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Hormesis - Holistic Family Dentistry Steven N. Green, DDS

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Hormesis - Holistic Family Dentistry Steven N. Green, DDS

  1. 1. 1 Hormesis – What doesn’t kill you, makes you stronger. If a little of something is good for you, more is not necessarily better, and might be worse. Smokingmore thanten moderntobaccocigarettes daily isthe single biggestriskfactorforprogressive periodontal disease aswellas the stressed metabolismof syndrome Xwhichincludesdiabetes, arthritis, depression, heartandarterydisease,stroke andcancer. Evenlowlevelsof secondhandsmokeare harmful tosome populations(especiallydeveloping children and the elderly). Mostmoderntobaccois sugar-cured,so habit-formingnicotine isnow synergized with the alluringaddictive taste of inhaledcaramelizedsugar while we seekourprimitively programmedoral sucklingrewards. Diabetesisbyitself the secondbiggestriskfactorfor modern society’sprimary killerdiseases. Diabetes iscontrolledbyeliminating addictivefoodswithhighglycemicloadsuchas boxedbreakfastcereals, breads, cakes, pancakes,waffles,pop-tarts,donuts, cookies, pretzels, Frenchfriesandchipsof all varieties. Like modern corporatized tobacco,these favorite foodsthattriggerhighbloodsugarresponsesalso feature the temptingtaste of caramelizedsugar. Repeatedhighbloodsugarresponse tothese heated and deformed foodmolecules createsastressed metabolismwithlossof homeostaticcontrols while enhancingenzymaticcaramelization andstiffeningof ourowntissues. Toastedsugars become brownedandrigidlyshapedwhen glycatedbyheat. Whenourowntissues stiffenand harden enzymaticallydue tohighavailability of sugar,itiscalledglycosylation. Inindustry these AGEs(advancedglycationend-products)are alsocalledacrylamidesorpolyacrylamidesandthey are well knowncarcinogens. CollectingincreasedAGEs inone’sbody causes cataracts, wrinklesand age spotsinthe skin as well as the rigidity,brittleness andneuropathy of oldage. AGEsmimicheatshockproteininour bodies, mimickingstressmessenger-moleculescreatedinresponsetoburnsor bacterial infection. If AGEs are sobad for us,whydo we love the taste of caramel somuch? The controlledcaramelization of the sugars,starches and proteinsinfoods creatingpleasingflavornuances isthe basisof most moderncooking. Surprisingly,alittle bitof such foodderived stressisgoodforus,makingus stronger and able tohandle biggerstrains. Itis justtoocheap andeasy formodernman to toastthings, thuswe too frequently sendthesetastybutoverwhelmingbiochemical stress-signalsof ‘forestfire’ toour primitive genes. The challengingand controversial conceptthatpoisonscanheal whengiveninlow doses isexploredin “Sippingfroma PoisonedChalice” (Science- Oct 17, 2003, Vol.302). Organisms canrespondwith a great variety of responsesafterexposuretoa stimulusorchemical,be itbeneficial,adaptive, orearly manifestationsonarange to toxicity,overttoxicity aswell as several of theseincombination. Forages, a small minorityof people (mostlyhomeopaths) have alsoknownthrough‘provings’thatsmall dosesof poisonscan paradoxically produce beneficialeffects.
  2. 2. 2 Usually one expectsagradedlinearresponse toastimulusfromlow tomediumtohigh. Hormesis describesthe unexpected findingthatinanorganism, oftenaspecificstressororchemical isable to induce biologicallyopposite effectsatdifferentdoses; oftenthereisastimulatoryorbeneficial effectat very lowdosesandan inhibitoryortoxiceffectathigherdoses. The wide range of hormeticeffects(stressresistance,alteredmetabolismwith increasedgrowth, fecundity, geneticstabilityand longevity,immune-regulationaswell as decreaseddiseaseincidence) indicates thatthese changesare fundamental endurance responses of the organism thataffect thousandsof genes. Althoughthere is nosingle specifichormeticpathway,there seems tobe a commonbiological continuedexistencestrategyunderlyingsuch beneficial observations. Hormesis defines the capacity of a chemical orphysical agentto conditionthe physiological state of an organismto tolerate higherstresswith very low dosesof otherwise harmful agents. Evolutionary evidence demonstratesthatthe continued existenceandlongevityof specieshinge ontheiroptimal abilitytoresiststress challenge. Hormesisisapotentsurvival strategytostimulate latentrepair processesto enhance overall tolerance tochallenge. It iscommon wisdomthatan infant benefitsfromearlierratherthanlaterexposure tothe worldatlarge and that withoutsuchchallengesisunlikelytocope as well withsuddendelayedexposure. This hormeticprinciple extendsintoadulthoodandfadeswithsenescence. Brief whole-bodyexposuretocoldwaterincreasesbothactivityandnumbersof peripheral natural killer(NK) cellsandCD8+ T lymphocytes. Likelytransientactivationof the sympatheticnervoussystem, the hypothalamic-pituitary-adrenal axisaswell asthe hypothalamic-pituitary-thyroidaxisresultsina brief actionof norepinephrine,adrenocorticotropichormone (ACTH),beta-endorphinaswell asthyroid hormones{triiodothyronine(T3) andthyroxine (T4)} oncytotoxicTlymphocytesandNKcells. Coldwaterstress enhancessurvival with itsanalgesiceffectandby encouragingcellularimmunitywhile reducingtumorformationandautoimmunity. A wide varietyof physical,chemical andbiological agentsexhibithormeticeffects,includingheavy metals,pesticides,antibiotics,chemotherapeuticagents, vitamins,hormonesandhormone mimicslike plasticizers, ethanol,aldehydes,chloroform, pro-oxidants,hypergravityandionizingradiation. Glucose and oxidation-mediatedproteinandDNA damage are common underlyingcausesof many age- relateddiseases. Physiological hormeticconditioningmaytrigger: 1) activationof latentstress resistance pathwaysof youthfulDNA repair; 2) increasedresistance tooxidizingpollutants; 3) improvedproteinstructure and function; 4) improvedimmunity; 5) damagedtissue remodeling; 6) adjustmentsincentral and peripheralnervoussystems; 7) alteredmetabolism;and8) delayor breaking of inappropriate protein cross-links. The hormeticdose–response challengeslong-standingbeliefs aboutthe nature of the dose–response in a low dose zone and hasthe potential toaffectsignificantlythe designof pre-clinical studiesandclinical trialsas well asstrategiesforoptimal patientdosinginthe treatmentof numerousdiseases.
  3. 3. 3 Hormeticmessengersormimeticsmayhelpprevent cancer,diabetes,age-relateddiseases, infectious diseases,heartandkidneyfailure,cardiovasculardiseasesandAlzheimer’sdisease. Small nucleotide SOS signals,dipeptides,ethanol,thiols andmetalsaswell as conservedpeptidesequencesfound in sharks,frogs,woodchucksandbears,can regulate cytokines,cellularimmunity aswellas central and peripheral neuronal regulatorypathwaystopromote healthybloodpressure maintenance,heartrate and metabolicpathways,reducingdisease sensitivity. Stressmimeticsrejuvenate DNA aswell as enhance repairof proteinsandthusmayinterveneinaging, disease andtrauma. Deltorphins (stress-inducedhibernation-induction triggermimetics whichfitdelta endorphin receptors), come tolightasnew hormeticagents,effective both aspre and postexposure to physiological conditionerstotolerate trauma aswell as preventdamage,and possibly delay aging. Botulinum Botulinumisone of the mostpoisonoussubstances known. A gramof botulinumtoxin,if dispersedand ingestedcouldkill20 millionpeople. Yet, Botox treatmenttoremove wrinklesisbotulinumin extremelydilute form. Otherapplicationsinclude relief of migraines,acure for crossedeyes aswell as a treatmentforthe spasticconditionsof multiple sclerosisandcerebral palsy. A combinationof botulinumandaprotein fromthe Mediterraneancoral tree couldprovide atreatmentforthe chronicpainthat afflictsmillionsof people,includingcancerpatients. Treatmentswithbotulinumtoxin canoftenhelpfocal dystonia,amisfiringof the brainthatcauses musclestocontract into abnormal and sometimespainfulpositions. Thiscareerthreateningdisorder oftenstrikesthose whodependonsmall motorskills:musicians,writersandsurgeons. Hydrogen sulfide (H2S) Accordingto the OSHA fact sheet,hydrogensulfideisacolorless,flammable,extremelyhazardousgas witha “rottenegg” smell. Hydrogensulfideisheavierthanairand maytravel alongthe ground.It collectsinlow-lyingandenclosed,poorly-ventilatedareas. Hydrogensulfideisbothanirritantand a chemical asphyxiantwitheffectsonbothoxygenutilizationandthe central nervoussystem. Its healtheffectscanvarydependingonthe level anddurationof exposure.Repeatedexposure can resultinhealtheffectsoccurringatlevelsthatwere previouslytoleratedwithoutanyeffect. Low concentrationsirritate the eyes,nose, throatandrespiratorysystem(e.g.,burning/tearingof eyes, cough,shortnessof breath). Asthmaticsmayexperience breathingdifficulties. The effectscanbe delayedforseveral hours,orsometimesseveral days,whenworkinginlow-levelconcentrations. Repeatedorprolongedexposuresmaycause eye inflammation,headache,fatigue,irritability,insomnia, digestive disturbancesandweightloss. Moderate concentrationscancause more severe eye andrespiratoryirritation(includingcoughing, difficulty breathing,andaccumulationof fluidinthe lungs),headache,dizziness,nausea,vomiting, staggeringandexcitability.
