Metabolism, Mitochondria and Epigene5cs

NeilMcKinney,BSc.,ND

NaturopathicPhysician

Dr. Neil McKinney, BSc, ND

•  Clinicalprac:ceofintegra:vemedicinefor33+years.

•  CancerResearchersince1977.

•  FounderofBoucherIns:tuteofNaturopathicMedicinewww.binm.organdtheB.C.NaturopathicAssocia:onwww.bcna.bc.ca

•  ProfessorofNaturopathicOncology.

•  AuthoroftextbookNaturopathicOncology

www.drneilmckinney.ca

In Sickness and in Health

Disadvantage

• Diabe:c

• Obese

•  Sedentary

• Carnivorous

•  Immuno-compromised

•  SAD-highlyprocessedfood

•  Exposedtopollutants,heavymetals

Advantage

• Pesco-vegetarian

• Mediterraneandiet

•  Lowcarbohydrateintake

• Wholefoods

•  Exercisehabit

• Non-chao:clifestyle

•  Zestforlife

• Cleanenvironment

Insulin, IGF-1 and Diet

• Highsugarandcarbohydrateintakemayrampupinsulin,anutri:onpumpthatsomecancersusetodriverapidgrowth.

• Pastacertainthresholdofbloodinsulin,humanliversmakeIGF-1,apotentgrowthfactorandamplifierofhormonereceptors.Linkedtoobesityanddisease.

•  IGF1andIGF2canpromotecancergrowththroughparacrineandautocrinesecre:on.

•  IGF-1naturallyoccursinthemeatandmilkofgrassfedherdanimals–eg.pigsandcows.

•  Itisdoubledifanimalsarecorn-fed.

Remember what happened to the last corn-based culture?

See “Guns, Germs and Steel”, by Jared Diamond, Pulitzer Prize

winner 1998.

SAD – Standard American Diet

• Ancestralhunter-gathererdiets,foralmostallofhumanhistory,providedasodiumtopotassiumra:oof1:10.

• Pre-agricultureandearlyagriculturedietsproducedaNEAPnetalkalinebalanceof88mEqdaily.

•  ThemodernwesterndietcreatesaNatoKra=o˃3:1-a30-foldchange!

• Andwithitcameachangetoanetacidresidueof48mEqdaily-a3foldchangeinalkalinetoacid!

• Acidformingfoods:salt,sugar,sodas,andmeat.Alkalinefoods:plants.

• Acidreducesoxygensatura:on,inducinghypoxia.Cancersareacidandhypoxic…

Acidosis,HypoxiaandBone,Arne`,Arch.Biochem.Biophys.2010;503(1):103-109

pH:DietInducedCellularAcidosis,JoePizzorno,ND©2012.

Diet,evolu>onandaging--thepathophysiologiceffectsofthepost-agriculturalinversionofthepotassium-to-sodiumand

base-to-chloridera>osinthehumandiet,Frasse`o,etal.,Eur.J.Nutr.2001Oct;40(5):200-13.

Cancer and Fetal Cells – Asymmetric Mitosis

• Humansstartoutasaneggandaspermfloa:nginalowoxygenfallopiantube.

• Undifferen:atedbiomassaccumulates.

•  In:methefetusimplantsandgetsastrongbloodsupplybybuildingaplacenta.Oxida:vemetabolismincreases.

• Alerthefirsttrimesterstemcellsreproducedifferen:atedcellsbyasymmetricmitosis.

•  Differen:atedcellslosttoapoptosis,

autophagy,necrosisortrauma,are

replacedbystemcells,whichalsogive

risetoareplacementstemcell.

Nuclear DNA Muta5ons and Cancer

•  Soma:cmuta:ontheorypostulatesmuta:onsinchromosomalDNAresultinthecancercellphenotype–exponen:algrowthbysymmetricalmitosis.

• WarrenSchaefferatUniversityofVermontshowedthatpunngahighlymutatedcancercellnucleusintoanormalenucleatedcelldidnotconvertthatcelltoacancerphenotype.

• However,punnganormal,non-mutatednucleusintoanenucleatedcancercellresultedinafullymalignantgrowthpa`ern.

Thereforecancerisdrivenbycytoplasmicfactors:mitochondria!

CytoplasmicMedia>onofMalignancy,Israel&Schaeffer,InVitroCellDev.Biol.1988;24(5):487-490.

Glycolysis Drives Cancer Growth and Spread

Howfastatumourgrowsandhowaggressivethecanceriscorrelateswith:

• alowernumberofmitochondria-aslowas50%thatofnormalcells.

• remainingmitochondriaincancercellsareolendamaged-ddistordistortedintodumbbellandcupshapes,missinginternalmememmembranes,andwithabnormalfatsandproteins.

• theincreaseinglycoly:cfermenta:onofglucose.

TrippingOvertheTruth:TheReturnoftheMetabolicTheoryofCancerIlluminatesaNewandHopefulPathtoaCure,TravisChristofferson,2014;CreateSpaceIndependentPublishingPlaqorm.

Mitochondrial Carcinogenesis

Seyfriedhasshowndamagedmitochondriaunleash

→ac:va:onofthep13/aktnetwork

→retrogradesignalling

→epigene:cchanges

→alterednuclearDNA

→metabolicreprogramming

→changesinmanycellularprocesses

Seyfried on Metabolic Carcinogenesis

• Warburgshowedcancercellscon:nueanaerobicglycolysisinthepresenceofoxygen.

• Pedersencirca1978showedincreasedfermenta=onascancersgrowfasterandmoreaggressively,linkedtolowernumberandstructuralabnormali=esofmitochondria.

•  Seyfriedshowedmitochondrialdamagealterssignalstotranscrip=onfactorMYCcontrollingabout15%ofthegenome,triggeringcarcinogenesis–reversiontoaprimi:veanaerobicmetabolicstate.

• Retrogradesignalling-cytoplasmtonucleus-precedesnuclearmuta:ons!

CancerAsAMetabolicDisease–OntheOrigin,ManagementandPreven>onofCancer,ThomasN.Seyfried,PhD,2012,JohnWiley&Sons.

MitochondriaandCancer,Wallace,NatureRev.–Cancer2012;12:685-697.

Kinases, Phosphatases and Hexokinase

• Kinasesaresignallingproteins.Theya`achaphosphategrouptoproteinstoturnonafunc:on.

• Phosphatasescleaveoffphosphategroups,oleninac:va:ngtheproteinorenzyme.

• CancercellsproducehexokinaseIItoturnglucosetoglucose-6-phosphate,

butunlikenormalhexokinaseH2isnotslowedbybuild-upofitsproduct.

