WhatisMetformin?

AndWhyDoScientistsThinkItCanExtend
YourLifespan?

ByDennisBuckley
05/11/2017 11minread

Oneoftheonlygivensinlifeisthatitwillcometoanend.

Ashumans,wereobsessedwithmaximizingthenumberofyearsinourlives,andtheamountoflifeinouryears.

Amongallthemanydifferentwaystosupportoptimalhealthandpromotelongevity(diet,exercise,minimizingrisk
exposure)isoneseeminglyunexpectedcompoundthatwasdevelopedtotreatdiabetes.

ItscalledMetformin,andforadrugwithsucharelativelysimpledesignandfunction,thecompoundhasgarnered
atremendousamountofattentionasoneoftheworldsmostpromisingwaytoincreaselifespan.

ASimpleDrugwithLifeChangingImplications

Metformin(soldasGlucophage)wasfirstsynthesizedinthe1920s,butdidntgaintractioninthemedical
communityuntilthe1980s,whereitbecame(andcontinuestobe)thedrugofchoicefortreatinginsulinresistant
type2diabetes[1].

Afewkeystudiesovertheyearsthatinitiallysoughttoinvestigatethedrugseffectonglucosemetabolism,
stumbleduponanunexpectedphenomena.Whencomparedtothehealthycontrolgroups,themetformingroups
appearedtogetlesscancer,andevenmorefascinating,whensubjectsinthemetformingroupdidgetcancer,
theylivedlongerthanthehealthycontrolgroup.

Whywouldthisbe?

Toanswerthatquestionrequiressomediscussionofafewkeyconceptsandtheoriessowedonthaveto
interruptthestorylateron.

Tostart,letstalkabouthowourcellsgettheirenergy.

HowHealthyCellsDeriveTheirEnergy

Youcanthaveadiscussionaboutcellularenergyproductionwithouttalkingaboutmitochondria.
Mitochondriaarequiteliterallythepowerplantsofyourcellstheyarethedirectsourceofover90percentof
yourbodysenergy[2].

Thesetinyorganellesarethoughttobederivedfrombacteriaandhaveevolvedtobecomeanintegralpartofour
humanphysiology[3].

Alas,inorderforeveryorganandtissueinyourbodytofunctioncorrectly,theyneedenergyenergythatis
producedbyyourmitochondria.

Toproducechemicalenergy,yourmitochondrianeedoxygen.Theycangetitfromtheairyoubreath,orfromthe
fatandglucoseyouingestfromyourdiet.Thisprocessofusingamixtureofoxygen,glucose,andfattyacidsto
createintracellularenergyiscalledoxidativephosphorylation[4].

Oxidativephosphorylationistheactionofturningglucoseandfattyacids(thatcomefromthefoodyoueat)
intoadenosinetriphosphate(ATP)energyusingoxygen(fromtheairyoubreathe).

ATP:TheCurrencyofEnergyUsedByTheBody

ATPthatisgeneratedinyourcellsmitochondriacanbeextractedintwoways:

Aerobicmetabolism
Anaerobicmetabolism

AerobicmetabolismistheprocessofextractingATPfromglucoseorfattyacidswhenthedemandforATPisnot
toogreat.Ifyouthinkaboutslow,steadystatecardioexercise,thisisprimarilyaerobicmetabolismdependent.It
isefficient,oxygenisreadilyavailable,anditentailsaminimalamountofmetabolicwasteproductsjustoxygen
andcarbondioxide.

Whenthereissufficientoxygeninthecell,themitochondriaareincrediblyefficientatgeneratingATP(about36
unitsfrommoleculeofglucose)[5].

Anaerobicmetabolism,ontheotherhand,isalessefficientprocessofextractingATPsolelyfromglucose.This
ishowyoufuelhighintensity,explosive,intermittentexercise.Inthisstateyourbodyhasadecreasedoxygen
efficiencyandyourcellspredominantlyrelyonglucosetogenerateATP.Thisprocessislessefficientand
generatemorewasteproductslikelactateandhydrogenions[4].

Anaerobicmetabolismischaracterizedbythebodysinabilitytodeliveroxygenquicklyenoughtothecells(only
about4unitsofATPpermoleculeofglucose).

Aerobicmetabolismisthepreferred,moreefficientwayyourbodygeneratesenergy,butanaerobicmetabolismis
dominantduringtimeswhenoxygenisnotreadilyavailable(HIITexercise,sprintingfromalionthatschasingyou,
etc.)
Healthycells(andtheirrespectivemitochondria)areabletoswitchbetweenmetabolisms,butinsomeinstances,
cellslacktheabilitytouseoxygenaltogetherintheircreationofATP.

A(Very)BriefPrimerOnCancerMetabolism

Acommonmisconceptionofcancercellsisthattheygrowexponentiallyfasterthanhealthycells.

Thisisactuallyincorrect.

Cancercellsgrowatroughlynormalspeedscomparedtohealthycells,buttheydonotrespondtonormalcell
signaling.Thismeansthatwhilenormalcellswillgrowandstopgrowingperiodically,cancercellsdonotknow
whentostopgrowing[5].