  4. 4. 4 Highconcentrationscancause shock,convulsions,inabilitytobreathe,extremelyrapid unconsciousness,comaanddeath.Effectscanoccur withinafew breaths,andpossiblyasingle breath. Hydrogensulfide isconsideredabroad-spectrumpoison,meaningthatitcan poisonseveral different systemsinthe body,althoughthe nervoussystem ismostaffected.The toxicityof H2Siscomparable withthat of hydrogencyanide.Itformsa complex bondwith ironinthe mitochondrialcytochrome enzymes,therebyblockingoxygenfrombindingandstopping cellularrespiration. Since hydrogensulfide occursnaturallyinthe environmentandthe gut, enzymesexistinthe body capable of detoxifyingitbyoxidationto(harmless)sulfate. Hence,low levelsof sulfidemaybe tolerated indefinitely. However,atsome thresholdlevel,the oxidativeenzymeswill be overwhelmed. Hydrogensulfide isproducedinsmall amountsbysome cellsinmammalsandhasa numberof biological functions. Itis enzymatically producedfromcysteine. Itacts as a vasodilatorandisalsoactive inthe central nervoussystem,whereitincreasesthe response of the NMDA receptorandfacilitates memory. Eventuallythe gasisconvertedto sulfites andfurtheroxidizedto thiosulfateandsulfate. Due to its effectssimilartoNO(withoutitspotential toform free radicals byinteractingwith superoxide), hydrogensulfideisnowrecognizedasa potential cardioprotective agent. Vasoactivityof garlicispartly causedby catabolismof the polysulfide groupinallicin toH2S,a reactionwhich likely dependson reductionmediatedby glutathione (which the otherpartsof garlichelprecycle). Hydrogensulfide bindstocytochrome oxidase andtherebypreventsoxygenfrombinding,whichleads to the dramatic slowdownof metabolism. Animalsandhumansnaturallyproduce some hydrogen sulfide intheirbody,perhapstoregulate metabolicactivityand bodytemperature. Mice can be putintoa state of suspendedanimationlikehypothermiabyapplyingalow dosage of hydrogensulfide(81ppmH2S) inthe air, roughlythe amountthat will cause eye damage tohumansat work. If the H2S-inducedhibernationcanbe made to workin humans,itcouldbe useful inthe emergencymanagementof severelyinjuredpatientsandinthe conservationof donatedorgans. Several interrelatedcellularsignalingmoleculesare involved inthe processof hormesis. Examples include the gasesoxygen,carbonmonoxideandnitricoxide,the neurotransmitterglutamate, the calciumionand tumornecrosisfactor. In each case low levelsof these signalingmoleculesare beneficial andprotect againstdisease,whereas highlevelscan cause the dysfunction and/ordeathof cells. Hormesis conditioningoffers powerful survival strategies. Combinationsof several mimeticsmaymore closely imitate environmental challenges. Oxygen Hormesismaybe inducedbyendogenouslyproduced,potentiallytoxicagents. Forexample, mitochondriaconsume oxygenwhichgeneratesfree radicals(reactive oxygenspecies) asaninevitable by-product.
  5. 5. 5 The biochemical basisforthe toxicityof oxygenisthe partial reductionof oxygenbyone ortwo electronstoformreactive oxygenspecies,whichare natural by-productsof the normal metabolismof oxygenandhave importantrolesin cell signaling. One speciesproducedbythe body,the superoxide anion(O2 – ), islikely involvedinironacquisition. The superoxideradical servesasbothan initiatoranda terminatorof the free radical-mediatedchain reactionresultinginlipidperoxidation. Lipidperoxidationisauniversal feature of oxidativestress, causinglossof cellularstructure andfunction. Underanygivenconditions,the optimalconcentrationof SOD isthat whichdecreaseschain initiation withouteliminationof the chain termination propertiesof the radical,resultinginaminimumof netlipidperoxidation. Higherthan normal concentrationsof oxygenleadtoincreasedlevelsof reactiveoxygenspecies. Oxygenisnecessaryforcell metabolism,andthe bloodsuppliesittoall partsof the body. Whenoxygen isbreathedat highpartial pressures,ahyperoxicconditionwill rapidlyspread,withthe most vascularizedtissuesbeingmostvulnerable. Duringtimesof environmentalstress,levelsof reactive oxygenspeciescanincrease dramatically,whichcandamage cell structuresandproduce oxidative stress. While all the reactionmechanismsof these specieswithinthe bodyare notyetfullyunderstood, one of the most reactive productsof oxidativestressisthe hydroxylradical (·OH),whichcaninitiate adamaging chainreactionof lipidperoxidationof the unsaturated lipidswithincell membranes. Highconcentrationsof oxygenalsoincrease the formationof other free radicals,suchas nitricoxide, peroxynitrite andtrioxidane,whichharmDNA andotherbiomolecules. Althoughthe bodyhasmany antioxidantsystemssuchas glutathione thatguardagainstoxidativestress,thesesystemsare eventually overwhelmedatveryhighconcentrationsof free oxygen,andthe rate of cell damage exceedsthe capacityof the systemsthatpreventorrepairit. Cell damage andcell death can thenresult. Free radicalsmay induce anendogenousresponse cumulatinginincreaseddefense capacityagainst exogenousradicals(andpossiblyothertoxic compounds). Indeed, suchinductionof endogenousfree radical production throughexercise extendslife spanof amodel organism. Interestingly,thisinduction of life spanispreventedbyantioxidants,providingdirectevidence those toxicradicals mayhormetically influencethe mitochondriaand exertlifeextendingandhealthpromotingeffects. Since mitochondrial activitywasfoundtobe increasedinthe before-mentionedstudies,thiseffect cannot be explainedbyanexcessof free radicalsthatmight markmitochondriafordestructionby lysosomes,andthatthe free radicalsactas an apoptoticsignal withinthe cellindicatingwhich mitochondriaare readyfordestruction. Carbon Monoxide Carbon monoxide isanexampleof a‘pollutant’thatisimportantforhumanexistence. Thisdeadlygas that killsthousandseachyearofferspotential helpforanumberof medical conditions. There are pathogenicimplicationsforconditionsthatsubstantiallyraise the tissue COcontentand produce oxidative stress, suchas smoking,airpollutionandCOpoisoningaswell ashemolyticor inflammatory statesthataccelerate hemeturnover. Althoughcarbonmonoxideinhalationcanbe lethal,
  6. 6. 6 our bodiesmake COmoleculesnaturallyinsmall amountswhenanenzyme calledheme-oxygenase-1 (HO-1) breaksdowna portionof the bloodproteinhemoglobin. Ventilator-inducedlunginjury(VILI) isamajorcause of morbidityandmortalityinintensivecare units. The stress-induciblegene product,HO-1andcarbon monoxide,amajorby productof the oxygenase catalysisof heme,have beenshowntoconferpotentanti-inflammatoryeffectsinmodelsof tissue and cellularinjury. Inhaledlow-dose COmightbe useful inminimizingVILI. Small amountsof carbonmonoxide mightalleviate symptomsof multiplesclerosis,astudyinmice suggests.Otherstudiesof laboratoryanimalssuggestthatcarbonmonoxide insmall dosescanprevent injurytobloodvesselscausedbysurgery.Inthisstudy,ratsthat inhaledcarbonmonoxide-lacedairfor1 hour before angioplastyhadmuchlesssubsequentarteryblockagethandidratsnot receivingthe gas. Rats that underwentavessel transplantalsofaredsignificantlybetterif givencarbonmonoxidebefore and afterthe surgery. Lowconcentrationsof CO act very rapidly on the macrophage and induce stabilization of the transcription factor hypoxia inducible factor 1α (HIF1α), a potent oxidant stress response gene responsible for regulating gene expressioninvolvedin angiogenesis, metabolism and survival. The ability of CO to increase HIF1α activity is mediated in part by a highly significant and transient burst of reactive oxygen species (ROS) arising from the mitochondria. CO-mediated HIF1α activity then leads to the induction and secretion of TGFβ, a potent anti- inflammatory cytokine. The induction of both HIF1α and TGFβ by CO are necessary to rescue lung macrophages from anoxia/reoxygenation-induced apoptosis and ischemia-reperfusioninjury. Modest increasesincellularCOconcentrationactivate mitochondrial biogenesis. Mitochondrial generationof reactive oxygenspeciesbyCOactivatesmitochondrial biogenesisinthe heart. Mitochondrial COandH2O2 are activatingfactors incardiacmitochondrial biogenesis. Mitochondrial H2O2 productionderivingfromCObinding tocytochrome coxidase isanactivatingfactorin mitochondrial biogenesis. Mitochondrial biogenesis isactivatedbygene andproteinexpressionof the nuclearrespiratory factor1 (NRF1) and NRF2,of peroxisomeproliferator-activatedreceptorgammaco-activator-1 ,andof mitochondrial transcription factorA (TFAM),whichaugmentedthe copynumberof mitochondrial DNA (mtDNA). Thisisindependentlyof nitricoxide synthase (eNOSandiNOS)orhypoxia. Nitric oxide (NO) Nitricoxide isanair pollutantproducedbycigarette smoke,automobile enginesandpowerplants. NO isalso an importantmessengermoleculeinvolvedinmanyphysiological andpathological processes withinthe mammalianbodybothbeneficial and detrimental. Appropriate levelsof NOproductionare importantinprotectinganorgan such as the liverfromischemicdamage. Howeversustainedlevelsof NOproductionresultindirecttissue toxicityandcontribute tothe vascular collapse associatedwithsepticshock,whereaschronicexpressionof NOisassociatedwithvarious carcinomasand inflammatoryconditionsincludingjuvenilediabetes,multiple sclerosis,arthritisand ulcerative colitis.