Thefermenta:onthro`leisstuckon.

• HexokinasebindstovoltagedependentanionchannelsVDACthatrelease

cytochromectoini:ateapoptosis.HexokinaseIIcompensatesforenergyloss

duetodamagedandabsentmitochondria,andimmortalizesdamagedcells.

Mighty Mitochondria from Mommy

• Upto40%ofacell’scytoplasm.

•  100,000inanoocyte.

•  100inaspermatozoa.

•  10trillioninanadult.

•  10%ofourbodyweight.

• GenerateourbodyweightinATPdaily.

•  9ouncesofATPincircula:onatanymoment.

Other Mighty Mito Func5ons

• Redoxmodula:on.

• Genera:onofROSforcellularsignaltransduc:on,regula:onofnucleartranscrip:onfactors.

• Biosynthe:cprecursors–acetyl-co-Aandpyrimidines.

• Biosynthesisofanaboliccarbonskeletonsandnucleicacidprecursors.

• Regula:onofcytosolicioniccalciumlevels.

• Controlofapoptosis–viapermeabilitytransi:onporeforcaspases.

Mitochondrial DNA

•  24genesinmitochondria.

• Bacteria-likecircularDNA!Abillionyearsofsymbiosiswitheukaryotecells.

•  3,000mitochondrialrelatedgenesinnuclearchromosomalDNA.

•  13cri:calOXPHOSgenesinmtDNA,someinnuclearchromosomalDNA.

• MitochondriahavetheirownDNArepairsystems.17Xhighermuta:onratethannuclearDNA.

• Highoxida:vestressfromleakageofoxygenandfreeelectronsduringoxida:vephosphoryla:on.10XhigherROSexposurethannuclearDNA.MitochondrialNADPHprotectsfromROS.

• Darlingtoncirca1948foundmitochondrialDNAfarmoresensi:vetoknown“carcinogens”thanchromosomalDNA.

Mitochondrial Poisons

•  arachidonicacid.

•  alcohol,tobacco,cocaine,methamphetamines,

• AIDSdrugssuchasAZT;an:-viralnucleosideanaloguessuchasganciclovir.

•  an:fungalssuchasketoconazole,griseofulvin,cyclosporine;cordyceps(?).

• NSAIDssuchasibuprofen,indomethacin,acetaminophen,aspirin.

•  an:bio:cssuchasrifampin,isoniazid,tetracycline,gentamycin,fluoroquinolone,adriamycin.

•  cyclophosphamide,amiodarone,valproate,phenytoin,chloroquine,quinidine,clofibrate,fenofibrate,fluoxe:ne,haloperidol,risperidone,chloroform,amytal,propofol,hydrazine,isoflurane,chlorpromazine,meqormin,lidocaine,bupivacaine,capsaicin,cholicacid,L-DOPA.

•  cyanide,heavymetals,andpes:cidesegheptachlor,chlordane,rotenone,anddioxin.

Mitochondria Burn Out

• MitochondrialDNAandit’srepairsystemsaredis:nctfromandlessrobustthanforparental,nuclear,chromosomalDNA.

•  Electronstransportspills1to2%ofelectronsand6%ofoxygenasROS(freeradicalsofoxygen)egsuperoxideradical.

• Over-feedingofsugarsandcarbohydratesarestokingthesefires.

Mitochondria Damage and Lifespan

•  8-oxo-7,8-dihydro-2’-deoxyguanosine

(8-oxodG),isamarkerofoxida:vestress.

•  Inverserela:onshipbetweenmaximum

lifespanand8-oxodGmtDNA–not

observedwithnuclearDNA.

•  8-OHdG˃4=hightoxicload,egmercury,

tobacco,persistentorganicpollutants(POPs).

Oxida>veDamagetoMitochondrialDNAisInverselyRelatedtoMaximumLifespanintheHeartandBrainofMammals,Barja&Herrero,FASEBJ.2000;14(2):312-318.

AUTOPHAGY

• Autophagyismediatedbymembranephospholipids,andmTOR.

• Autophagyremovesproteinaccumula:onsinvolvedinneurodegenera:vediseases,andpurgesandrecyclesdamagedcellorganelles.

• Dysfunc:onofautophagymayresultinabnormalmitophagy.

•  Lossofmitochondrialfunc:onandoxida:vestressarehallmarksofaging.

•  Supportautophagywithsulforaphane,resveratrol,co-enzymeQ-10,berberine,querce:n,greenteaEGCG,vitaminE,curcumin.

Mitochondropathies

• Metabolicsyndrome

• Diabetes

• Cardiovasculardisease

• Neuro-degenera:vedisease

• Neuro-behaviouraldisorders

• Psychiatricdisease

•  Fa:guesyndromes

• Musculo-skeletaldisease

• Aging

• Mitochondropathies(MCP)shouldbeconsideredinanypa:entwithunexplainedprogressivemul:systemdisorder.Finsterer2004

Mitochondropathies

• Centralnervoussystem:schizophrenia,bipolardisease,migraineheadaches,uppermotorneuronsigns,ataxia,extrapyramidalmanifesta:ons,calcifica:ons,epilepsy,Alzheimer’sneurodegenera:vedemen:a,atrophicdemen:a,Parkinson’sdisease,amyotrophiclateralsclerosis,transmissiblespongiformencephalopathies,transientischemica`ack,stroke,MELASsyndrome-mitochondrialencephalopathy,lac:cacidosis,andstroke-like-episodes,myoclonicepilepsywithraggedredfibers(MERRF)syndrome,Kearns-Sayresyndrome(KSS),maternallyinheritedLeighsyndrome(MILS),andtheneuropathy,ataxia,andre:ni:spigmentosa(NARP)• Peripheralnervoussystem:neuropathicpain,myopathy,polyneuropathy.

Mitochondropathies, con5nued

• Cardiovascularsystem:cardiomyopathy,coronaryarterydisease,impulsegenera:onorconduc:ondefects,lelventricularnon-compac:onheartfailure,heartischemia.

• Metabolic:diabetes,lactacidosis,shortstature,hyperhidrosis,hyperlipidaemia,hypogonadism,amenorrhoea,delayedpuberty

•  Sensory:re:ni:spigmentosa,cataract,glaucoma,op:catrophy;deafness,:nnitus,peripheralver:go.

• Gastrointes=nal:hepa::sC,primarybiliarycirrhosis,dysphagia,vomi:ng,diarrhea,pancrea::s,pancreasinsufficiency,pseudo-obstruc:on.

