L-Carnosine (B-alanyl-L-histidine)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 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. 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 14;93(10):4765-9.
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”
“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).”
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.
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.
“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.”
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 cell dysfunction. Circ Res. 2004 Aug 6;95(3):233-8.
Loeser RF, Jr. Aging cartilage and osteoarthritis – 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.
““Betty Betty CrockerCrocker
Slow-Cook Slow-Cook Oven”Oven”
Beyond CarnosineBeyond Carnosine Compounds that Inhibit Sugar attachment to Protein
(Glycation)Pyridoxal 5’ phosphatePyridoxal 5’ phosphate
ASA (Aspirin) Compounds that Inhibit or Block formation of Crosslinks
Guanidine (Goat’s Rue – Galega officinalis)(Goat’s Rue – Galega officinalis)
Aminoguanidine Compounds that Trap reactive Carbonyl Intermediates
(C=O compounds lead to AGEs)Guanidine(Galega)(Galega)/Aminoguanidine, Carnosine, L-ArginineCarnosine, L-Arginine
Chelating Agents that inhibit conversion of Schiff Bases to Amadori Products
EDTA EDTA (Liposomal oral EDTA, rectal suppository or IV)(Liposomal oral EDTA, rectal suppository or IV)
Penicillamine Antioxidant Agents that inhibit conversion of Schiff
Bases to Amadori ProductsVitamin CVitamin C
Vitamin EVitamin E
Lipoic AcidLipoic Acid
Botanical Antioxidants that may inhibit conversion of Schiff Bases to Amadori products
Green Tea, Hawthorn, Grape Seed, Milk Thistle, Ginger Root, Ginkgo
AbocaAboca provides these botanicals as organic cold processed, freeze-dried whole phytocomplex concentrates!
Compounds that Inhibit formation of Amadori ProductsGuanidine (Galega)(Galega)/Aminoguanidine
Glucose Glycated Amadori + proteins Adducts AGES
Protein-NH2 (Schiff Base)
Pyridoxal 5’ Phosphate
Aspirin Galega GuanidineAminoguanidine
EDTA
Penicillamine
Vit C, E, ARLA
Galega
Guanidine
Aminoguanidine
Galega
Guanidine
Aminoguanidine
Carnosine
L-Arginine
Reactive
Intermediates
C=O
Pyridoxal 5’ phosphatePyridoxal 5’ phosphate
Bioactive form of Vitamin B6 Significantly reduces non-enzymatic
glycation of proteinsInhibits AGE formationExceeded only by aminoguanidine
ThiamineThiamine 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
UNDUEUNDUE existing crosslinked proteins.Thiamine is an effective Thiamine is an effective crosslink crosslink
breakerbreaker (Pearson and Shaw) Breaking existing crosslinks has been shown to
improve arterial elasticity.
Galega officinalis (Goat’s Rue)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 AcidAlpha 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; 22:359-378.
–Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Rad Biol Med. 1997; 22:359-378.
Antioxidants and NeuroprotectionAntioxidants and Neuroprotection
Vitamin E Alpha R Lipoic Acid Coenzyme Co Q10
Antioxidants reduce formation of Amadori adducts
Antioxidants reduce formation of Amadori adducts
Vitamin E and Cognitive Decline in Older Vitamin E and Cognitive Decline in Older PersonsPersons
Vitamin E and Cognitive Decline in Older Vitamin E and Cognitive Decline in Older PersonsPersons
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
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 ethinolDMAE:Dimethyl amino ethinol
Alleviates behavioral problems and hyperactivity associated with Attention Deficit Disorder (ADD)
Made naturally in the brainIncreases attention spanDecreases aggressionImproves learning abilityOccassionally shows increase in IQ (70% of ADD
patients)
DMAEDMAE Inhibits and reversesInhibits and reverses cross-linking of proteins cross-linking of proteins Facilitates removal of lipofuscin from neurons Facilitates removal of lipofuscin from neurons
and skin (age spots)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
Inhibits and reversesInhibits and reverses cross-linking of proteins cross-linking of proteins Facilitates removal of lipofuscin from neurons Facilitates removal of lipofuscin from neurons
and skin (age spots)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
DMAEDMAE 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
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
DMAEDMAEReferences: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. 30:1293-1296, 1978.
Zs-Nagy, I, et al. Zs-Nagy, I, et al. On the role of cross-linking of On the role of cross-linking of cellular proteins in aging.cellular proteins in aging. Mech Agi Dev. 14:245- Mech Agi Dev. 14:245-251, 1980.251, 1980.
Hochschile R. Hochschile R. Effect of dimethylaminoethanol on Effect of dimethylaminoethanol on the life span of senile male A/J mice.the life span of senile male A/J mice. Exp Gerontol, Exp Gerontol, 1973, 8: 4, 185-191.1973, 8: 4, 185-191.
Also present in:
PABA (para amino benzoic acid)PABA (para amino benzoic acid) Antioxidant
Quenches singlet oxygenProvides protection against:– Ozone– Smoking– Other air pollutants
Anti-Crosslinking AgentAppears to slow or reverse crosslinking in protein connective tissue structures (ie. Collagen)
PABAPABA Anti-Aging
Promotes greater flexibilityUseful in Tx of vitiligo (a depigmenting disease)Helps prevent graying of hair or restore normal hair color in 10-25% of patientsReduces fibrotic processes:– Peyronnies disease– Dupuytrens contracture– Scleroderma
Some PABA referencesSome 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, 248:550-561
Dean W. DMAE and PABA, An Alternative to Gerovital (GH3), the Romanian Youth Drug. Vit Res Prod. (vrp.com)
Additional ReferencesAdditional 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, 8:67-72.
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:BioGenesis products to consider for Anti-Aging:AGExLiposomal EDTA CogniFactors Aboca botanicals: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
“May your practices and your patients be blessed
by your care”