Anotherlesserknownfact:yourbodyactuallymakesdamagedandcancerouscellseveryday[6].

Inmostcasesthisisactuallyagoodthing.

See,yourcellshaveatightlycontrolledsystem,ornetworkofprogrammedselfdestructiontriggersincluding:

Disruptionofintracellulargrowthfactorsignaling
Damagedproteins
DNAdamage
Presenceofreactiveoxygenspecies(ROS)

Allcellshaveacontrolled,programmedcelldeathiftheirenvironmentisntveryhospitable.

Whendamagedorcancerouscellsarepresent,metabolicbyproductsofATPproduction(suchasROS)normally
setinmotionacascadeofeventsthattriggersthiscontrolledcelldeathcalledapoptosis.

Theresultisthedisposalofdamagedcellssoyourbodycanreplacethemwithnormal,healthycells[6].

Theproblem,ofcourse,isthatcancercellsseemtohaveabuiltinmechanismthatmakesthemresistanttothis
suicideprotocol[6].

Foradeeperdiveonapoptosis,checkoutthisindepthvideo:


CancersMitochondrialDefect

Cancercellsdonotknowwhentodie,andamajorreasonforthisisthatmost,butnotnecessarilyall,cancercells
havedefectsintheirmitochondriathatpreventthemfromcarryingoutoxidativephosphorylation.

Remember,oxidativephosphorylationistheprocessofourcellsmitochondriausingglucoseandfatwiththehelp
ofoxygentogenerateATP.Thisprocessofenergyproductionnecessarilyentailsthecreationofmetabolic
byproductsandROSthatareusedtotriggerapoptosis.

Mostcancercellsdonotundergothisprocess.

Oneofthemechanismsofhowchemotherapyworksisthatchemodrugsforcecancercellstotriggerapoptosisby
stimulatingtheirmitochondriawithROS.

HeresDr.RhondaPatricktoexplainitfurther:

Oneofthemechanismsbywhichchemotherapeuticdrugsworkistheycreatereactiveoxygenspecies.They
createdamage,andthatsenoughtopushthatcancercelltodie.

Thereasonforthisisbecause,acancercellwhichisnotusingitsmitochondria,meaningitsnotproducing
thosereactiveoxygenspeciesanylongerallofthesuddenyouforceittouseitsmitochondriaandyougeta
burstofreactiveoxygenspeciesbecausethatswhatmitochondriado,andboom,death,becausethatcancercell
isalreadyprimedforthatdeath.

Itsreadytodie.

Sincemostcancercellscannotundergooxidativephosphorylationtogettheirenergy,howdotheygettheir
energy?

TheGlucoseTheoryOfCancerMetabolism

Whiletheexactexplanationhasyettobeelucidated,thereisevidencetosuggestthatmost(again,notall)cancer
cellsexclusivelyuseglucosetomakeATPwithouttheuseoftheirmitochondria[7].

WhethertheydothisbecauseofDNAdamage,oractivationofcertaingenesthatpromotecellgrowth
unresponsivetonormalcellsignaling,isunclear.

WhatISclearisthatcancercellsareabletogenerateenergywithoutundergoingaerobicmetabolismandwithout
usingtheirmitochondriaatall.Itdoesntmatterhowmuchoxygenorfattyacidscancercellshaveaccessto,they
preferentiallyuseglucosetomakeATP.
Thismeansthatwhilehealthycellsinthebodyareabletoderiveenergyfromtwopathways(aerobicand
anaerobicmetabolism),cancercellsarefueledbythelatter,highlyinefficientpathway.Itisforthisreasonthis
metabolicquirkthatscientistshavebeenfeverishlylookingforatherapytotargetthisquirkypathwaythat
makescancergrowthpossible.

So,ifweknowthatcancercellsalmostexclusivelyrelyonglucosetogrowandproliferate,thatbegsthemillion
dollarquestion:whathappenstocancerifwereducetheamountofglucoseinthebody?

Isitpossibletostarvecancercells?

LetsTalkAboutMetformin

CancersabilitytopreferentiallyuseglucosetogenerateATPwithoutoxygenandwithouttheirmitochondriais
indeedametabolicabnormality.Anditsthisparticularmetabolicquirkthatisatargetmechanismforanumberof
differenttherapiesincludingmetformin.

Metforminhasbeenthesubjectofatleastthreedifferentretrospectivestudies.AsImentionedintheintroduction
tothisarticle,evenwhenresultsofthesestudieswereadjustedforfactorslikebodyweightandothermedications,
individualswhotookmetforminappearedtogetlesscancer,andwhentheydidgetcancer,theyseemedtolive
longer.

Whymightthisbe?

Theanswertothequestioninvolvesabasicunderstandingofthepharmacologyofmetformin,thatis,whatit
actuallydoesinthebody.

HowMetforminWorks

Metforminisaprettysimpledrugthatmayjustbeoneofthoseraregooddrugsthathassignificantlybeneficial
propertiesinalteringglucosemetabolismwithnoforeseeabledownside.