• Other:chronicfa:guesyndrome,fibromyalgia,renalfailure,renalcysts,sideroblas:canaemia,prematureaging.

Mitochondrial Phospholipids

• Mitochondrialinnermembranesseeoxida:vedamagetophospholipidslikecardiolipinandothermolecules,resul:nginlossoftransmembranepoten:al,electrontransportfunc:on,andgenera:onofhigh-energymolecules.

•  Lipidsarecentralinrestoringmitochondrialfunc:onandreducingfa:gueinagedsubjectsandpa:entswithavarietyofclinicaldiagnosesthatarecharacterizedbylossofmitochondrialfunc:onandincludefa:gueasamajorsymptom,egCFS.

• Oralsupplementsformembranerepairandreplacementu:lizemixturesofglycerophospholipids,n-3andn-6unsaturatedFAandotherlipidcomponentsderivedfromlegumes,milk,liver,fish,krill,andsealoil.

Mitogenesis

• Mitogenesisismediatedbyperoxisomeproliferator–ac:vatedreceptorgammaγcoac:vator1α(PGC-1α);PPARisinhibitedbyFWGEandredwine.

• PGCisrelevanttomitochondrialdynamicssinceitisatranscrip:onalcoac:vatorofthefusionmediatormitofusin-2.

• Mitochondrialfusionwithendoplasmicre:culumnetworkstheoxygenandnutrient-sensingpathways.

• Mitochondrial-ERcalciumchannelsregulatePDHac:vityandapoptosis.

•  Themitochondriaandendoplasmicre:culumalsointeracttocreatemicro-environmentsthatdirectfission.

MitochondrialDynamics–MitochondrialFissionandFusioninHumanDiseases,Longo,N.Eng.J.Med.2013;369(13):2236-2251.

Mitochondrial Biogenesis

•  Exercise.

•  Cellularnitricoxidelevels;increasedbygrapeseedextract.

•  Ac:va:onand/orincreasedcontentoftheproteinAMPK-

AMP-ac:vatedproteinkinase,ametabolicmasterswitch.

AMPKisac:vatedbyberberine.

• Ac:va:onand/orincreasedcontentofthe“fountainof

youth”sirtuinproteinSIRT1,aNAD-dependenthistone

deacetylase;SIRT1isincreasedbycaloricrestric:on,

resveratrol,querce:nandexercise.

• PGC-1αtranscrip:onalcoac:vatorisalsokeyto

mitogenesis,andisalsoincreasedbyresveratrol.

Rx, or take a walk…….

• MeRorminac:vatestheenzymeAMPK

(5’AMP-ac:vatedproteinkinase)which

directlys:mulatesmitogenesis.

•  Sodoescurcumin,querce=n,(-)-epigallocatechin-3-gallate

EGCGingreenteaextract,andresveratrol

•  Sodoesexercise.

Mitochondrial Biogenesis

• Ac:va:onand/orincreasedcontentofthe“fountainofyouth”sirtuinproteinSIRT1,aNAD-dependenthistonedeacetylase;SIRT1isincreasedbycaloricrestric:on,resveratrol,querce:nandexercise.

• PGC-1αtranscrip:onalcoac:vatorisalsokeyto

mitogenesis,andisalsoincreasedbyresveratrol.

• PQQ–pyrroloquinolinequinones:mulatesbiogenesis.

•  Fuelledbyhighenergysubstratessuchasketonesandlactatewhichcanbescavengedfromstromalfibroblasts.

Mitochondrial Rescue

• R+ALA300mgbid–:d

• D-ALAbyIV150mgbiweekly

• Thiamineorbenfo:amine-vit.B1-100-160mgbid.

• Acetyl-L-carni:ne1,000mgbid

• Co-enzymeQ-10300+mg

• Glumetza(ERmeqormin)Rx500mgqd-bid.

• Low-doseNaltrexoneRx4.5mghs.

•  IV-DCA,LAMC,thiamine,grapeseedextract,querce:n,berberine,HBO2T,riboflavin-5-phosphate,niacinamide,Ca,Mg,Zn,Cu,Cr,Fe,proline.

• Acup:CV-4,PC-6,ST-36.

MetabolicTreatmentofCancer:IntermediateResultsofaProspec>veCaseSeries,Schwartz,Buhler,Icard,etal.,An=cancerRes.2014;34(2):973-980.

Mitochondrial Resuscita5on

•  PQQ-pyrroloquinolinequinone–potentcon:nuouscyclingan:oxidant.Ac:vatesAMPkanenzyma:cmasterregulatorofenergymetabolism.

•  Synergis:cwithCo-Q10inmanagingelectrontransport,protec:ngmitochondrialmembranesandDNAfromoxida:vedamage.Rx10–20mg.

• Melatonin,vitaminA,magnesium,B-complexvitamins,selenium,SOD,glutathione,resveratrol,coriolus,berberineandiodine.

•  Aerobicexercisecanhelp,andfoodssuchasoliveoil,lemongrass,berries,grapes,pomegranate,apples,chilipeppers,onions,garlic,Brassicasandwholegrains.

•  Centellaasia>careducesmitochondrialROSandpreventsdysfunc:onoflipids,proteinsandDNA.

•  Curcumin?Resveratrol?Ginkgo?Crea:ne?VitaminE?MCTs?

•  HeavymetalsincreasemitoROSincreasingDNAmuta:ons.Cadmiumisapotentmitochondrialpoison.WalterCrinnion,ND-liverenzymesthatdetoxifyorganicsfunc:onbe`eralertoxicmetalsareremoved.

DCA - Dichloroacetate

• DCAselec:velypromotesmitochondria-regulatedapoptosisandinhibitstumourgrowthinpreclinicalmodelsbyshilingtheglucosemetabolismincancercellsfromanaerobictoaerobicglycolysis.

• DCAselec:velyinducesphospha:dylserineexternalisa:onbutsuppressescaspase3/7ac=va=on,interferingwithefficacyofcispla:nanddoxorubicin.

• DCAdoesnotinfluencethecytotoxicityoftemozolomide,usefreely.

• Accumulatesinnervous:ssue.Neuropathylimitsitsoraluse.Publishedresultswithhumanbraintumoursat6.25mg/kgbid-about750mgdaily.

• Oraldosesof12.5mg/kgX1month,about500mgbid,then:d-ordoubledose,un:lAEsoccur–numbness,:ngling,psychosis,paralysis,ataxia.

DCAac=vatespyruvatedehydrogenasekinase,triggeringaninfluxofacetyl-CoAintomitochondria.ThisdrivesmoreNADHintocomplexI.