  7. 7. 7 The dilatingmechanismismediatedbythe formationof gaseousnitricoxide fromnitrites. Nitricoxide (NO) isa molecule usedbythe endothelial cellsliningthe surface of bloodvesselstosignal surrounding muscle torelax,leadingtoa reductioninbloodpressure,reducedbloodclottingandprotectionagainst myocardial infarctionandstrokes. Coexpressionof eNOS,VEGF(vascularendothelialgrowthfactor) andangiopoietin-1resultsinmore mature vascularizationof connective tissue,andgeneratesnew arteriolesaswell asnew capillaries. Combininghemodynamicforceswithgrowthfactorsprovidesamore physiological therapeutic approach thansingle growthfactoradministration. VEGF is part of a sub-familyof cystine-knotgrowthfactors includingplatelet-derivedgrowthfactor (PDGF) and placentagrowthfactor. Cystine knotsare the resultof an unusual arrangementof six cysteine residues. Cystine knotstructuresare foundinnerve growthfactor,tumor growthfactor-beta,chorionic gonadotropin, luteinizinghormone,follicle stimulatinghormoneandthyrotrophin(thyroidstimulating hormone or TSH) also containsubunitswitha cystine knotstructure. Sulfur-containingcysteinedoes much more than functionasthe rate-limitingaminoacidforthe formationof critical glutathione,so pivotallyimportantforenergyproductionandcellularimmunity. VEGF productionisinducedincellsthatare not receivingenough oxygen(asinanemiainducedby nitrite-inducedmethemoglobin). Whena cell isdeficientinoxygen,itproducesHIF, hypoxiainducible factor,and a transcriptionfactorwhichstimulatesthe release of VEGF,amongotherfunctions(including modulationof erythropoeisis). CirculatingVEGFthenbindstoVEGFreceptorsonendothelial cells, triggeringatyrosine kinase pathwayleadingtoangiogenesis. Generationof contractile microvessels(arteriogenesis) isrequiredforthe developmentof therapeutic angiogenicstrategies. Thiscanbe achievedbycombiningvasculargrowthfactors(VEGFand angiopoietin-1) witheNOSoverexpression,providingextramessagingforneovasculargene therapy. However,excessiveproductionof NOcan leadtoefficientlyfeedingnew tumors,maculardegeneration, diabeticretinopathy,hypertrophyof kidneyglomeruli allowingproteinuriaorthe production of toxic oxidizingperoxynitrites,causingarterialinjuryorneuropathyleadingto‘brainonfire’expressedas cognitive dysfunction,Alzheimer’sorParkinson’sdisease. The formationof reactive nitrogenspeciesisnotthe usual consequence of synthesizingNO. NOis efficientlyremovedbyreactingwithcirculatingoxyhemoglobintoformnitrate,whichpreventseventhe highestratesof NOsynthesisfromdirectlyreactingwithoxygentoformsignificantamountsof nitrogen dioxide. However,the simultaneousactivationof superoxide synthesisalongwithNOwillcompletelytransform the biological actionsof NObyformingperoxynitrite. Several enzyme complexes,suchasNADPH oxidases(NADPHox)andxanthineoxidase (frompasteurizedcow’smilkprotein), canbe activatedin manycellularsystemstoactivelyproduce large amountsof superoxide. What happenswhensuperoxideandNOare producedsimultaneouslyinclose proximity?Modestly increasingsuperoxideandNOeachat a 10-foldgreaterrate will increase peroxynitrite formationby
  8. 8. 8 100-fold. Under proinflammatoryconditions,simultaneousproductionof superoxideandNOcan be stronglyactivatedtoincrease production1,000-fold,whichincreasesperoxynitrite formationbya 1,000,000-fold. Withoutsuperoxide,the formationof nitrogendioxide bythe reactionof NOwithoxygenisminiscule by comparison.However,NOandsuperoxide donotevenhave tobe producedwithinthe same cell to formperoxynitrite,becauseNOcanso readilymove throughmembranesandbetweencells. NO ismostlyremovedbyreactingwithoxyhemoglobintoformnitrate,withonlyasmall fractionbeing oxidizedbyheme proteins. NOisthe one molecule producedinhighenoughconcentrationsandreacts fastenoughto competitivelyreactwithendogenousSOD(superoxide dismutase) forsuperoxide. Nitric oxide reactsrapidlywithsuperoxide toformthe potentfree radical peroxynitrite. Cellscanbe activatedtoproduce large amountsof superoxide byspecificNADPHoxidasesandother enzymaticsources. Because the rate of peroxynitrite formationrises100-foldforeach10-foldincrease insuperoxide andNOproduction,the productionof superoxideoffersadynamicmechanismtoredirect NO frombeinga signalingmolecule toanimportantcomponentof host-defense andinnate immunity. This primaryperoxynitriteweaponof the immunesystemisusuallytightlycontrolledwithinthe peroxisomesof white bloodcells. Unbufferedperoxynitritesmayproduce anumberof typesof tissue damage,includingfree radical damage tothe mitochondria(energyproducingorganelleswithincells) and to cell membranesthroughoxidative chainreactions. Adequate recycledreducedglutathione from precursorsand freshorganicfoodsisthe keyto quicklyquenchingperoxynitrites. Extreme cautionmustbe exercisedinaddingnitrate ornitrite tomeat,since these ingredientstendto be toxicto humans. In usingthese materialsneveruse more thancalledforinthe recipe. A little is enough. Potassiumnitrate cancause gastroenteritis(violentstomachache),low bloodpressure,anemia,kidney disease aswell asgeneral weaknessandtorpor. Italsohas an alarminglydepressive effectonthe heart. Potassiumnitrate andothernitratesdosuccessfullycombathighbloodpressureandare usedmedically to relieve anginaandcoldvasoconstrictivemigraine. Potassiumnitrate isalsousedindental cements and toothpastestoinstantlydesensitize hypersensitive teeth. Nitratesthemselvesare relativelynontoxic. However,whenswallowed,especiallyif one haslow stomachacid, opportunisticbacteriaconvertnitratestonitritesthatcanreact withcirculating hemoglobin,oxidizingitsdivalentirontothe trivalentformandcreatingmethemoglobin. Methemoglobincannotbindoxygen,whichdecreasesthe capacityof the bloodtotransport oxygenso lessoxygenistransportedfromlungstobodytissues,causingmethemoglobinemia. Normal individualshave lowlevels(0.5-2%) of methemoglobinintheirblood. Whenthislevelincreases to 10%, the skinandlipscan take on a bluishtinge (cyanosis) andlevelsabove 25% can cause weakness and a rapidpulse. Atlevelsabove 50-60%,a personcan lose consciousness,gointoacoma and die.
  9. 9. 9 Infantsare muchmore sensitive thanadultstonitrates/nitrites. Essentiallyall deathsfrom nitrate/nitrite poisoninghave beenininfants. Long-termexposure tonitratesandnitritescancause diuresis(anincrease inthe excretionof urine,andstarchydepositsorhemorrhaginginthe spleen). Nitratesare foundnaturallyinspinach,eggplant,beets,greenlettuce,turnipgreens,greenbeans, carrots, radishes,celery andcollards. Mostbabies’liverdetoxificationenzyme systemsare wellenough developedby9 monthsof age to handle pureesof these wonderful fiber-richandnitrate-richfoods. Nitrogeninchemical fertilizersoxidizesintonitratesthatthese plantsabsorb. These nitratescause part of the bitterflavorassociatedwithsome greenssuchascollards. Organicvegetablescontain significantlylessnitratesbecausenatural compostisusedtofertilize the soil. Organic vegetablesare alsoricherinpolyphenols,antioxidants,vitaminsandminerals. Nitrate fears shouldnotbe usedas an excuse toavoidthem, since theirfiberssafelysequesternitrites. Itis, however,one more reasontovote ‘organic’ withyourfood-purchasingdollar. Homeopathy and Water Hormesisvalidateshomeopathy, whichis controversial (mostlytoconventional medical doctorswhose mindshave been brutally trainedtothink only linearly). The homeopathictherapeuticconceptbelieves that extremelydilutedtoxicants canbe beneficial tohumanhealth,relievingsimilarsymptoms generatedbylargerdoses. Hormesisis truly areal biological phenomenon,supportingthe homeopathic conceptof “like treatinglike.” Homeopathicvaccinations actually create abalancedandmodulatedimmune protection,creatingmore regulatoryorsuppressorT-cellsasopposedtothe expected imbalances(diminishedcellularimmunity and heightenedautoimmunity)createdby the farmore toxicinjected vaccineswiththe addedimmune- irritatingadjuvants of corporate conventional medicine. Most vaccinatedpeople endupwithdepressedcellularimmunity(since the skin triggerof cellular immune response wasbypassedwiththe shot) andincreasedhumoral immunity(whichmeansmore autoimmune disease andcancer). Evenmore insidious,dependingonwhetherthe injectedmedicine endsup inan artery(where itbecomesamajorimmune insult) orthe plannedmuscle orsubcutaneous tissue,small percentagesof childrenwithweakdetoxificationsystemsare muchmore severelyinjured. Everyone knowswater. Itshapesourbodiesand supportslife on ourplanet. Butdespite the magical liquid’s everpresence,the molecularstructure of waterremainsamystery. Waterexhibitsastrangely varyingdensity,large heatcapacityandhighsurface tensionattemperatureswhichare relevanttolife. Comparedto otherliquids,waterhasbizarre propertiesthatare still poorlyunderstood. The molecular structure of watermightbe comparedto a crowdedclubwitha dance floor,where participants(the molecules) switchbetweendancingexcitedlyandsittinginorderlyfashionattables. Watermolecules can form longpolymersof dipolesassociatedbyhydrogenbondsandthe electromagneticradiations that theyemitenable themtoavoiddecay.
  10. 10. 10 Water molecules polymerizethemselvessolidlyinice, andforma less-dense tight“tetrahedral”lattice, witheachmolecule bindingtofourothers. Asice melts, water’stetrahedral structurestheoretically loosentheirgrip globally,breakingapartconsistently asthe temperature rises,butall still strivingtore- mainas tetrahedral aspossible,resultinginasmoothdistributionarounddistorted,partiallybrokentet- rahedral structures. New X-raystudies of liquidwatersurprisingly foundtwodistinctstructures(eitherverydisorderedor verytetrahedral) thatexistnomatterthe temperature. The twotypesof structure are spatiallyseparat- ed, withthe tetrahedral structuresexistinginclustersmade of upto about100 moleculessurrounded by disorderedregions. Organized tetrahedral waterislow-density andchaoticwaterishigherindensity. Most “normal”liquidsbecomedenser,ormolecularly more packed,astheygetcolder. Waterhowever, reachesitsmaximumdensityatabout4 degreesCelsius. Aboveandbelow thistemperature,wateris lessdense;thisiswhy lakesfreezefromthe surface down. Water alsohas an unusuallylarge capacitytostore heat,whichstabilizesoceantemperatures,anda highsurface tension,whichallowsinsectstowalkonwater,dropletstoformand treesto transportwa- ter to greatheights. Water isa fluctuatingmix of the two molecularorganizationsattemperaturesrangingfromambientto all the way to nearthe boilingpoint. Asthe temperature of waterincreases,fewerandfewerof these clumpsexist;buttheyare alwaysthere tosome degree, inclustersof asimilarsize. The disorderedre- gionsthemselvesbecome more chaoticastemperature rises. Clustersof moleculeswithinliquidwater have beendiscovered,identifiedandcharacterized thatform unique stable (non-melting)‘ice crystals’ thatmaintain avibrational memoryof the dilutedmaterial as a characteristicsubtle electromagneticfield. These nanometer-sized,rod-shapedwaterclusters (specific aqueousnanostructures) are createdwhenasubstance isplacedindistilledwater,thenvigorously shakenor stirred,andthen homeopathicallyrepeatedlydiluted tentimeswhile againandagainbeing vigorously shakenorstirred. Some bacterial DNA sequences induceelectromagneticwavesathighaqueousdilutions (anewly discoveredenergeticpropertyof DNA). Itseemstobe a resonance phenomenontriggeredbythe ambientelectromagneticbackgroundof verylow frequencywaves. The aqueoussolutionswere stronglyagitatedandseriallydilutedsince thisstepwas“critical forthe generationof signals”. Pathogenicbacteriaandvirusesshow adistinctelectromagneticsignature at waterdilutionsrangingfrom10(-5) to 10(-12) (correspondingto5Xto 12X) and small DNA fragments (responsible forpathogenicity)are solelyaccountable forthe electromagneticsignal. One experimentfoundsignificanteffectsfromdilutionsashighas10(-18) (equivalentto18X). The electromagneticsignature changedwithdilutionlevelsbutwasunaffectedbythe initial concentration and remainedevenafterthe remainingDNA fragmentswere destroyedbychemical agents.
