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Lecture Notes | Approved: 7 years ago | 343.88 kB | Comments: 0
...areinTable2.ThenormalcomplementofcomplexIVkeepsoxidantstoamini-mum;deficitsofcomplexIVresultinoxidantleakage,DNAdamage,acceler-atedmitochondrialdecay,andcellularaging(8,83,85).Table2isincompletebecausetheeffectsofsomedeficienciesonhumancellsinculturehavenotyetbeendetermined.Deficienciesofiron,zinc,andbiotinarediscussedbelow.Irondeficiencyisthemostcommonmicronutrientdeficiencyintheworld,andanemiaiswidespreadinunderde-velopedcountries(87).IronintakeinU.S.menstruatingwomenislow;arebelowtheEAR(4).Hispanicwomenandtheobeseareatgreaterriskofbeingiron-deficient(6).Inhumans,irondeficiencyanemiaisassociatedwithpoorcognitivedevelopmentintoddlers(92),suggestingthatirondeficiencyinhumansduringcriticalperiodsofdevel-opmentharmsthedevelopingbrain(92).SevereirondeficiencycauseslossofmitochondrialcomplexIVinselectedregionsinthebrainofneonatalrats(93)andotherchangesinfunction,mor-phology,andphysiologyofthebrain(88,94).Irondeficiencyinratsdamagesmitochondriaandcausesoxidantre-lease,oxidativeDNAdamage,andde-creasedmitochondrialefficiency(79).Irondeficiencyalsoisassociatedwithdiminishedimmunefunctionandneuro-muscularabnormalities(95,96).Theprimarymeasureusedtoidentifyirondeficiencyinmosthumanpopulationsisareductioninhemoglobintothepointofanemia(malaria,HIV,andothernutrientdeficienciesmayalsoleadtoanemia).Theeffectsofirondeficiencyoccuralongacontinuum(88,97),andsubclinicalirondeficiencymayhavedel-eteriouseffectsonhemebiosynthesis.Irondeficiencywithoutanemiacanalsooccurinnewbornsexposedtointrauter-inehypoxia,suchasinfantsofpre-eclampticordiabeticmothers(98).Insuchcases,ironisprioritizedtoery-throidandhemoglobinsynthesis,puttingthenonerythroidtissuesatriskofirondeficiencyandhencehemedeficiency(99,100).Dietaryirondeficiencyintheabsenceofanemiadecreasesaerobiccapacityandphysicalworkperformance,whichareimprovedbyironsupplemen-tation(101).Irondeficiencyhasnotbeenadequatelystudiedasapossibleriskfactorforcancer,andtheresultsarediscordant(102).However,manystudiesarelookingforamonotonicre-lationshipanddonottakeintoaccountthatonemightexpectcanceratlevelsofironthatarebothtoolowandtoohigh(79),asinhereditaryhemochromatosis,aknownriskfactorforcancer(103).Zincinadequacyiscommonin12%ofwhomarebelowtheEAR(4).Inhumancellsinculture,zincdeficiencycausescomplexIVdeficiencyandthereleaseofoxidants,resultinginsignificantoxidativedamagetoDNA(7678).Zincdeficiencyalsocauseschromosomebreaksinrats(31)andisassociatedwithcancerinbothrodentsandhumans(104).Asdiscussedabove,theseobservationsreinforcetheneedtodeterminewhatdegreeofdeficiencyinhumansresultsinDNAdamage.Wethinkitislikelythatthetriggerfordecreasedhemesynthesisistheinactiva-tionofthesecondenzymeofthepath--aminolevulinatedehydratase,whichcontainseightatomsofzinc(85,105).Zincdeficiencyinhumancellsalsoinactivatesotherzinc-containingpro-teinssuchasthetumorsuppressorpro-teinp53andtheDNAbaseexcisionrepairenzyme,apyrimidinicapurinicendonuclease,witharesultingsynergis-ticeffectongeneticdamage(76,77).Biotindeficiencyismorecommonthanpreviouslythought;40%ofpreg-nantwomenwhodonottakeamultivi-taminshowmetabolicsignsofdeficiency(106).Marginalbiotindeficiencyistera-togenicinmice(106).Biotinisapros-theticgroupinfourbiotin-dependentcarboxylases(threeofwhicharesolelypresentinmitochondria)thatreplenishintermediatesinthetricarboxylicacidcycle(107).Biotindeficiencydecreasestheactivityoftheseenzymes,leadingtoadecreaseoftwohemeprecursors,mi-tochondrialsuccinyl-CoAandglycine,thusresultinginhemedeficiency(83).Biotindeficiencyinnormalhumanlungfibroblastsinculturecauseda4050%decreaseinhemecontent,oxidantre-lease,prematuresenescence,andDNAdamage(83).Therelationshipoftheseeffectstohumanintakeneedstobede-termined(108).ANewHypothesis:AllocatingaScarceMicronutrientbyTriageIsthereanexplanationfortheobserva-tionthatmanymicronutrientdeficien-ciesareassociatedwithchromosomebreaksandcancerinhumans,causeDNAdamageinrodentsorhumancellsinculture,and,whereassayed,causeearlysenescence?IproposeDNAdamageandlateonsetdiseasearecon-sequencesofatriageallocationmecha-nismdevelopedduringevolutiontocopewithepisodicmicronutrientshort-ages.Forexample,livingcreaturesalwayshaverequired15metals/miner-alsfortheirmetabolism,whicharedis-tributedveryunevenlythroughouttheEarth.Thus,episodicshortagesprobablywerecommon,asprobablyalsowasthecaseforvitaminsandotheressentialmicronutrients.Naturalselectionisknowntofavorshort-termsurvivalattheexpenseoflong-termhealthwhentheyareinconflict.Ihypothesizethatasthescarcityofamicronutrientin-creases,andafterhomeostaticadjust-ments,suchasinductionoftransportproteins(109),atriagemechanismforallocatingscarcemicronutrientsisacti-vatedthatfavorsshort-termsurvivalattheexpenseoflong-termhealth,inpartthroughanadjustmentofthebindingaffinityofeachproteinforitsrequiredTheconsequencesofsuchtriagewouldbeevidentatalllevels.Forexam-ple,inmetabolicreactions,enzymesinvolvedinATPsynthesiswouldbefa-voredoverDNA-repairenzymes;incells,erythrocyteswouldbefavoredoverleukocytes;andinorgans,theheartwouldbefavoredovertheliver.Isozymeswithdifferentbindingcon-stantsforthecoenzymeormetalintheheartorlivercouldbeoneofseveralwaystoaccomplishthisend.Physiologi-caltriageiswellknown:whenOliverytothetissuesisinadequate...vitalorganfunctionismaintainedbyintrinsicneurohormonalcompensatorymechanismsresultingindistributionoforganbloodflowprimarilytotheheart,brain,andadrenalglandsandawayfromothernonvitalorgans(110).Similarly,underconditionsofdeficiency,organssuchastheliverlosecertainmi-cronutrientsfirst,beforeothermorevi-talorgans(111116,150).Table2.MicronutrientdeÞciencyandheme:effectsonhumancellsincultureandanimals ComplexIVPyridoxine7576Ð7876Ð78Riboßavin75Iron7979Copper808182Biotin8383838383Pantothenate7584Numbersrepresentreferences.,H.Atamna,S.Askree,andB.N.A.,unpublisheddata.November21,2006vol.103no.47 Thetriagehypothesissuggestsaddi-tionalmechanismsthatmaybeusedbythebodytoallocatescarceresources.Thishypothesisistestable,and,ifvali-dated,suggeststhatitmaybenecessarytooptimizeintakesofmicronutrientsaccordingtotheneedsofthemostdis-pensableorganorcellsinordertomaxi-mizelongevityandretardcancerandotherdegenerativediseasesofaging.Thereisincreasingevidencethatnutri-tionalinadequaciesduringdevelopmentcanhaveconsequenceslaterinlife(117).Forexample,fetalmalnutritionduringtheDutchfaminein19441945wasassociatedwithcoronaryarterydis-easeinadulthood(117,118),althoughbothmicronutrientandmacronutrientmalnutritionmayhavecontributedtothislate-onsetdisease.Broadly,suchproteintriagewouldrepresentanin-stanceofantagonisticpleiotropy,asproposedalmost50yearsagobyWil-liams(119)inwhichasingleallele(e.g.,anisozymewithalowaffinityforami-cronutrient)mayencodebothabenefi-cial(short-termsurvivalofepisodicdeficiency)andaharmful(anincreaseindegenerativedisease)phenotype.Theconceptofenzymetriageisalsobroadlyconsistentwithrecentevolutionarythe-oryaboutaging,whichstressesthatse-lectionforreproductivesuccessearlyinlifemayinvolvetrade-offsthatshortenlifespan(120).Malnutritionhasbeendiscussedinrelationtoinvestmentpri-oritiesinbirds(151),fetalprogram-minginhumans(152,153),andtypeofimmunocompetence(154).Moderatereductionindietaryintakeofmacronutrients(calorierestriction)withadequatemicronutrientsextendslifespaninvariousanimals(121)butisnotinconsistentwiththetriagehypoth-esisbecausethenormallevelofcalo-riesfedcontrolscouldbeinexcessofwhatisoptimalformaximumlifespan.ShouldPeopleTakeanMVMSupplementforInsurance?TheNationalHealthandNutritionEx-aminationSurveys(NHANES)(4)indi-catethatthedietsofmanyintheUnitedStatesdonotprovideadequateintakesofallofthevitaminsandminer-alsrecommendedbyofficialbodies(Ta-ble1).FromNHANESandTable1,itseemslikelythatactualintakesofvari-ousmicronutrientsfromfoodarenotonlyinadequateforthepoor,teenagers,menstruatingwomen,theobese,andtheelderly,butformuchoftherestofthepopulationaswell.However,decadesofpublichealtheffortstoimprovetheAmericandiethavenotbeenverysuc-cessful,particularlyamongthepoor.WhynotrecommendthataMVMsup-plementbeaddedtoahealthylifestyle?Thisapproach,focusingonmicronutri-entmalnutrition,withadditionalatten-tiontofoodfortification,inadditiontocontinuingeffortstoimprovediet,mightbemoresuccessfulinimprovinghealth.ItmaybeeasiertoconvincepeopletotakeaninexpensiveMVMsupplementthantomarkedlychangetheireatinghabits.EvidenceisaccumulatingthataMVMsupplement,orsmallercombina-tionsofvitaminsandminerals,alsoim-provelong-termhealth,reducingheartdisease,cancer,andcataractsandim-provingimmunefunctionforthosewhoconsumeinadequatediets(122137,155).ThepotentialbenefitsofanMVMininfectionhavebeencriticallyreviewed(138).Shoulditbenecessarytofirstdemon-strateefficacyforpreventingordelayinglong-termchronicdiseasessuchascan-cerinRCTsbeforerecommendingMVMuse(45,156)?RCTsformicronu-trientsandlong-termeffectsareex-tremelydifficulttodocorrectlyformanyreasons(45):decadesaresome-timesrequiredinlonglatencydiseases(139,140);therearedifferent,andoftenmultiple,consequencesofeachmicronu-trientdeficiency;largepopulationsarerequired;thistypeofRCTisveryex-pensive,and,unlikefordrugs,thereisnocommercialincentivetodotrials;andcomplianceisdifficulttomaintainformanyyears,particularlyincontrols,whocantakereadilyavailableMVMsupplements.Forallofthesereasonsitisunlikelythatitwillbepossibletoob-taindefinitiveresultsfromthistypeofRCT,whetheritbetargetedatsinglemicronutrientsorMVMs.Forexample,twoverylargeRCTsexaminedeffectsofsupplementationwithalimitednum-berofvitaminsandmineralsoncancerrisk(134,135).AlthoughbothoftheseRCTsreportedareductionincancerincidenceormortalitywithsupplemen-tation,methodologicalconcernshavebeenraisedtoarguethattheresultsarenotdefinitive(156).Insteadofrelyingonlyonlong-termRCTs(156),allscientificevidenceshouldbetakenintoaccountinmakingsupplementationrecommendations(45,141).RCTsonshort-termendpointssuchasDNAdamage(10)ormarkersofinflammation(125)arefeasibleandaremorelikelytoyielddefinitivere-sults.Manyothertypesofexperimentsinhumansandanimals,includingbio-chemical,mechanistic,andepidemiolog-ical,arealsorelevant.OnedoesneedtobeconcernedthatcumulativeeffectsofsupplementationandfortificationmightexceedULs.In-creasingconsumptionofsupplementsandincreasingfortificationemphasizetheneedforvigilancetopreventover-consumptionofcertainmicronutrients.Forexample,consumingtoohighadoseofmanyofthemineralsistoxic(e.g.,iron,zinc,copper,andselenium,andsomeofthevitamins,suchasvitaminA).VitaminAwasofparticularconcernuntilmostMVMmanufacturersswitchedrecentlytousingmoreprovita-minA.Excessironisalsonotdifficulttoachieveinmenandpostmenopausalwomen,whoshouldtakereadilyavail-ableMVMswithoutironandshouldlimitredmeatconsumption.Inmice,bothlow(one-thirdofnormal)intakeofamixtureofvitaminsanda5-foldex-cesscausedanincreaseinintestinalneo-plasia(142).Inrats,bothtoolittleandtoomuchironresultedinmitochondrialdamage,releaseofoxidants,andDNAdamage(79).However,thepercentageofthepopulationconsumingmorethantheULfromfoodisverylowcomparedwiththepercentageconsuminglessthantheEAR(4).Thus,micronutrientdefi-cienciesarelikelytobeafarmoreim-portantpublichealthproblemthanexcessconsumption(4).Thisconclusionissupportedbythemanyepidemiologi-calandotherhumanstudiescitedinthisarticle.Thus,takingadailystandardMVMsupplementisunlikelytobeofconcern,becausetheseamountsofmi-cronutrientsarenotclosetotheUL(4).Despitethelackofdefinitiveproofofefficacy,IandothersbelievethatpublichealthofficialsandphysiciansshouldrecommendthatpeopletakeaMVMsupplementinadditiontoleadingahealthylifestyle(133):therearewide-spreadlowintakes(4);animpressivearrayofevidenceforMVMsupplemen-tationexists,andthereisanabsenceofrealisticsafetyconcerns.Ifthissimplechangecouldbeimplemented,andpar-ticularlyifMVMscouldbemadeavail-abletothepoor,amarkeddecreaseintheprevalenceofmicronutrientintakesbelowtheRDAwouldresult.Fortificationoffood,suchasfolatefortification,isanotherapproachthathasbeenshowntoimprovehealthandisvaluable.Fortification,however,mightnotbesufficientforpopulationsub-groupsthathavespecialneeds.Forex-ample,mostAfricanAmericansareverylowinvitaminDdespitemilkfortifica-tion(33);75%arelactose-intolerant(53);anditseemsprudentforAfricanAmericanstotakeavitaminDorMVMsupplement(54).Fortificationisalsoproblematicwhensomegroupsinthepopulationwouldbebenefitedandsomeharmed.Thisisrelevantforiron,be-causemenstruatingwomenneedmorethanmenorolderwomen,someofwhommaybegettingtoomuch. OtherPossiblyUsefulSupplementsOtherusefulsupplementsincludefiber,andomega-3fattyacidsfromfishoil,particularlyeicosapentaenoicacidanddocosahexaenoicacid,whichappeartobeimportantforbrainfunctionandhavepotentantiinflammatoryactivity(63,141,143).Inadequatefiberintakes,bothsolubleandinsoluble,arewide-spreadandhaveadversehealthconse-quences(144);supplementationisinexpensive.AdvicetotakeMVMsup-plements,fiber,andomega-3fattyacidsupplementsshouldalwaysbecoupledwithadvicetoeatagooddiet,becausewealsoneedothernutrientsandproba-blyphytochemicalsthatmaynotbepresentinsupplements(145).VariableOptimalRequirementsTheelderlymayneedmoreorlessofcertainvitaminsandmetabolitescom-paredwithyoungerpeople,butthisis-suehasnotbeenthoroughlyexamined(146,147).Forexample,25%ofDutchadults70yearsofageshowedmild-to-severevitaminB12deficiency(148),mostlikelybecauseofmalabsorp-tionratherthanlowdietaryintakes(4).VitaminB12intakesatlevelsmanytimestheRDAreversedthedeficiency(65,148).Mostsmokershaveaninade-quateintakeofvitaminC;76%arebe-lowtheEAR(4).Theoptimalintakeofmicronutrientsandmetabolitescanalsovarywithgeneticconstitution(146,147,149)(e.g.,ironrequirementsvarywithageandgenderasdiscussedabove).Astudyofacommonpolymorphisminthegeneformitochondrialmanganesesu-peroxidedismutasedemonstratedthatselenium,-tocopherol,orlycopeneprotectedagainstprostatecancer,andthecombinationofallthreeshoweda10-foldgradientofriskacrossquartilesinoneformofthepolymorphism(149).AvarietyofMVMsupplementshavebeendevelopedthatreflectdifferentneedsdependingononesageandgen-der,andmorearelikelytobedevelopedwithnewknowledge.Althoughmanyresultsarenotdefinitiveandmuchmoreresearchisneeded,alargeliteraturesuggeststhatmicronutri-entinadequacycanleadtocancerandotherlong-termdeleteriousconse-quences.Ipresentatriagetheorythatexplainswhytheseconsequencesmightbeexpected.Short-termRCTsusingendpointsassociatedwithlong-termdisease,suchasDNAdamageandin-flammatorymarkers,arelikelytoiden-tifypopulationsatriskandfurtherrefinelevelsofmicronutrientsrequiredforoptimumlong-termhealth.Micronu-trientinadequaciesarewidespreadinthepopulation,andaMVMsupplementisinexpensive.Asolutionistoencour-ageMVMsupplementation,particularlyinthosegroupswithwidespreaddefi-cienciessuchasthepoor,teenagers,theobese,AfricanAmericans,andtheel-derly,inadditiontourgingpeopletoeatamorebalanceddiet.IamindebtedtoG.Ames,S.Askree,H.Atamna,K.Beckman,G.Block,B.German,L.Gold,H.Helbock,D.Killilea,J.King,T.Klask,A.Lal,G.Li,M.Mietus-Snyder,J.Nides,M.Stampfer,J.Suh,J.Vance,F.Vit-eri,P.Wakimoto,W.Willett,andespeciallytoJ.McCannfortheirsuggestionsandcon-tributions.ThisworkwassupportedbyNationalFoundationforCancerResearchGrantM2661,NationalCenterforMinorityHealthandHealthDisparitiesGrantP60MD00222,NationalCenterforComplemen-taryandAlternativeMedicineGrantR21AT001918,andResearchScientistAwardK05AT001323.1.BlockG(2004)JFoodCompositionAnal17:439447.2.KantAK(2000)AmJClinNutr72:929936.3.KarpR(2006)inModernNutritioninHealthand,edsOlsonJA,ShikeM,RossAC(LippincottWilliams&Wilkins,NewYork),pp861874.4.MoshfeghA,GoldmanJ,ClevelandL(2005)WhatWeEatinAmerica,NHANES20012002:UsualNutrientIntakesfromFoodComparedtoDietaryReferenceIntakes(U.S.DepartmentofAgricultureAgriculturalResearchService,Washington,DC).5.StandingCommitteeontheScientificEvaluationofDietaryReferenceIntakes,FoodandNutri-tionBoard,InstituteofMedicine(1997)DietaryReferenceIntakesforCalcium,Phosphorus,Mag-nesium,VitaminD,andFluoride(NatlAcadPress,Washington,DC),pp190249.6.NeadKG,HaltermanJS,KaczorowskiJM,AuingerP,WeitzmanM(2004)Pediatrics114:104108.7.AmesBN(2005)EMBORep6:S20S24.8.AmesBN,AtamnaH,KillileaDW(2005)AspectsMed9.AmesBN,LiuJ,AtamnaH,HagenTM(2003)ClinNeurosciRes10.FenechM(2003)NutrResRev16:109122.11.FenechM(2005)12.ShigenagaMK,HagenTM,AmesBN(1994)ProcNatlAcadSciUSA13.HagenTM,LiuJ,LykkesfeldtJ,WehrCM,IngersollRT,VinarskyV,BartholomewJC,AmesBN(2002)ProcNatlAcadSciUSA99:18701875.14.HagenTM,MoreauR,SuhJH,VisioliF(2002)AnnNYAcadSci15.LiuJ,HeadE,GharibAM,YuanW,IngersollRT,HagenTM,CotmanCW,AmesBN(2002)ProcNatlAcadSciUSA99:23562361.16.LiuJ,KillileaDW,AmesBN(2002)ProcNatlAcadSciUSA99:18761881.17.SuhJH,ShenviSV,DixonBM,LiuH,JaiswalAK,LiuRM,HagenTM(2004)ProcNatlAcadSciUSA18.SuhJH,WangH,LiuRM,LiuJ,HagenTMArchBiochemBiophys423:126135.19.SmithAR,ShenviSV,WidlanskyM,SuhJH,HagenTM(2004)CurrMedChem20.WakimotoP,BlockG(2001)JGerontolABiolSciMedSci56:6580.21.FoxCH,MahoneyMC,RamsoomairD,CarterCA(2003)JNatlMedAssoc22.VaqueroMP(2002)JNutrHealthAging23.FordES(1998)EthnDis8:1020.24.U.S.DepartmentofAgricultureAgriculturalRe-searchService.(1999)DataTables:FoodandNutrientIntakesbyIncome,199496.Availableatwww.foodsurveyhtm.Ac-cessedSeptember20,2006.25.HartwigA(2001)MutatRes26.FolsomAR,HongCP(2006)AmJEpidemiol27.LarssonS,BergkvistL,WolkA(2005)JAmMed293:8689.28.BlondellJM(1980)MedHypotheses6:863871.29.HeK,LiuK,DaviglusML,MorrisSJ,LoriaCM,VanHornL,JacobsDR,Jr,SavagePJ(2006)30.LeoneN,CourbonD,DucimetiereP,ZureikMEpidemiology17:308314.31.BellLT,BranstratorM,RouxC,HurleyLSTeratology32.BlacheD,DevauxS,JoubertO,LoreauN,S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