Superoxidesthatformareconvertedintohydrogenperoxidebymanganese-superoxidedismutase.TheH2O2inhibitsproton(H+)efflux,reducingmitochondrialmembranepoten:alΔψm,theproton-drivingforce→ATP

Thisopensthemitochondrialtransi=onpore(MTP),inhibi:ngcalciumionentryviavoltage-dependentchannels.Reducedintra-mitochondrialcalcium(Ca++)suppressesatonicac:va:onofnuclearfactorofac:vatedT-lymphocytes(NFAT).

NFAT1isanucleartranscrip:onac:vator,similarinac:ontoac:vatorprotein1(AP-1)andnuclearfactorkappaB(NFκB).

ThisreducesKv1.5expression,increasingpotassiumionK+efflux,reducinginhibi:onofcaspases,andfinallytriggeringcancercellapoptosis.

AMitochondria-K+ChannelAxisisSuppressedinCanceranditsNormaliza>onPromotesApoptosis&InhibitsCancerGrowth,Bonnet,Archer,Allalunis-Turner,etal.,CancerCell2007;11(1):37-51

Managing DCA Neuropathy

•  ThiamineorB1asfatsolublebenfo=amine100-200mgbidpreventsperipheralneuropathy

• R+alphalipoicacid300mgbid–:dpreventsseda:on,confusion,hallucina:ons,memoryproblems,handtremor.CanbegivenIVornebulized.

• ProtonpumpinhibitorssuchasPantoprazole(Pantoloc)40mgqdpreventsheartburn,nausea,vomi:ngandindiges:on.

• Methylcobalamin(B-12)1000-2000mcg,acetyl-L-carni:ne1,000mg:d.

EffectofThiaminePhosphatesontheAc>vityofRegulatoryEnzymesofthePyruvateDehydrogenaseComplex,Parkhomenko,Chernysh,Cjurilova,et.al.,Ukr.Biokhim.Zh.1987;59(5):49-54.

IV-DCA •  Lemmoprotocol:DCA–1,000→2,000→3,000mg

(rampupin3increments:4,8and12mLof250mg/mLDCA).

•  Saline100ml.

•  VitaminC–2,500mg.

•  B-complex–1cc.

•  B12–1mg.

•  B6–100mg.

•  B5–250mg.

•  B1–100mg.

•  Infusedover30-60min.

•  Twiceweeklyfortwoweeks,thenaweekbreak,repeat.

•  Evaluateprogressat10–12infusions.

ANovelForm(IV)ofDichloroacetateTherapyforPa>entswithAdvancedCancer:AReportof3Cases,Khan,Marier,Marsden&Andrews,Altern.Ther.2014;20(Suppl.2):21-28.

DCA Synergies

• Givepiggy-backwithD-ALA150mginfusions.

• CaffeinecanimproveresponsestoDCA,indosesofabout480mgdailyorabout12cupsdailyofblacktea.

• Meqorminishighlysynergis:c.Othersynergistsaregrapeseedextract,curcumin,querci:n,resveratrol,selenium,IV-vitaminC,Temozolamide.

• Aninteres:ngnewconceptisweeklyalterna:ngwithartemesinin,orIVartesunate,asDCAhelpscancercellsrechargewithiron.

Alpha Lipoic Acid

• An:oxidant,hypoglycemic,mitochondrialandepigene:ceffects.

• PotentnaturalPDKac:vator(cfthiamine–B1),inhibitsPDK1andreprogramscancercellmetabolism,likeDCA.

• Modulatescancerstemcells,chelatesheavymetals,increasesglutathione&immunoglobulins.InhibitsTGFβ-1,angiogenesis,NFκB.

• Preventsandtreatsneuropathy.

• Mayprovokehypoglycemia.Maymildlyinhibitthyroidfunc:on.

• AvoidcurcuminandartemesininwhileonALAtherapy.

R-LipoicAcidInhibitsMammalianPyruvateDehydrogenaseKinase,Korotchina,Sidhu&Patel,FreeRad.Res.2004;38(10):1083-1092.

Alpha-LipoicAcidinducesApoptosisinHumanColonCancerCellsbyIncreasingMitochondrialRespira>onwithaConcomitantO2-*-Genera>on,Wenzel,Nickel&Daniel,Apoptosis2005;10(2):359-368.PMID15843897

IV-D-ALA

• BiweeklyD-ALA150mgIVdrips.

•  10mLof15mg/mLD-ALAin250mLsaline.

• nothingelseinthebag.

• protectfromlight,withfoil.

•  runin≤1g`/sec.

•  takesabout1.5hours.

•  con:nueoraldosingofR+ALA300mgbid.

CurcuminInducestheMitochondrialPermeabilityTransi>onPoreMediatedbyMembraneProteinThiolOxida>on,Morina,Barthelemyc,Zinia,etal.,FEBSLe]ers2001;495(1-2):131-136.

Nebulizing D-ALA

•  Injectablegrade15mg/mLD-ALA.NOTracemicDL-ALA!

• Alwayskeepoutofthelightasmuchaspossible.

• Rentorpurchaseanebulizerfromapharmacy.

• Usea3ccsyringetopulloutthemedicinefromarubber-topmul:-dosevial.

• Alwayswipethetopofthevialwithalcoholbeforepunngawayinthefridge.

• Put1mLmedicineinthemedicinecupofthenebulizer,whichisprotectedfromlightbywrappingitwith:nfoil.Dilutein4mLcleanwater.

• Over:meyoucantryincreasingthedoseto2to3mLofmedicine,dilutedin2to3mLcleanfilteredwaterqstomake5mLtotal.

Nebulizing D- ALA and DCA

•  Turnonthepumpandthroughafacemaskorbreathingtubebreathinthemedicineasamist.Breathenormally.Alerabout10minutesthemedicinewellwillgodryandyou’llhearitspu`ering.Turnoffthenebulizerpump,andrinseeverythingofffornext:me.

•  Youcandothistwiceadayathome,itisaboutaseffec:veasanintravenousdrip,andalotcheaper.

•  Itissynergis:ctoaddDCA(dichloroacetate)250mg/mLwiththeD-ALA.Westartwith1mLofeachmedicine,plus3mLofwater.Laterwecangoupto2mLofeachplus1mLwater.Donotletstandlong,asaprecipitatecanform.

Lipoic Acid Mineral Complex

• Poly-MVAisapalladium-lipoicacidcomplex.

• Redoxagent,facilitatesenergychargetransfer,co-factorforoxida:onofpyruvatetoacetylco-A.

• Reduceslipidperoxida:onandincreasesGSH.

• Oraldoses:10-20mLbid–:d.