  11. 11. 11 These characteristicfrozen crystalsof magneticallyorganizedclustersof harmonicallyvibratingwater molecules remainstable athightemperatures,and itsintriguingthatthe ice crystals seemtostill exist withvaryingfluctuation evenafter23 repeateddilutions (whichis beyondAvogadro’snumber,meaning no original moleculesof the formerlypotentordangerous dilutedsubstance seemtoremaininthe dilutedandshakenwater,only tracesof itsstoredelectromagneticvibrationalmemory). The phenomenaof hormesisandtoxicitythresholdsare likelyrelatedtoactivationof allostatic adaptive pathwaysresponsible forcellularandphysiological homeostasis (our‘steadystate’). Disruptionof homeostasis triggersmodestovercompensation andthe reestablishment of harmonic homeostasis viathe adaptive nature of thisprocess. Thus, fasting, heatshockor hotand coldhydrotherapy, pro-oxidantslike mega-dose vitaminC,one or twoalcoholicdrinksperday,plantpolyphenols andaldehydes,moderateexerciseaswell as mild irradiationorsunshine canall be interpretedbyourgenesas gentle beneficentstressors. The keyfactor inthe hormesisconceptisnot the irritantor chemical,butthe organism’s response of overcompensationtoadisruptioninhomeostasis. Therefore,anyagent orstressorcan induce a hormeticresponse,dependingondose. Homeostasisisdefinedasthe maintenance of aconstantinternal environmentalstate forefficient functioningandperformanceof the organism. However,convincingargumentshave beenput forward to replace the termhomeostasiswith homeodynamics, takingintoaccountthe harmonicdynamic rhythmicnature of livingprocesses withinthe ever-changingparabolicwave of life. The harmonicvibrational patternof these internal rhythmsinherentlyresistsperturbation. A critical part of the homeodynamiccharacterof livingsystemsistheircapacityto respond andadaptto environmental stress. Inthiscontext,the term"stress"isdefined asasignal generatedbyanyphysical, chemical orbiological factor(stressor),which,inalivingsystem,initiatesaseries of biochemical events inorder to counteract, change andsurvive bymaintainingallostasis (the compensatorysteadystate). Thermoregulation,detoxification,cell proliferation orreductionthrough apoptosis,DNA repair,heat shockproteinsynthesis,proteinturnoverandantioxidative responsesare some of the crucial homeodynamicresponses. Often,these survivalmechanismsare commontoseveral stressesaswell as differentspecies,andhave beengivenacollectiveterm "the general-adaptive syndrome." Relativelysmall individual hormeticeffects canbecome biologicallyamplifiedresultinginthe collective significantimprovementof cellular,tissue andorgan functionsenhancingsurvival of the whole organism. Higherexposure switches cellstoa stressedstate whenallostaticloadreaches the limitof homeostaticcontrol. Inthe highly stressed state of exhaustion, the immune system typically becomes activatedleadingtoinflammatoryresponses. Cellsinadaptive orstressed state canstill returntonormal,unstressedstate afterremoval of the stressor,dependingonduration. However,veryhighdosesof stressors fortoolongare likelytodrive cellsirreversiblytoa toxicstate,where cellsdie by apoptosisornecrosis.
  12. 12. 12 Apoptosisisanactive,programmedself-terminatingprocessof the cell inthe eventthatthe cellular damage istoo large to be repairedor worthrepairing,orthe cell’scontinuedsurvivalnolongerbenefits the organismas a whole. Asopposedto overwhelmingtoxicityorexcessive inflammation inciting explosive cellulardeathbynecrosis, quietapoptosiseliminatesonlydamagedparts,whileprepackaging cellularcomponentsforefficientreclamationandreuse byassociatedphagocyticwhitebloodcells. As earlyas 1898, studiesinradiobiologyfoundthatirradiatedalgae grew more quicklythannon- irradiatedcontrols. Physicians,the publicandresearchscientists showedmuch interestinthe possible beneficial effectsof lowlevelsof radiation. Such enthusiasmswere soondampenedbyreportsof deathsandsevere injuryfromlarge amountsof radiation. AfterHermanMuller's1928 publicationongeneticdamage infruitflies,radiationbecame associatedwithchromosome damage. Datapublishedinthe 1930s-1950s again showed small amounts of radiation tobe beneficialto biofilmcellulargrowthandrepair,explained by hormeticconcepts. Considerable moneyandefforthasbeenspent toreduce radiationdosestothe lowestpossiblelevel, since mostpeople have come to believe there isnosafe level of radiation. Some of these effortsmaybe misplaced, since the radiation fearisbasedonthe incompletelinear‘no-thresholdtheory’of carcinogenesis,which theorizes that"if 1 Gy (100 rad) of exposure givesacancerrisk R, thenthe risk from0.01 Gy (1 rad) of exposure is R/100, the riskfrom 0.00001 Gy (1 mrad) is R/100,000, straighton to infinity. Accordingto the errant no-thresholdtheory,the cancerriskisnotzero regardlessof how low the exposure (sincewe are surroundedbyambientradiation). Intermsof imagingexams,a hormetically beneficial back-to-frontchestx-raydeliversasurface entrance dose of about0.02 cGy (rad),at least100 timeslowerthanthe moderatelyrisky doseof 2-5 cGy (rads) of a standardchestCT. Accordingto the no-thresholdtheory,"asingle particle of radiationhittingasingle DNA molecule inthe nucleusof a single cell of the humanbodycan initiate acancer." "The probabilityof sucha cancer initiationistheoretically proportional tothe numberof suchhits,whichisproportional tothe numberof particlesof radiation,whichisproportionaltothe dose. Thusriskis proportional tothe dose." But real-worldexperience does notjibe withthistheory. Workingtoprevent mostcancersare the body'sdefense mechanisms. The bodyproducesenzymesthatrepair 99.99% of cell damage,andlow- level radiationis now knownto hormetically stimulate apoptosis,bywhichdamaged ordefective cells "commitcell suicide"quietly eliminatingthemselvesbeforetheybecome tumors. Cancer mortalityrates actually decrease followingexposure tolow dose irradiation. Hormesis(Greek HORMO= I excite) strictlyspeakingisthe beneficial stimulationof anysystembylow dosesof anyagent. Ultra lowdosesof many agentsevoke abiologically positive effect;whereas large doses mayproduce a harmful effect. The message issimple: smalland largedoses often induceoppositephysiologicresults.
  13. 13. 13 Radiationhormesisimpliesbeneficialstimulationby small dosesof ionizingradiation.Cancerinduction isthe mostfearedactionof large dosesof ionizingradiation. Cancermortalityratesillustrate radiation hormesisinhumans. Large dosesof ionizingradiation harmfully increasecancermortalityrates. Since small dosesdecrease cancermortalityrates,low dose irradiationis surprisingly beneficial. Althoughsmall dosesof radiation ordietarystressorslike plantpolyphenols canstimulate cell and cancer growth,the stimulationof differentcomponentsof ourcomplex immune systemmore than compensatesforsimple cellulareffects. The neteffectisdecreasedcancermortality. Radiation-inducedgenomicinstability,inwhichthe progenyof irradiatedcellsdisplayahighfrequency of nonclonal genomicdamage,occursat a frequencyinconsistentwithmutation. Inhumanmammary epithelial cells(HMEC) exposedtolowdosesof radiation,centrosome deregulationoccursinthe first cell cycle afterirradiation,isdose dependent,andthatviable daughtersof these cellsare genomically unstable asevidencedbyspontaneousDNA damage,tetraploidy andaneuploidy. TGFbeta inhibitionsignificantlyincreasescentrosome aberrationfrequency,tetraploidyandaneuploidy innonirradiatedHMEC. Ratherthan preventingradiation-inducedorspontaneouscentrosome aberrations,TGFbetaselectivelydeletesunstablecells(whichmightbecomecancer) viap53-dependent apoptosis. Radiationderegulatescentrosome stability,whichunderliesgenomicinstabilityinnormal humanepithelial cells,andthatisopposedbylow-dose radiation-inducedTGFbetasignaling. A studyof naval shipyardworkerswhoservicednuclear-propelledshipscomparedworkerswhowere and those whowere not occupationallyexposedtoradiation. Workersexposedtothe highestlevelsof radiation(>0.5 cSv) hadcancer mortality rate that was only 85% of the rate experiencedbyworkers whowere notexposed. The mostconvincingfindingwasthe verysignificant decrease of 24% in deaths fromall causesamong workersexposedtothe highestdoses(U.S.Deptof Energy,1991). A studyof lungcancer ratesamongwomenexposedtofluoroscopicexaminationsfor TBcame to similar conclusions. Lungcancerrates amongthese Canadianwomen,aswell asaone-pointstudyof 10,000 tuberculosispatientsinMassachusetts,showeda protectiveeffectupto20 cSv and 100 cSv (Radiation Research,June 1995, Vol.142:3, pp. 295-304; and CancerResearch,November1989). Radiation-induced noncancerhealtheffectsare notdetectableforfetal dosesbelow about50mGy (1 mGy =100 milli rad). Noncancerhealtheffectsmaybe expectedafterfetal doses>=100mGy and appear to have the most significanteffectsbetweenthe gestational ages of 8-25 weeks. Dental x-raysbarely reach the fetus(exceptinahormeticway) at.001 rads. Anaverage chestx-raydeliversonly.00007 rads. A single mammogramfilm, onthe otherhand, delivers.1-.2rads. If two mammogramfilmsare takenof each breast,thenthatmeansthat a breast wouldreceive about .001 rads duringa chestx-rayas opposedtoabout .2-.4 rads witha mammogram. Thismeansthat a mammogramprocedure can be 250-500 timesmore intense thanachestx-ray,if no extrafilmsare requestedforclarification.