Metformindoesseveraldifferentthings,butmostnotablyit:

Drasticallydecreasesglucoseproductionintheliver
Increasesinsulinsensitivityinbodytissues
Improvesglucosedisposal
Improvesfattyacidutilization

Forthesereasons,metforminisusedasafirstlinemedicationforthetreatmentoftype2diabetes.

Sodoesmetforminhavesomeuniqueanticancerproperties,oristhereductionincancerandincreasein
longevityattributabletothedecreaseinglucose?
Itsunclear.Sure,thismaybeachickenortheeggscenario,butwehavemorethanenoughcluestodrawsome
curiousinsights.

Metforminhasbeenshowntoactonseveralpathwaysthatareknowntobeinvolvedinthegrowthandsurvivalof
cancercells.

TheFirstPathway:AMPK

Metforminhasbeenshowntoactivatesomethingcalledadenosinemonophosphateactivatedproteinkinase
(AMPK),anenzymethatisexpressedinnumeroustissuesthroughoutthebody,thatplaysacriticalrolein
regulatingcellularenergyhomeostasis.

AMPKisalsoapathwaythatkicksinduringautophagy,thecellularprocessofcleaningupandbreakingdown
damagedcells,cellulardebris,andevenprecancerouscells.

WhetheradecreaseinglucoseasaresultofincreasedactivationofAMPKisacontributingfactortoreduced
cancerrisk,orwhetherAMPKpossesssomeuniqueandundiscoveredanticancerpropertiesisunknown.Butwe
doknowmetformin,forsuchasimple,innocuousdrug,mediatesAMPK,whichisoneofthekeypathwaysthatis
activatedduringexercise,fasting,frompolyphenolconsumption,andfromcalorierestriction,allofwhichare
closelyassociatedwithincreasedlongevity[8].

TheSecondPathway:mTOR

Themechanistictargetofrapamycin(mTOR)isasignalingpathwaythatregulatesavarietyofgrowthfactorsin
thebody,andstimulatesactivationofinsulinreceptorsandinsulinlikegrowthfactorreceptors(IGF1),among
others.ActivationofmTORallowsustoputonmuscle,increasevarioushormoneconcentrations,increaseATP
productionandcreatenewmitochondria[9].

Ontheonehand,mTORisresponsibleformanyoftheperformancerelatedprocessesthatimprovequalityoflife
(physicalstrength,mentalacuity,increasedenergyefficiency,tonameafew),butelevatedmTORactivationhas
alsobeenimplicatedasacontributingfactortoanincreasingnumberofpathologicalconditionslikecancer,
obesity,type2diabetes,andneurodegeneration[10].

MTORinhibitionhasbeenshowntoslowaginginyeastandinvertebrates,extendlifespaninmice,andhasan
impactonavarietyofagerelateddiseases,andmetforminhasbeenshowntopartiallyinhibitthispathway[11].

Fromalongevitystandpoint,thereisagoodamountofevidencetosuggestlowactivationofmTORisassociated
withincreasedlongevity.

TheBiggerPicture

Metforminisasimpledrug,pharmacologically,andtheimplicationsithasaresomethingtokeepaneyeon
movingforward.Currentlythereisnodataregardingmetforminsupplementationandlongevity,butthereare
somehumantrialsunderwaywhichwillprovidesomenewdataonthesubject.
Metforminlookspromising,andtherearecurrentlyoveradozenclinicaltrialsunderwaytryingtoreplicate
metforminseffectintargetingthismetabolicquirkwithglucoseand/orinsulinreductiondiets,ortryingtotarget
anyimplicatedmechanismsofactionrelatedtocancersmetabolicabnormality.

Whenitcomestolongevity,thefollowingpracticesworkonthesameAMPkpathwayasmetforminandare
believedtoconfermanyofthesamebenefitsregardinglongevityandreducedcancerrisk:

Caloricrestriction
Intermittentfasting/alternativedayfasting
Lowproteindiet
Ketogenicdiet
Exercise
Polyphenolintake

Untilwelearnmoreaboutthemetforminseffectonlongevity,itssafetosaythataregimenofadiethighinplants
andpolyphenols,someformoffasting,andexerciseisoneofthebest,mostwellresearchedwaystolivelong
andlivewellthatweknowof.

TakeAwayPoints

Takeaway#1:Metforminisacommonandeffectivedrugtohelptreattype2diabetes,withnoforeseeable
downside.

Takeaway#2:Retrospectivestudieslookingatpatientstakingmetforminhaveshownthatdiabeticpatientswho
takemetforminappeartogetlesscancerandlivelongerthanthecontrolgroup.

Takeaway#3:Reducingglucoseandorinsulininthebodymaystarvecancercellsoftheirpreferredfuel
source(metformindoesthisverywellviaAMPKactivationandsubsequentdecreasedglucoseproduction).

Takeaway#4:ActivationofAMPKandpartialinhibitionofmTORviametforminmayharmcancercellsinsome
otherwaythathasyettobeelucidated.