•  IV–5to40mL2Xweeklyin100-250mLD5W/NS.

•  Instage4:upto5days/weekX4weeks,then3X/weekX8weeks,then1X/weekfor12weeks.

•  Synergis:cwiththiamine,dichloroacetate.

Polygonatum spp.

Solomon’ssealherborPolygonatumcan:

•  induceautophagyincancercells.

•  Induceapoptosisincancercells

•  Bothinvolvemitochondria-mediatedROS-p38-p53pathways

•  AlsoblocksRas-RafandP13K-Aktpathways.

•  BlocksepidermalgrowthfactorreceptorEGFR.

•  InhibitsexpressionofhexokinaseIIwhichdrivesglycolysisorfermenta:on,andlocksthemitochondrialvoltagedependentanionchannels(VDAC)throughwhichATP,caspasesandcytochromec,blockingapoptosisandimmortalizingthecancercell.

Wang,Yu,Bao&Liu,PolygonatumcyrtonemaLec>n,APoten>alAn>neoplas>cDrugTarge>ngProgrammedCellDeathPathways,Biochem.Biophs.Res.Comm.2011;406:497-500.

Zhang,Du,Sun,etal.,Lec>nPCLInhibitstheWarburgEffectofPC3CellsbyCombiningwithEGFRandInhibi>ngHK2,Oncol.Rep.2017Jan.16,DOI:10.3892/or.2017.5367.PMID:28098871

Querci5n

•  Abundantinapplesandonions.Themostconsumedbioflavonoidinthehumandiet.

•  Plantsuseittoextractnitrogen–lessifar:ficiallyfer:lized,soeatorganic.

•  Isquerci:nmutagenicandcarcinogenic?NottohumanDNA.

•  Inhibitsmitochondrialmembrane-boundhexokinase.HexokinasesupportsOXPHOSwhilehexokinaseIIsupportsglycolysis.

•  Blockslactateexport,supportsmitochondria.

•  Supportsclearanceofcancercellsbyapoptosis,viamitochondrialcytochrome-Crelease.

•  InhibitsHeatShockProtein90whichsuppressesapoptosis.

BioflavenoidRegula>onofATPaseandHexokinaseAc>vityinErlichAscitesCellMitochondria,Graziani,Biochim.BiophysicaActa1977;460(2):364-373.

SpontaneousMitochondrialMembranePoten>alChangeDuringApopto>cInduc>onbyQuerci>ninK562andK562/adrCells,Kothan,Dechsupa,Leger,etal.,Can.J.Physiol.Pharmacol.2004,82(12):1084-1090.

Querci5n

• Querci:ncanincreaseordecreasemitochondrialmembranepoten:alDeltaPsim(Δψm)dependingonconcentra:on,inducingapoptosis(Kellner2004,Kothan2004,Yang2006,Zhang2005).

•  Thisversa:lean:-canceragentinterfereswithglycolysisviareducedgenera:onofglycoly:csubstratesadenosinediphosphateandinorganicphosphate.

ApoptosisofMurineMelanomaB16-BL6CellsInducedbyQuerce>nTarge>ngMitochondria,Inhibi>ngExpressionofPKC-alphaandTransloca>ngPKC-delta,Zhang,Chen,Xia&Xu,CancerChemother.Pharmacol.2005;55(3):251-262.PMID:15538571

TheEffectofFlavonoidsonAerobicGlycolysisandGrowthofTumorCells,Suolina,Buchsbaum&Racker,CancerRes.1975;35(7):1865-1872.

Me^ormin

• BiguanideisfoundingoatrueherbGalegaofficinalis

• ↓livergluconeogenesis,↓glycogenolysis.

• Hypoglycemic,↓insulin,↓IGF-1,↑IGFBP-1.

• Ac:vatesAMPK,whichinhibitslipogenicenzymes,andinhibitsfa`yacidreleasefromadiposecells.

• Reducedlipidbiosynthesisinhibitscellmembrane

genera:on,slowingtumourgrowth.

• Reducesproteinsynthesis.

Me^ormin Hurts Cancer

•  InhibitsmTORsignalling

•  InhibitsMAPKinvolvedinglutaminolysis.

•  InhibitsNFκB

•  inhibitsVEGF

•  InhibitscyclinD1

•  Inhibitsovariancancercellgrowth,prolifera:on,

metastasisandincreasessurvival:me.

•  Turnsoffcancerstemcellsinbreast,ovarianandendometrialcancers.

Berberine

• BerberinesignificantlyincreasemRNAexpressionsofAMPK,PGC1α,UCP2,CPT1α,andHadhbrelatedtomitochondrialenergymetabolism.

•  ThismaybedrivenbyincreasedexpressionofFiaf-fas:ng-inducedadiposefactor,akeyproteinnega:velyregulatedbyintes:nalbiome.

• Berberineincreasesinsulinsensi:vityandproteinkinaseC-dependentup-regula:onofinsulinreceptorexpression.

• Reducesinsulinresistancewithoutprovokinghypoglycemia.

•  DavisLamson,NDcau:onsthatberberineisnotcompletelyinter-changeablewithmeqormin.

•  Itisacoldherb,andmaybemildlyimmuno-suppressive.

Acetyl-L-Carni5ne

•  Fatsolublecondi:onalenergysourceformitochondriaandbrain.

•  Acetyl-L-carni:nerestoresbeta-oxida:onoffa`yacidstoacetyl-co-A.

•  Outstandingforchemobrain–alsostrokeandheadinjury.

•  Synergis:cwithR+AlphaLipoicAcidforneuropathiesandmitochondrialrescue.

• Mayhaveroleinneuropathypreven:onwithTaxanes.

•  L-carni:neovercomesresistancetoEPObloodbuilders.

•  ProtectstheheartfromHercep:n.

•  Contraindicatedinseizuredisorder,orifthereisahistoryofepilep:cseizures.

Co-enzyme Q-10

•  Electrontransportmoleculeinoxida:verespira:on,essen:altoATPproduc:on.

•  Freeradicalscavenger.Protectsmitochondriafromoxida:vestress.

• Co-Q10stronglyprotectstheheartfromdamagefromanthracyclines.Doxorubicinisanan:bio:clethaltohealthycellsaswellascancercells,linkedtoinjurytomitochondria,whichhavebacteria-likeproper:es.

•  Supportsrecoveryfromorganfailureincludingheart,liverandkidneys.

• Rxdaily300+mgofubiquinoneor100+mgofubiquinol.

PQQ

• Pyrroloquinolinequinoneisaverypotentan:oxidantfoundinparsley,greentea,greenpeppers,spinach,carrots,kiwi,papaya,andtofu.