  14. 14. 14 Repeatedmammogramsdonotimprove survival ratesandare associatedwithanincreasedriskto cancer. Perhapsitisnot the radiation. Some believe thatthe compressionforce usedmayrupture existingcancercellsthatare contained ina localizedmass,andcause malignantcellstobe releasedinto the bloodstream,therebypromotingmetastaticcancer. Thermograms are a saferalternative andmake more sense because theycanpickup an area thatis coldor hot, before ithasactuallyturnedinto cancer. Mammograms farm for industryand findestablished cancers. Thermogramscanpreventthem. Summary of the effectsofchronic, whole body radiation exposuresonfour physiologicfunctions: Beneficialradiationhormesis riseswithupto a 100 foldincrease inambientlevelsof radiation. Positive effectsare representedbythe definedareaabove the horizontalline. Whencompared withcontrols, representedbythe horizontal line,largerdose ratesexerta negative effect. Conclusion:“The linearno-thresholdtheory failsbadlyinthe low-dose region, because itgrossly overestimates riskfrom low-levelradiation. This meansthat cancer risk fromdiagnosticX-raysis much lowerthanisusually estimated,maybe zero." Thiscurve representsthe classichormeticresponse tostressors, the mostcommonformof the hormeticdose-response curve depictinglow-dose stimulatoryandhigh-dose inhibitoryresponses,the - or invertedU-shapedcurve. Justthe opposite mayoccur withthe hormeticdose-response curve depictinglow-dosereductionandhigh-doseenhancementof adverse effects,the J- orU-shapedcurve. Minimal dose detectable bychromosomeanalysis is5-25 rads. Typical chestX-raywithtwoviewsis 1/20 rad. A cervical orthoracic spine studywithmultiple viewsisabout½ rad. Lumbar spine views dose us with2 rads and a routine GI studywithfluoroscopyis5-10rads. Head CT (measuredatthe centerof a phantom) is6rads; bodyCT (measuredatthe peripheryof aphantom, 1 cm beneaththe surface) is4 rads. As reportedin NaturalNews, astudyinthe medical journal Radiology foundthatpeoplewhohad numerousCTscans overtheirlifetime hadasignificantlyincreasedriskof cancer. Infact, manyCT scans increasedthe risk tocancer by 2.7-12%.
  15. 15. 15 Many medical imagingtechniques,includingcardiacangiographyandCTscans, ofteninvolve the use of contrast agents,substancesthatcontainiodine (likeiopamidolandiodixanol) andbarium, because they enhance the contrastbetweenbodystructuresorfluidswithinthe body.Thisallowsbloodvesselsand changesintissuestobe more clearlyvisualized. Exposure tocontrast agentscan cause damage eveninseeminglyhealthykidneys,butpatientsare typicallyassuredthisisjustatemporaryside effectthatwill resolve onitsown. If followedayearor two afterimagingwithcontrasthowever,13% of patientsexperienceamajorevent,suchas death,stroke, heartattack or end-stage renal disease. Those whodevelopedcontrast-inducedkidneyinjurieshad twice as manylong-termnegativehealtheffectsascomparedwithpatientswhodidnotsufferkidney damage. The average total backgroundradiationof about1/3 remper yearroughlycomparestohaving7 (2 view) chestx-rays! (Anotherexampleof how low the exposuresare for many diagnosticx-rays!) Intra-oral (cavity-detectingdental bite-wingsusingfilm) measuredexposure atskinentrance averages 250 milli rads. If skindosesare compared,many medical officescouldproduce all 7cervical spine films ina comprehensive studyforlessskindoseradiationthanone ortwo traditional bite wingfilms! Intra- oral (digital)average is about¼ less, ataround70 milli rads. Cephalometric(film) skinentranceisusuallyjust15milli rads, similartothe chest. Literature reports that the effectivedose of apanoramicslittedview isbut0.3-1 milli rads. Jetflightexposesusto½-1 mrem/ hour in the air and luggage inspection0.002 mrem. Endogenousligandsformanyreceptorsexhibit similarparabolicorbiphasicdose-responsecurves,with highdosesbeingtoxic. A prime exampleisglutamate,the majorexcitatoryneurotransmitterinthe brain. In lowto moderate amountsthatare releasedfrompresynapticterminalsduringthe normal activityof nerve cell networks,glutamate mediatesprocessessuchaslearningandmemoryandsensory- motor behaviors. Bindingof glutamate toitsreceptorscausesmembrane depolarizationandcalciuminflux through ligand-gatedandvoltage-dependentcalciumchannels. The beneficialeffectsof low tomoderate levels of glutamate receptoractivationresultfromcalcium-mediatedactivationof transcriptionfactorssuchas nuclearfactor (NF)-κBandCREB(cyclicAMP response elementbindingprotein) thatinduce the expressionof genesthatencode proteinsthatpromote the survival andplasticityof neuronsincluding brain-derivedneurotrophicfactor(BDNF) andthe anti-apoptoticproteinBcl-2. However,excessivelyhighlevelsof glutamate canoverwhelmanyhormeticpathwaysandkill neurons by a processcalledexcitotoxicity. Mercury Mercury deservesspecialmentionsince itisthe mosttoxicnon-radioactive substance inour environment. Atlow micromolarconcentrations,mercuryuncouplestubulin, astructural protein necessaryfornerve formationandsynapses aswell as chromosomal reorganizationduringreproductive
  16. 16. 16 meiosisandmitosis. There seemstobe almostnosafe level (smallestmicromolaramountsare hormetic,lessthantenmillionths) of elemental mercury. Onlyveryhighhomeopathicdilutionshave clinical use,usuallyto calmirritabilityandcombativeness, relievepainoraiddetoxification of mercury. Bacteria are evenmore vulnerabletodamage frommercurythan us. Before the age of antibiotics, mercurywas oftenusedtotreat syphilis. Doctorsof the day notedinitial salutaryeffectsbeforetoxicity tookover. People whowere dull andphlegmaticbecame passionate aboutthe issuesof life,eventothe pointof becomingcombative. Nowthatwe understandhow dangerouselemental mercuryis, backgroundexposure isalreadyhigherthan beneficialhormeticlevels(justlikefluoride). However,at the homeopathicvibrational level,benefitcanbe created justfromthe energeticimprintof mercuryleft inthe electromagneticmemoryof water. Fluoride The range of fluorine-containingcompoundsisconsiderableasfluorineiscapable of forming compoundswithall the elementsexceptheliumandneon. Structurally,andtosome extentchemically, the fluoride ionresemblesthe hydroxideion. Inbiochemistry,fluoride saltsare commonlyusedto inhibitthe activityof phosphatases,suchasserine/threonine phosphatases. Itmay do thisby replacing the nucleophilichydroxyl ioninthese enzymes'active sites.
  17. 17. 17 The mechanismof toxicityinvolvesthe combinationof the fluorideanionwiththe calciumions inthe bloodto forminsolublecalciumfluoride,resultinginhypocalcemia;calciumisindispensableforthe functionof the nervoussystem,andthe conditioncanbe fatal. Fluoride-containingcompoundsare usedintopical andsystemic fluoridetherapy forpreventingtooth decay. Theyare usedfor waterfluoridation andinmany oral hygiene products. Originally, sodium fluoride wasusedtofluoridatewater; however,the waste-producthexafluorosilicacid anditssalt sodiumhexafluorosilicateare more commonlyusedadditives,especiallyinthe U.S. Publichealth officialsworsenedthe situationbyaddingfluoride (itscurrentindustrial wastesource alsoincreasesthe amountand absorptive availabilityof lead,arsenicandaluminum) inourwater. Fluoride ingestionor absorption/inhalationgreatlyenhancesuptake of radioactiveelements,includingiodine131 and strontium90. The fluoridationof waterhasbeen‘scientificallyproven’ (withthe backingof the biggestfluoride polluters) topreventtoothdecayandisconsideredbythe U.S. CentersforDisease Control and Prevention as"one of 10 great publichealthachievementsof the 20th century". It isa commontheorythat the reasonfluoride was proventoreduce toothdecayinMichigan(a glaciatedarealowinsoil iodine,where hypothyroidismisendemic) wasthroughastatistical trick. The keystatistical dental parameterimproved(inMichigan) byaddingone partpermillionfluoride in communitywaterwasdecayed,extractedorfilled6yearmolars. Degreesof hypothyroidism progressivelydelaythe eruptionof teeth. Fewerteethresultsinfewercavities. The amountof fluoride amodernAmericangetsfromfluoridatedwaterandcontaminatedfoodsisthe amountGerman physicianssometimesstill use todaytopoisonthe thyroidtotreathyperthyroidism. Furtherfluoride competition(withalreadylow iodine) accentuatedsubclinical hypothyroidismand delayederuptionof studied‘6year’molars(perhapsslowedasmuchas a year) and accountedfor statistical improvementof decayscores. Delayederuptionof teethwasinterpretedasa"benefit"in fluoridatedareaswhensame-age children'steethwerecompared. Fluoridationof wateris however(especiallysince there isnow somuchinthe environment),not withoutcritics. Russell LBlaylock,MDnotesthat fluoride isstronglyassociatedwithdamagingDNA, interferingwiththyroidfunctionleadingtohypothyroidism, creatingproblemswithfluoridatedorganic molecules(Paxil,Prozacandsome antibiotics),significantlyincreasingmanytypesof cancer,increasing heartdisease,increasingoral cancerand evenperiodontal disease,reducingzincinbodytissues (includingthe brain),increasingDown'sSyndrome,reducingtestosteroneandspermcount,increasing Alzheimer'sandloweringIQ. Perfluorinatedchemicals,(pervasive infoodpackaging,pesticides,clothing,upholstery,carpetsand personal care products),maydelaypregnancy. These chemicalsare alsocommonlyusedinnon-stick cookware. Usingnon-stickcookware encouragesingestingperfluorinates,whichare beingphasedout inthe U.S. because of theirtoxicity. However,theyremaininthe environmentandinthe bodyfor decades,andare linkedtodevelopmental problems. Danishwomenwithhighlevelsof perfluorooctanoate(PFOA) andperfluorooctanesulfonate(PFOS)take longertogetpregnant. Womeninthe three groupswiththe highestlevelsof PFOStookfrom70-134% longerto getpregnant than womeninthe lowestquartilewiththe lowestPFOSlevels. Womenwiththe highestPFOA levels