•  Supplementedat10-40mgitishighlyeffec:veformemory.

• Protectsmitochondriafromoxida:vestress.

•  S:mulatesmitochondrialbiogenesis.

• Chemo-protec:ve,neuro-protec:ve,s:mulatesnervegrowthfactors,blocksintrinsicnitricoxidesynthase,protectscellsfrombetaamyloid.

Niacinamide – Vitamin B3

• Niacinamidebecomesnico:namideadeninedinucleo:de(NAD+),acri:calregulatorofredoxandmitochondrialfunc:on.

• NAD+determinesfunc:onofsirtuinmetabolicsensorsandregulators.

• MammalianlongevityproteinsirtuinSIRT1-7u:lizesNAD+todeacetylateproteinsindifferentfunc:onalsubcellularcompartmentswithastrongconvergenceonop:mizingmitochondrialfunc:on.

• NAD+isneededbyPARP[poly(ADP-ribose)poly-merase]family,protectorsagainstgenotoxicstress.

NAD+Metabolism,ATherapeu:cTargetforAge-RelatedMetabolicDisease,Mouchiroud,Houtkooper&Auwerx,Crit.Rev.Biochem.Mol.Biol.2013;48(4):doi:10.3109/10409238.2013.789479.

Miscellany for Mitochondria

• Cysteine

• N-Acetyl-Cysteine

• Methionine

• Hesperidin

• Diosmin

• DHEA

• Vit.B2-Riboflavin

• D-ribose

• Carnosine

• Melatonin

• Resveratrol

•  Ellagicacid

• Curcumin,

• Cinnamicacid

•  Lutein&Zeaxanthin

•  Lycopene

•  Indole-3-carbinol

•  Selenium

• Ginkgobiloba

• Vit.E-mixedtocopherols

Epigene5cs

•  Epigene:cswitchesdeterminetheexpressionandfunc:onofgeneswithoutchangingtheinheritednucleo:desequences.Cellscanadaptandreprogramthegenesettoop:mizesurvival.

•  Environmentalsignals“select,modify,andregulategeneac:vity…..Ourgenesareconstantlybeingremodeledinresponsetolifeexperiences….Ourpercep:onsoflifeshapeourbiology.”

BruceLiptonTheBiologyofBelief2015HayHouse

Simple gene set – but complex controls

•  Thehumangenomeisremarkablysimple,butthecomplexityoftheepigene:cmodulatorsisalsoremarkable.

•  Epigene:ccontrolsactthroughchangesinDNA:

o  methyla:onandhydroxyl-methyla:on

o  methyla:on,acetyla:on,andphosphoryla:onofhistonetails

o  non-codingmicroRNA

o  chroma:nstructure

Epigene>cs:APrimerforClinicians,Paluch,Naqash,Brumberger,etal.,BloodRev.2016

Genes ↔ Metabolism

•  Nutri:on,behaviour,stressandtoxins→adap:vepa`ernsofmethyla:onandhydroxyl-methyla:on;methyla:on,acetyla:on,andphosphoryla:onofhistonetails,non-codingmicroRNA,chroma:nstructure,andnon-codingRNA→Epimuta:ons.

•  Theseepigene:cchangesarereversiblearereversibleormodifiablebydietarypolyphenolssuchassoygenestein,resveratrol,curcumin,sulforaphaneandcatechins.

•  NutrientsandmetabolitessuchasNAD+,iron,acetyl-coA,ketoglutarate,andS-adenosylmethioninearenecessaryforDNArepairenzymes,methyla:on,histonemodifica:ons,microRNAandchroma:nrearrangements.Thesedependonmitochondrialfunc:onandthebalanceofglycolysisandaerobicmetabolism.

•  “Generegula>onisthuslinkedtothemetabolicstatusofcells.”

Epigene>cImpactofDietaryPolyphenolsinCancerChemopreven>on;LifelongRemodelingofOurEpigenomes,W.V.Berghe,Pharmacol.Res.2012;65:565-567.

Epigene>cTargetsofBioac>veDietaryComponentsforCancerPreven>onandTherapy,Meeran,Ahmed,&Tollefsbol,Clin.Epigen.2010;1(3-4):101-116.

Epigene>cs:APrimerforClinicians,Paluch,Naqash,Brumberger,etal.,BloodRev.2016

Chroma5n Remodeling

• Chroma:nstatesdetermineac:vityinmanytumour-promo:nggenes.

• Chroma:nremodelingfactorBmi-1issuppressedanditsphosphoryla:ondecreasedbygreenteapolyphenolEGCG.

• Bmi-1isamemberofthepolycombrepressivecomplex1whichprotectsDNAintegrity.

•  Inhibi:ngBmi-1reducessurvivaloftransformedcellssuchassquamouscellcancers.

Ross,Dwyer,Umar,etal.,Introduc>on:Diet,Epigene>cEventsandCancerPreven>on,Nutr.Rev.2008;66(Suppl.1):S1-S6.

Methyl Cycle

Methylcycleinfluences:

• Ornithine/argininecycling.

• Catecholaminereduc:on.

• Histaminereduc:on.

•  Sulfitereduc:on.

• Phase2primarydetox:ammonia,urea.

• Rapidlygrowing:ssues:GIlining,bonemarrow,muscle,cancer.

•  Lowmethyla:on=lowAMP!

Agou5 Mice (from NWNPC 2012)

•  Shortlifespanduetocancer,diabetes,obesity–iffedbasicPurinaRatChow.

• Hypo-methyla:onleadstolossofimprin:ngoftheIGF-1gene.

•  Feedingextrazinc,methionine,folate,cholineandB12alterstheirgenes,

andaslongasagooddietisgiven,theoffspringarenormalforgenera:ons!

Methyla5on in Cancer

• Methyla:onisacri:calepigene:cmodulatorofoncogenes.

• Methyla:onresourcesareusedupindetoxifica:onofcarcinogens,excesshormones,catecholamines,hormonedisruptors,andtoxicpollutantsiePOPs.Glutathionedeple:oncorrelateswithmethyla:onarrest.

• Methyla:ondeficittriggersinac:va:onofphosphatases.Thedamagedphosphataseslocalizetothenucleus,triggeringdysregula:onofcellcycleproteins,andinac:va:onofcontrollersofmitosis.

• Reac:va:onofthefetalgrowthgenecasse`e→symmetricalmitosis→undifferen:atedandexponen:alcancercellgrowth.

PP2A Methyla5on

• Anepigene:cbrakeonexcessmitosisismethylatedphosphatasePP2A.