  18. 18. 18 took60-154% longertoget pregnantcomparedwithwomenwithlowestlevels. Inanimals,these chemicalshave avarietyof toxiceffectsonliver,immunesystemanddevelopmentalaswell as reproductive organs,alsoinducing impairedfetal growth. Environmental contaminantssuchasPCBs,PBDEs,and mercurycan alterbrain neuronfunctioningeven before achildisborn. These changestothe brain can be long-lasting.Stain-resistantchemicals,foundin up to 98% of Americanssampledinthe late 1990s, are foundinclothing,carpeting,upholstery,and eventhe liningof foodcontainers. Hormone-like vitaminA alsohashormeticeffects. VitaminA inrelativelylow amountsisessentialfor normal development,immunity andeye function,butinhighamountscancause anorexia, dryskin, headaches,drowsiness,alteredmental statesand immunesuppression. Studiesonthe use of the stressoralcohol have shown hormeticprotective effectsagainstcoronary heartdisease. These studiesshowthatone ortwo alcoholicdrinksperdayincreaseshigh-density lipoproteins. Also,moderate alcohol consumptiondecreaseslow-densitylipoprotein(LDL) cholesterol and triglycerides. Finally,alcohol consumptiondecreasesplateletaggregation. Redwine hasbenefitsthat othersourcesof alcohol donothave. Redwine reducesC-reactiveprotein, a marker of inflammationrelatedtoatherosclerosis andcancer. Redwine hashigherconcentrationsof antioxidantmolecules,calledpolyphenols,thanotheralcoholicdrinks,whichprotectagainstcoronary heartdisease byreducingoxidationof LDLcholesterol. The polyphenolsinredwine include anthocyanins,proanthocyanidinsandresveratrol, aswell as flavonoids,includingcatechins,kaempferol and quercitin. Twelve healthysubjectsimbibedeitheravitamin-enrichedbeverage twice dailyorthe same vitamin- enrichedbeveragesupplementedwithanadditional 500 mg of the plant-basedflavonoidquercitin. Overa week-longperiod,participantsweremonitoredtoassessthe amountof time ittookto show fatigue duringastationarybike ridingsession,asmeasuredbyVO2max (alsoknownasmaximal oxygen consumption),amarkerof physical fitnessthatmeasures maximalcapacityof the bodyto use and transportoxygenduringexercise. Supplementingwithquercitin mimicsexercise traininginthatit increasedVO2max by3.9% compared to placebo,amarginal improvement. However,fatiguetimestoldaverydifferentstory. Those who receivedaquercitinboostshoweda significantly higher13.9% increase inphysical stamina duringbike- ridingexercise. Red wine tendsto reduce mutagenicDNA damage andimprove endothelial functionwhenincludedina highfat diet. Wine canstimulate gastricacidsecretionandgastrinrelease. Perhapsthisis why moderate tohighwine intake seemstopreventHelicobacterpylori infection. Redwine mayhelpto preventnoise-inducedhearingloss,reduce the riskof developingage-relatedmaculardegeneration, may helptopreventcataracts andmay helppreventrheumatoidarthritis. Many studiessuggestsalutary rolesof dietaryphytochemicals producedin survival response tostress inprotectingagainstchronicdisorders. Several dietaryphytochemicalsalsobenefitthe nervoussystem
  19. 19. 19 and,whenconsumedregularly, reduce the riskof disorderssuchasAlzheimer’sandParkinson’s diseases. Notall grapes(norredwines) containthe same amountof resveratrol. Because resveratrol is createdby the grape plant primarily inresponse to fungus,grapesthatare sprayedwithfungicides produce virtuallynoresveratrol. Onlyorganically-grownplantsproduce the highestlevelsof resveratrol. One general mechanismof actionof phytochemicalsisthattheyactivate hormeticadaptive cellular stress-response pathways. Fromanevolutionaryperspective,the noxiouspropertiesof such phytochemicalsplayanimportantrole indissuadinginsectsandotherpestsfromeatingplants. Howeveratthe relativelysmalldoses inplantsingestedbyhumans,the phytochemicalsare nottoxic and insteadinduce beneficialstrengtheningthroughmildcellularstressresponses. Hormesis hasbeenwidelyobservedinbiologyandmedicine,andhasbeendescribedas ‘preconditioning’. Hormeticpathwaysactivatedby pigmentedphytochemicalsmayinvolvekinasesand transcriptionfactorsthatinduce the expressionof genesthatencode antioxidantenzymes,protein chaperones,phase-2detoxifyingenzymes,neurotrophicfactorsas well as otherprotective proteins. A familyof histone deacetylases calledsirtuinshasplayedpivotal rolesinstressresistancethroughavast expanse of evolutionaryhistory. Specificexamplesof suchpathwaysinclude the life-extendingsirtuin–FOXOpathway triggeredalsoby calorie restriction orresveratrol,the protective (whentethered) proinflammatory NF-κBpathwayand the Nrf-2/AREpathway,whichupregulatesexpressionof phase IIdetoxifyingenzymesandantioxidants, thusenhancingeliminationof noxiousstimuli. Hormeticphytochemical actions of the Nrf-2/ARE signalingpathwayare aclassical expression of aneuroprotective mode of actionof many specificdietary phytochemicals. The termhormesisiscommonlyusedbytoxicologiststodescribe the parabolicorbiphasicdose response curve where achemical mayhave a beneficial stimulatoryeffectatultralow doses,but become harmfully toxicathighdoses. Thishas ledsome toargue that environmental healthstandards can be relaxedbecauseif lowdosesare beneficial,thenthere isnoneedtoachieve stringentcleanup standards. However,lowdosescan sometimes have surprisingimpactsthatcannotbe predictedfrom highdose experiments. Hormesis as a programming modifier Bisphenol A ismoderatelytoxicathighdosesand at ultra-low doses hasevenmore problematic hormone-like effects,(literally changinggene expression,sometimesatcritical developmental phases). Highertoxicologicaldoses of estrogeniccompoundslikeestradiol and bisphenol A actas a hormone mimicthroughestrogenreceptors,andcanactuallyturnoff genesturnedonby lowerdoses. Traditional highdose testingmissesmanylow dose adverseeffects. Currenttestingproceduresare vulnerable todramaticunder-estimations of healthrisksbecause of lackof knowledgeof molecular detailsof justhowendocrine disruptionof estrogenicsignalingactuallyworks.
  20. 20. 20 Highdosesof the estrogenicdrugdiethylstilbestrol cause weightlossinadultsfollowingexposure inthe womb. Lowerdoses (withinthe range thatleadtoa wide arrayof adultdisordersof the reproductive tract) have no effectonadultweight. Butdosesfarlowerthan those (1 ppb) cause grotesque obesity. Atrazine For decades,farmers,lawncare workersandprofessional greenthumbshave reliedonthe popular weedkilleratrazine toprotecttheircrops,golf coursesandmanicuredlawns. Butatrazine oftenwashes intowatersuppliesandhasbecome amongthe mostcommoncontaminantsinAmericanreservoirsand othersourcesof drinkingwater. At highdoses, atrazine isa neurologicalpoison thatcanleadto Parkinson’sdisease andisdetoxifiedby the cytochrome P450 enzymes (whichhave greatindividualvariability),specificallyCYP1A2. Caffeine, melatonin,diflucan,clozapine andmanyotherdrugsare oxidized fordetoxification bythisenzyme,and may overloadthe system. Drugs like artemisininorethynilestradiol thatinhibitCYP1A2will predictablyincrease the plasma concentrationsof atrazine andmany medicationsandinsome casesadverse outcomeswill occur. Of particularnote isfluvoxamine,whichisapotentCYP1A2 inhibitorandalsoinhibitsotherCYP450 enzymes,suchasCYP2C19, the mostimportantCYP3A4, and tosome extentCYP2C9. Thus,fluvoxamine may preventothermetabolicpathwaysfromcompensatingforthe CYP1A2inhibition. The fluoroquinolone antibiotics,enoxacinandciprofloxacin,alsosubstantiallyinhibitCYP1A2. Cigarette smokingupregulatesandinducesCYP1A2enhancingdetoxificationof atrazine orreducing beneficial levelsof theophylline. Smoking,grilledmeatandcruciferousvegetablesorbarbituratesalso reduce the serumconcentrationsandefficacyof the atypical antipsychotics,clozapineandolanzapine. Inrecentyears,five epidemiological studiespublishedinpeer-reviewedjournalshave foundevidence suggestingthatsmall amountsof atrazine indrinkingwater,includinglevelsconsideredsafe byfederal standards,maybe associatedwithbirthdefects — includingskull andfacial malformationsand misshapenlimbs — aswell aslowbirthweightsinnewbornsandpremature births. Suchdefectsand premature birthsare leadingcausesof infantdeaths. Some studies note thatas atrazine concentrationsrise, the incidence of birthdefects grows. One study done at Purdue University,publishedinthe journal EnvironmentalHealthPerspectives — suggeststhat concentrationsassmall as0.1 parts per billionmaybe associatedwithlow birthweights. Atrazine maybe safe duringmany periodsof life butdangerousduringbrief windowsof development, like whenafetusisgrowingandpregnantwomenare toldto drinklotsof water. There are short,critical times(like whenafetus’sbrainisdeveloping), whenchemicalscanhave disastrousimpacts,eveninvery small concentrations. The E.P.A.generallydoesnotrequire watersystemstonotifyresidentsunlessthe yearlyaverage of atrazine indrinkingwaterexceeds3parts perbillion,andunderadeterminationmade earlierthis decade,the agencyconsidersone-dayexposuresof upto 297 parts per billionsafe. Anotherstudysuggeststhatconcentrationsof atrazine indrinkingwaterbelow the E.P.A.thresholds may disruptmenstrual cycles. Manyof those studies examinedlarge populationsalreadyexposedto
  21. 21. 21 atrazine andsoughtto exclude the effectsof othercontaminantsandenvironmental orhealthfactors. However,suchepidemiological studiescannotprove thatatrazine causesspecificdiseases. The conceptof hormesishasbeenadoptedinthe fieldsof biologyandmedicine to describe the adaptive response of cellsandorganismstomoderate stress. Mild stressinducesthe activationof signalingpathways,leadingtointrinsicchangesconferringresistance to more severe stresses. Usually, the stressorelicitsmolecularresponsesthatnotonlyprotectthe cell againsthigherdosesof the same agent,butalso againstotheragentsor evenlessspecificstressorsincludingoxidative,metabolicand thermal stress. Major componentsof the hormeticresponse includevariousstressresistanceproteinssuchasheat- shockproteins (whichAGEsmimic),antioxidantsandgrowthfactors. Besides AGEsincaramelsor toast, classicexamplesof hormeticstressare hotand coldhydrotherapy, exerciseandcalorie restriction. Studieshave consistentlydemonstratedthatmoderate levels of exerciseand calorie restriction promotes goodhealth,where higherlevelsare harmful. Growingplants needprotectionagainstradiation, bacteria,fungi,viruses andhazardousenvironmental changes. Plantsconcentrate defensive chemicalsintheirmostvulnerable parts:leaves,flowersand roots. Like the mildstressof a coldshower,analcoholicbeverage ortwo, moderate exerciseorfasting, manyof these plant‘poisons’alsoexhibithormeticproperties,beingharmful athigh individual doses yetbeingespecially beneficial atharmoniccombinationsatdietarilyrelevant low doses fromherbs, vegetablesandfruitaswell assoakedseeds, beans,nutsandgrains. The hormeticnon-linearbiphasicdose-responseexhibitsaparaboliccurve. A hormeticresponse isa special case of a largersetof dose-response curvescalled‘non-monotonicdose-response curves’, because the slope of the curve changes direction somewhere alongthe curve. Thus,J-shapedorU- shapedor inverted-Ushapedparaboliccurvesare all non-monotonic. Curvescontrast withlinearmonotonicresponses(where anincomplete range of dilutionsare tested, creatinga small linearsectionof alargerparabolic curvilinearresponse) inwhichthe slope never changessign(inotherwords,if the curve or line isupwarditalwaysremainsupward(althoughitcan change slope and flattenout). Hormesiscan be initiatedbyexposure tovariousenvironmental stressorsincludingingestionof phytochemicals. Suchexposurestypicallyresultinmildcellularstressinvolvingfree radical production, ionfluxesandincreasedenergydemand. Asa result,adaptive stressresponsepathwaysare activatedleadingtothe synthesisof proteinsthat protectthe organism againstmore severe stress. Examplesof stressresistance proteinsinclude antioxidants,proteinchaperones,growthfactors andproteinsinvolvedinthe regulationof energy metabolismaswell ascellularcalciumhomeostasis. The amountsof stress-inducingphytochemicals foundin the fruitsandvegetablesusually consumedby humansfall withinthe low-dose beneficial stimulatoryrange of concentrations. However,itiswell-
  22. 22. 22 knownthat some plantsandfungi produce andconcentrate toxinsinamounts greatenough tocause sicknessordeathinhumans. Consumptionof plantphytochemicalsinformof concentratedsupplementshasthe potential for negative healthconsequencesif the dosesconsumedexceedtoxicthreshold. Eachindividual phytochemical wouldbestbe extensivelyevaluated (andthen incombinations),includingdetaileddose- response studiesthatreveal safetyandeffectivenessinregardtodisease prevention. Low-dose extrapolationsemployedinriskassessmentswill have tostayweddedtothe low-dose linearand threshold methodologiesthatare nowfavoreduntil muchmore researchisdone. Combinationsof stimulicanhave unpredictable outcomes. Mildtomoderate exercise derivesits hormeticeffectfromthe productionof stressfulreactiveoxygenspecies. Moderate doses of antioxidant vitaminscan‘mopup’ these mildlystressful oxidants,cancellingthe benefitof exercise. Paradoxically, large dosesof antioxidant supplementsincrease oxidativestress,hormeticallyincreasingtoleranceto otherstressors. UV hormesiscanbe thoughtof as an inducedeffectthatoccursoverintervalsof time measuredin hoursor days,incontrast to the virtuallyinstantaneous damagingeffectsof UV onDNA. It relieson elicitingametabolicresponse bythe planttissue incounteringwhatitperceivesasanappliedstress. The response ischemical. Forcertaintypesof fruit,the compoundsproducedasa resultof low-dose UV treatmenthave beenidentified, includingawide range of phytochemicalsandenzymes. The critical factoris that these compoundsconferresistance toattackby manydifferenttypesof microorganisms,andmoldsinparticular. More importantly,thesenaturallyoccurringcompoundsand microbial inhibitioncanbe achievedwithoutthe use of exogenousbiocides. Manyspeciesof fruitsand vegetableshave beenshowntorespondtothisformof treatment. In commercial terms,thisstressresponseoffersawayto extendthe shelf life of freshcommodities. Hormetictreatmentsalsohave the potential toreduce waste throughdecreasingthe rate of senescence. However,muchworkremainstobe done inscalingup laboratorystudiestoenable hormetictreatmentstobe appliedcommercially. There is anotherbenefitof hormetictreatment,andthatisthatmany of the compoundsproducedby the plantin response toUV are actuallybeneficial tohumanhealth. The beststudiedexample is resveratrol ingrapes (where recentworkhasshownthatthe levelsof thiscardio-protectantmaybe increasedmanyfoldbytreatinggrapeswithlow dosesof UV). The lethal effectsof UV usedasa germicide maybe increasedbycombiningUV treatmentwiththe use of powerful oxidants,suchashydrogenperoxideand/orozone. Althoughbothof these compoundsare moderately bactericidal intheirownright,the addedeffectof UV isto bringabout a synergistic inactivationthroughthe enhancedgenerationof highlyreactive freeradical species. Ozone hasbeenassignedthe classification“generallyrecognizedassafe”(GRAS),buthydrogen peroxide residualscanpersist infoods forconsiderableperiodsof time. Thismayprove problematicin
  23. 23. 23 the treatmentof foods,asopposedtofoodprocessingequipment,oreventhe fabricof foodprocessing facilities. Careful control of peroxideconcentrationandUV dose isrequired toensure total photolysisof peroxide. The evidence supportinghealthbenefitsof vegetablesandfruitsprovidesgrounds foridentificationof the specificphytochemicalsresponsible,andforinvestigationof theirmolecularandcellular mechanismsof action. Practicallyall plantsprovidefelicitousphytochemicals,here are afew: The primarypolyphenol foundinfleshof grapesandconcentratedinwhite grape juice, hydroxycinnamicacids(alsomajorphenolicacidsinblueberriesandblackberries)are asupersetof phenolicacidswhichincludesp-coumaric,caffeicandferulicacid(majorphenolicacidsinblueberries and blackberries). Ferulicacidisabundantincell wallsof seedsof brownrice,whole wheatandoats and richin apple,artichoke,orange,peanutandpineapple. Ferulicacidisprecursor to vanillinandisantioxidantandanticancer,exhibitingantitumoractivityin breastand livercancer. Vanillin(primaryextractfromvanillabean) isantimutagenicandantioxidant, inhibitscarcinogenesis,isanti-inflammatory(inhibitsperoxynitrite) andinhibitsdouble-strandDNA breaks. Cinnamicacid(phenyl acrylicacid) providesoil of cinnamon'scharacteristicodorandflavor. It has antibacterial,antifungalandantiparasiticproperties. Cinnamicacidisbuildingblockforlignans. Ferulicacidisfoundin the leavesandseedsof manyplants,butespeciallyincerealssuchasbrownrice, whole wheatandoats. Ferulicacidisalso presentintomatoes,sweetcorn,coffee,apple,artichoke, peanut,orange andpineapple. Ferulicaciddecreasesthe levelsof inflammatorymediators (prostaglandinE2andTNF-α and nitricoxide synthase expressionandfunction. Ferulicacidandits estersare potentiallypowerful anti-inflammatorydrugs. Ferulicacidbelongstothe familyof hydroxycinnamicacid. The chemical structure of ferulicacidisverysimilartothatof curcurmin. Curcumin(diferuloylmethane) isacomponentof the yellow powderpreparedfromthe rootsof Curcuma longa(Zingiberaceae),alsoknownastumericorturmeric. Itis widelycultivatedandusedasa foodingredientintropical areasof Asiaand Central America. Treatmentof mid-passage humanepidermal keratinocyteswithcurcuminresultedinabiphasic hormeticdose–response withrespecttoproteasome activity. Curcumintreatment(upto1 μM for 24 h) increasedchymotrypsin-like activityby46% comparedto that inuntreatedkeratinocytes. However, higherconcentrationsof curcuminwere inhibitory,andat10 μM the proteasome activitydecreasedto 46% of its initial value. Furthermore,the preincubationof humankeratinocytesat43°C for 1 h, followedby24-h treatment with3 μMcurcumin,ledto an increase inheat-shockprotein(hsp70andhsp90) levelsby24% and 19%, respectively,andthe effectwassustainedatconcentrationsupto10 μM. Onthe other hand,the level of the small hsp27 wasunaffectedbycurcuminconcentrationsof 0.3–1 μM, while itdecreasedby34% at 10 μM.