• Cellulardistribu:onofmethylatedPPA2isalteredbyaccumula:onoftriglycerides,crea:ngdysmethyla:on.

• Poormethyla:onofPP2Aallowstheinsulinreceptortooperateunopposed,triggeringmitosis.

• UnmethylatedPP2AfailstodephosphorylateM2pyruvatekinase(PK)andpyruvatedehydrogenase(PDH).Theyremaininac:ve,crea:ngabiochemicalbo`leneck,whichcreatesanewmetaboliceconomy.

Methyla5on of microRNA and Carcinogenesis

•  Methyla:onofspecificmicroRNAs(MIR1,MIR9,MIR124,MIR137,MIR34B/C)olenoccursinanage-dependentmanner,asafielddefectinsomeinstances,andmaybeanearlyeventincoli:s-associatedcarcinogenesis.

•  SpecificmRNAsignaturepa`ernscouldbeusedtoiden:fypa:entswithulcera:vecoli:s(UC)pa:entswhoareatincreasedriskforcolorectalneoplasia.

•  Methyla:onofallmiRNAswassignificantlyhigherinsamplesfrompa:entswithdysplasiaorCRCcomparedtosamplesfrompa:entswithoutneoplasia.

•  Methyla:onlevelsofmiRNAsinrectalmucosaaccuratelydifferen:atedpa:entswithCRCfromthosewithout.

Toiyama,Okugawa,Tanaka,etal.,APanelofMethylatedMicroRNABiomarkersforIden>fyingHigh-RiskPa>entsWithUlcera>veColi>s-AssociatedColorectalCancer,Gastroenterology2017Aug25;[EPubAheadofPrint].

Betaine

• Betaineisfoundinfoodsuchaswholegrains,

marineinvertebrates/seafood,andspinach:

egPesco-vegetarianMediterraneandiet.

• Betaineisamethyldonor.Methyla:onisvital

tolipidmetabolismandepigene:ccontrols.

• KeyinmetabolismofB6,B12,folate,methionine,homocysteine.

• Betaineprotectsproteins,enzymesandcellsfromstress.

• Preventsandtreatsfa`yliverdisease(steatosis)duetoexcessintakeofsucrose,fructoseandfat.

• Betaineandmethyla:onresourcesareusedupindetoxifica:onofcarcinogens,excesshormones,hormonedisruptors,andtoxicpollutants.So...organicpesco-vegetarianMediterranean.

BetaineInHumanNutri>on,Craig,Am.J.Clin.Nutr.2004;80:539–549.

Leaving a Legacy

•  DNAmethyla:onisalterableanddurablethroughgenera:ons.

•  Non-codingRNAandchroma:nproteinsingametestransmitphenotypestooffspring.

•  Environmentalmemoriespassedonfor14genera:onsinroundworms.

………………………………………

•  Nematodesbrieflyexposedtohightemperaturesalterthemethyla:onofhistonesintransgenesforfluorescence.

•  Thesegenesremainac:vatedin14+genera:onsofprogenykeptatlowertemperaturesthanwouldac:vatethegene.

•  Short-livedwormsleaveaverylonglegacyoftheirenvironmentalchallenges.

EnvironmentalEpigene>cInheritanceThroughGametesandImplica>onsforHumanReproduc>on,Wei,Scha`en&Sun,HumanReprod.Update2015;21(2):194-208.

Klosin,et.Al.,Transgenera>onalTransmissionofEnvironmentalInforma>oninC.elegans.Science,April212017.

Sins of the Father

• Paternalgenemethyla:onisremodeledduringspermatogenesis.

• Lifelongexposuretofolateexcessordeficiencycausedvarianceingenemethyla:on.

• Spermmethyla:onchangescanalsobeseen10yearsalerchemoforosteosarcoma.

• Offspringinheritedunstablemethyla:onpa`ernsandincreasedriskofmortality.

Ly,Chan,Aarabi,etal.,Intergenera>onalimpactofpaternallife>meexposurestobothfolicaciddeficiencyandsupplementa>ononreproduc>veoutcomesandimprintedgenemethyla>on,Mol.HumanReprod.2017.

Epigene5c Miasms – Taints that Last a Life5me, or More.

•  Epigene:cchangeshavebeenfoundinthelungsofsmokersandcordbloodofinfantsprenatallyexposedtosmoke.

•  Studiesshowanassocia:onbetweenfamineinSweden,GermanyandChinaandshortenedlifespansandschizophreniainsubsequentgenera:ons.

•  Inmiceandhumansstudiesofnutri:onaldeficienciesthatleadtodisease,thereisanindica:onthatepigene:cchangesmayoccurearlyinlifeandcanbeheritable.

•  Themodernrevolu:oningenesequencinghasrevealedmanymuta:onsincancersthatcontrolepigene:cfactors.

TheKeyRoleofEpigene>csinHumanDiseasePreven>onandMi>ga>on,Feinberg,N.Eng.J.Med.2018,378(14):1323-1334.

The Gamete Game

• Pre-diabe:cfathershavechangesintheirspermcytosinemethyla:on.

• Differen:allymethylatedlocicanbetransmi`edtopancrea:cisletcellsinprogeny.Theseincreaseriskofdiabetesforatleast2genera:ons!

• Otherepigene:caltera:onsingametes,includingchroma:nchangesandnon-codingRNA,cantransmitphenotypestooffspring.

• Gameteepimuta:onsareseeninfruitflies,roundworms,rats,miceandhumans.

Wei,Scha`en&Sun,EnvironmentalEpigene>cInheritanceThroughGametesandImplica>onsforHumanReproduc>on,HumanReprod.Update2015;21(2):194-208.

Perinatal and Childhood Imprints

Acri:calsetof9inflamma:onregula:nggenesisinfluencedbyneo-natal,peri-natalandchildhoodcircumstances,including:

•  Socioeconomicstatus

• Birthinastressfulperiod,suchasthedryseasoninthetropics

•  Extendedparentalabsencesinchildhood

• Nutri:onalstress

• Microbialstress

• PsychosocialexposuresImpactsoccurrencesinadultlifeofinflammatorydiseasessuchascardiovascularevents.

McDade,Ryan,Jones,etal.,SocialandPhysicalEnvironmentsEarlyInDevelopmentPredictDNAMethyla>onofInflammatoryGenesInYoungAdulthood,Proc.Nat’l.Acad.Sci.2017;114(29):7611-7616.

Epigene5c Taints are Reversible

• Miceexposedtotraumapassalongtoprogenyincreasedglucocor:coidreceptorexpressioninthehippocampus,alteringbehaviouralresponsestostressorsrela:vetocontrols.

• TheGRgeneisrela:velydemethylatedinthegermlinecellsofstressedmice.The“spermmethylome”passestotheprogeny.

• Theadap:veandcopingresponsestotraumaareenhanced,includingincreasedavoidanceofstressors.

• ThisGRaltera:oncanbecorrectedbyprovidingaverycalmandsuppor:veenvironmentfortheimpactedprogeny.Enhancedsensory,motorandcogni:ves:mula:onandsocializa:onreversetheinheritedchanges.

Gapp,Bahacek,Grossmann,etal.,Poten>alofEnvironmentalEnrichmenttoPreventTransgenera>onalEffectsofPaternalTrauma,Neuropsychopharm.2016;41:2749-2758.

Hug ‘em up!

•  Holdinganda`endingtoinfants

improvestheirresistanceto

epigene:caging.

•  Highcontactchildrenhadaltered

methyla:onin5genes,involving

func:onssuchasimmunityandmetabolism.

•  Theyexhibitlessstressandfussing.Theythrive.

•  Fouryearslaterthebenefitpersists.

•  Perinatalphysicalcontactandcomfortimprovestheirlife,lifelong.

Moore,McEwen,Quirt,etal.,Epigene>ccorrelatesofneonatalcontactinhumans,Devel.Psychopathol.Pub.onlineNovember222017doi:10.1017/S0954579417001213

Demethyla5on by Botanicals

• O6-methylguanine-DNAmethyltransferase(MGMT)eliminatesmutagenic,carcinogenicandcytotoxiclesionsfromO6-alkylguaninesinducedbyexogenousalkyla:ngagents.

• Neem,ashwagandha,holybasilandoreganoincreaseMGMTmicroRNAanditsdemethyla:onac:vity,increasingDNArepair,protec:ngthegenome.

•  LesspotentMGMTeffectsareseenwithgooseberry,spearmintandcommonbasil.

Niture,Rao&Srivenugopal,Chemopreventa>veStrategiesTarge>ngtheMGMTRepairProtein:AugmentedExpressioninHumanLymphocytesandTumorCellsbyEthanolicandAqueousExtractsofSeveralIndian

MedicinalPlants,Int.J.Oncol.2006;29(5):1269-1278.

Histone Regula5on

Modula:nghistoneproteinde/acyla:onpreventssilencingofgoodtumorsuppressorgenes,turnsoffoncogenes,andsupportsDNAregula:on:

•  vitaminC.

•  cruciferaeisothiocyanates–egsulforaphanedownregulatesdeacetyla:onenzymes.

•  curcumin,greenteaEGCG,grapecyanidins.

•  garcinol,milkthistlesilymarin,parsleyapigenin,baicalein,rosemary,niacinamide.

Citrate Replaces Pyruvate

•  Cancercellsmustfindanotherwaytoobtainacetyl-Co-A,sincepyruvateisnolongergenerated.Instead,tumoursrelyonlipolysisandfa`yacidβ-oxida:onfrombodyfatstores.

•  Thisacetyl-Co-Aiscondensedintocitrate.

•  Lessketonebodiesandbutyrateareproduced,de-inhibi:nghistoneproteindeacetyla:on.

Loss of Oncogene Silencing Histones

Shilsinhistonedeacetyla=ontriggerup-regula:onofoncogenekinases.Tyrosinekinasesarenecessarytoreprogrammitosis.

Insulin-tyrosinekinasesignalingincreases,triggeringaninfluxofglucose,anincreaseinmitosis,andaninhibi:onofapoptosis,ieincreasedcancercellsurvival.

Switchingoffofpyruvatekinaseandpyruvatedehydrognasekinasesfavorstumorproduc:onofcellularcomponents:lipidsforcellmembranes,RNA,DNA,ribosomes,etc.Thismixedaerobicandanaerobiceconomysupportsrapidcellreproduc:on.

Israel & Schwartz, On the Metabolic Origin of Cancer: Substances That Target Tumour Metabolism, Biomed. Res. 2011; 22 (2): 130-164.

Epigene5cs and Extravirgin Olive Oil

• OliveoilactsthroughtheendocannabionoidreceptorCB1toup-regulateCNR1gene.

•  10daysintakeresultedina4-foldincreaseinCB1ac:vity.

•  Thiss:mula:onwasinverselycorrelatedwithDNAmethyla:onattheCNR1CpGpromotormiR23aandmiR-301a.

•  Thismaybeusedpreventortreatcoloncancer.

Francesco,Falconi,Germanio,etal.,ExtravirginOliveOilUp-RegulatesCB1TumorSuppressorGeneinHumanColonCancerCellsandInRatColonViaEpigene:cMechanisms,J.Nutr.Biochem.2014;26(3):250-258.

Foods that Protect and Repair Genes

• Redbellpeppers

•  Tomato

• Paprika

• Cinnamon

•  Epazotespice

•  Endive

•  Spinach

• Asparagus

•  Teapolyphenols

• Berries

• Cruciferousvegetables

• Broccolisprouts

• Mustardgreens

•  Turnipgreens

• Basil

• Ginger

• Garlic

• Persimmons

• Grapes

•  Eggs

• Duckliver

Vitamins and Epigene5cs

• VitaminCpoten:atesTET’scataly:cac:vity.

•  Vit.As:mulatesexpressionoften-eleventransloca:ondemethylases(TET).

•  Synergis:callytheyenhancereprogrammingofdifferen:atedcells.

• VitaminCenhancementofDNAhistonedemethylasesregulatesepigene:csignaturesofstemcells,improvingsoma:ccellreprogramming.

• VitaminCalsoactsasacofactorforFe+2/αKG-dioxygenaseswhichregulatestemcellepigene:cs.

Hore,Modula>ngEpigene>cMemoryThroughVitaminsandTET:Implica>onsforRegenera>veMedicineandCancerTreatment,Epigenomics2017;9(6):863-871.

Keys to Healthy Metabolism, Mitochondria, & Epigene5cs

• Mediterraneandiet–vegetables,seafood,wholegrains,oliveoil,legumes,seeds,berries.

• Reducesugar,salt,meat.

• VitaminC,querce:n,alphalipoicacid,thiamine,resveratrol,curcumin,sulforaphane,catechins,proanthocyanidins,omega3oils,Co-Q10,PQQ.

• Berberine,Centellaasia>ca.

•  Exercise.

• Apeaceful,secure,suppor:veenvironment.

• Cogni:veandsocials:mula:on.Hugs.Love.

• Detoxfromheavymetals,avoiddrugs,anddechemicalize.

www.drneilmckinney.ca