  24. 24. 24 Chalcone isan α,β-unsaturatedaromaticketone presentinashitaba(Angelica keiskeiKoidzumi),a white turmerictraditionallyusedinJapanese’scuisine. Chalcone hasantibacterial,anti-fungal,anti- tumor andanti-inflammatoryactivities. The anti-inflammatoryeffectsof chalconesrelyontheirability to regulate nitricoxide andcytokineproductioninmacrophages,aswell as topreventtumornecrosis factor-α andlipopolysaccharide-inducedneutrophil adhesion. Chalcone alsosuppressesthe activityof cycloxygenase-2and5-lipoxygenase. Bloodsugarlevelermethyl hydroxychalconeisfoundincinnamon. Hops contain chalcones,xanthohumol anddehydrocycloxanthohumol hydrate. Polyphenolcompoundsfoundingreenteainclude epigallocatechin-3-gallate (EGCG),epicatechin-3- gallate (ECG),epigallocatechin(EGC) andepicatechin(EC),andtheirintake hasbeenassociatedwith reducedriskof coronary arterydisease. EGCG isthe most abundantandactive catechinderivative,and has beenshowntopossessbothanti-inflammatoryandanti-atherogenicproperties. EGCG up-regulates hemeoxygenase-1(HO-1) expressionby hormetically activatingthe Nrf2/AREpathwayinendothelial cells,conferringresistance againstH2O2-inducedcell death. Luteolin isa widespread citrusflavonoid aglyconstructurallyrelatedto quercitin. Most oftenfoundin leaves,butitisalsoseenindandelion,rinds, barksandcloverblossomand ragweedpollen. Dietary sourcesinclude celery,greenpepper,thyme, aswell as perillaandchamomile tea. Topical applicationof luteolincausessignificantreductionof skintumorincidence andmultiplicityinamouse model. Incell culture studies,luteolinhasbeenshowntobe apotentinhibitorof cyclin-dependentkinases,toinduce cell cycle arrestin humanmelanomacellsandapoptoticcell deathinhumanmyeloidleukemiacells. Luteolinalsosensitizescancercell linestoTNFα-dependentapoptosisbyinhibitingthe NF-κBpathway. In additiontoanticancerpropertiesluteolinhasalso showntoprotectneuronal cell linesagainstH2O2 inducedoxidative damage. Phenethylisothiocyanate occursnaturallyincruciferousvegetablessuchas Chinese cabbage,turnips, rutabagas,watercressandradishes. Isothiocyanateisliberatedfromitsglucosinolate precursor gluconasturtiinbyhydrolysisfollowingdisruption (crushing,shreddingandchewing) of the planttissue and liberationof the plantenzymemyrosinase. Glucosinolateshave beenshowntoinhibitthe tumor causingeffectsof variouscarcinogens. Sulforaphaneisarelatedphytochemical presentinhighamounts inbroccoli sproutsand cruciferousvegetables. Piceatannol isolatedfromthe seedsof Euphorbia lagascae,isastructural homologof resveratrol and bothare foundinred wine. Piceatannol isananti-inflammatory,immune modulatoryandanti- proliferative compound. Piceatannol inhibitsthe release of nitricoxide,PGE2and pro-inflammatory cytokinesinadose-dependentmanner. The protective effectaffordedbypiceatannol isreportedly strongerthan the effectof resveratrol. Life extensionandneuroprotectiveeffectsof resveratrolhave beenreportedbymanydifferent researchers. ItprotectedculturedPC12neural cellsagainstAβtoxicityanddopaminergicneuronsin midbrainslice culturesagainstseveral differentinsults. Resveratrol alsoprotectedhippocampal neuronsagainstnitricoxide-mediateddeath,preventedaxondegenerationandprotectednematode and mammalianneuronsagainstmutantpolyglutaminetoxicity.
  25. 25. 25 Resveratrol wasfoundinvaryingamountsbetween7- 5800 ng/gdry sample inbilberry,cranberry, deerberry,Elliott'sblueberry,highbushblueberry,lingonberry,lowbushblueberry,rabbiteye blueberry, sparkleberry andPartridgeberry. Lingonberrywasfound tohave the highestcontentcomparabletothat foundingrapes,6500 ng/gdry sample. Seanolis a unique patentedpolyphenol/phlorotanninextractfromEckloniacavamarine red/brown algae grownoff the coasts of Koreaand Japan. Polyphenols,whichare antioxidantsfoundinmanyland- basedproductssuch as berries,tealeaves,grapes,pomegranates,fruits,andvegetables(andin Seanol), have a molecularstructure of twoto four connectedrings. These rings“trap” damagingfree radicals. Trans-resveratrol fromredgrapeshasa two-ringmolecularstructure and,greenteahasa four-ring molecularstructure. However, Seanolhassimilarpolyphenolsandphlorotannins,whichhave amore sophisticatedmolecularstructure of eightrings,whichallowsittotrap manymore free radicals. Seanolis bothwaterand fat soluble,soit caneasilypenetrate phospholipid membranes,workinginside of cellsformaximumprotection. Evenbetter,iteasilycrossesthe blood/brainbarriertogive the brain extraantioxidantprotection. Since Seanolisfatsoluble,itstaysinthe body longer,asmuch as 12 hours, comparedto watersoluble antioxidantswhichare excretedinthe urine in roughly 30minutes. Seanolhelps increase brainalphawaves,agoodindicationof relaxingbloodvesselsto the central nervoussystem andincreasingbloodflow,promotingbrainactivity aswell as increasingenergyand endurance. Seanolalsohelpsstimulate the productionof acetylcholine,the brainchemical of learning and memoryaswell asthe neurotransmitterthatmodulates andreduces immune inflammatory response inthe digestive system, jointsandarteries viathe vagusnerve. Blueberrysupplementationpreventedlearningandmemorydeficitsinamouse model of Alzheimer’s disease. Dietarysupplementationwithblueberryextractincreasedthe survival of dopamine-producing neuronsina model relevanttoParkinson’sdisease. Blueberriesextractincreasedthermal stress resistance andincreasedlifespanin the nematode,suggestinganevolutionaryconservationof phytochemical hormeticresponse pathways. Supplementationof the dietof 19 month-oldratswith strawberry,blueberryorspinachextractsfor8 weeksresultedinthe reversal of age-relateddeficitsin several neuronal andbehavioral parameters. Inan animal model of stroke,curcurmin (fromturmeric) protectedneuronsagainstischemiccell death and amelioratedbehavioral deficits. Inarat model of Parkinson’sdisease,curcurminprotected dopaminergicneuronsagainst6-hydroxydopamine toxicity. A hormeticmechanismof actionof curcurminis likely since levelsof expressionof the stressresponse proteinHO-1were increasedin culturedhippocampal neuronstreatedwithcurcurmin. Curcurminalsohasbeenshowntoreverse chronicstress-inducedimpairmentof hippocampal neurogenesisandincrease expressionof brain- derivedneurotrophicfactorinananimal model of depression. Wildgingeris alsoa likelycandidatefor a hormesiseffect. The radiumpad (lowdosage radiation) isanexample of hormesis fromthe EdgarCayce readings. The Cayce readingsoftenextolledthe healingpropertiesof oliveoil. The followingstoryillustratesan
  26. 26. 26 unusual applicationinvolvingverysmall amounts of oliveoil takenorallyforacidreflux (oftencausedby large amountsof fat or oil): "SevenyearsagoI had my gallbladderremovedbecause of gallstones,andwithinafew monthsI beganto have acid reflux (heartburn). TUMS relievedit,butwithinacouple yearsIwasup to four of the largestsize TUMS a day. Preferringtointerfere withmydigestive physiologyaslittle aspossible,Ididn't wantto take anyof the acid blockermedicinesthatare now available. Instead,Irecalledthatthe Cayce readingshadsaidthat olive oil takeninverysmall doseswouldbe soothingandhealingtothe digestivesystem,alongitsentire length. Forexample,reading5422-2, given for ulcers,saidtotake a half teaspoonfuleveryfewhours. Anotherreading,760-7,for impactedcolon, explainedthat,"Thischaracterof oil,as seen,isfoodvalue fortissue thatisdeadenedbyinactivity throughthe form of conditionsexistentinsystem." The readingswere clearthatsmall doseswouldbe the most effective,nomore thana half a teaspoonful takeneveryfewhours. "I begantotake verysmall dosesof extravirginoliveoil (nomore thana quarteror half of a teaspoon about4- 5 timesa day),basedon the mostcommonrecommendationinthe readings. Withinacouple weeksInoticedthatI had lessneedof TUMS. Afterafew months,Iwas downto needingatmostone TUMSa day, and mostdaysno medicine atall. My overall digestionfeltalotbetter,too. Agingisprimarilythe resultof afailure of maintenance andrepairmechanisms. Hormesisisa promisingapproachformodulatingagingandage-relateddiseasesviamodeststimulationof various cellularandbiochemical functional characteristicsof humanskinfibroblasts. Beneficial effectsincludethe maintenance of afavorable stressproteinprofile,reductioninthe accumulationof oxidativelyand glyco-oxidatively misfolded damagedproteins (AGEs),stimulationof the proteasomal activitiesforthe degradationof abnormal proteins,improvedcellularresistance toother stressesandenhancedlevelsof cellular andmitochondrial antioxidantability. The progressionof cellularagingcanbe slowedwithoutupsettingthe regulatorymechanismsof the cell cycle byusingthe body’sintrinsiccapacityforself-maintenanceandrepair,where through protective low-dosetoxinhormeticeffects,the qualityof lifeof cellsintermsof theirstructural and functional integritycanbe improvedwithoutpushingthem intoapotentiallycarcinogenichyper- proliferative mode. Progressiveaccumulationof moleculardamage tohumanskinfibroblastsandkeratinocytes,ahallmark of cellularaging,isthustreatable by targetedbiological hormeticinterventionsandpreventions. Applicationof hormesisasananti-agingapproachisgainingwide recognitionandacceptance. Various chemical stressors,includingoxidants,bothsyntheticandnatural (suchas hydrogen peroxide and1,4- dioxane) are reportedtodelayagingandprolonglife invarioussystems, whentheyactas hormetins. Almostall antioxidantsshowhormeticdose response andbecome pro-oxidantsabovecertaindoses. Furthermore,insome casessuchas alphalipoicacidandcoenzyme Q10, itis theirpro-oxidantactivityin
  27. 27. 27 producinghydrogenperoxide (whichinducesdefensive responses),which isthe sourcesof theiroverall beneficial effects. Hormesis isa commonphenomenonindermatology. Skinisanexcellenthormesiscandidatedue toits repertoire of inflammatoryandimmune-modulatingcytokines,hormonesandvitamins, aswell as its unique responsestoultravioletlight,toxinsandinjury. More focus couldbe redirectedfromlooking onlyat adverse effectsathighlevelsof exposure tocharacterizingthe complex beneficial biological effectsthatoccur at low and ultralow levelsof exposure. Molecularmechanismsfacilitatinghormeticeffectscomprise of acascade of stressresponse maintenance andrepairpathways. Althoughthe extentof immediate hormeticeffectsafterexposureto a particularstressmay onlybe moderate,chainsof eventsfollowinginitial hormesiscanleadto biologicallyamplifiedeffectsthatmaybe much larger,synergisticand pleotropic. The consequence of hormeticamplificationisincreasedoverall cellularandsystemicdefensecapacity of the organism. Exposure tolowdosesof potentiallyharmfulagentscanhave a varietyof beneficial anti-agingandlongevity-extendinghormeticeffects. Too muchstress can overwhelmandexhaust,but the right amountcan increase strengthandendurance, prolonglife andbringotherbenefits. Just about any stimulus can be beneficial or harmful, depending on dose, duration, perception and individual response. Steven N. Green, DDS, 10261 SW 72 St., #106, Miami, FL, 33173, 305-273-7779 ddsgreen@bellsouth.net antiagingdentist.com September 26, 2009

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