Letterhttps://doi.org/10.1038/s41586-018-0162-7Disruptionofthebeclin1–BCL2autophagyregulatorycomplexpromoteslongevityinmiceÁlvaroF.Fernández1,2,9,SalwaSebti1,2,9,YongjieWei1,2,3,ZhongjuZou1,2,3,MingjunShi4,KathrynL.McMillan4,CongcongHe5,tabithating1,2,YangLiu1,2,3,Wei-ChungChiang1,2,DeniseK.Marciano2,GabrieleG.Schiattarella2,GovindBhagat6,OrsonW.Moe2,4,7,MingChangHu2,4*&BethLevine1,2,3,8*Autophagyincreasesthelifespanofmodelorganisms;however,itsroleinpromotingmammalianlongevityislesswell-established1,2.Herewereportlifespanandhealthspanextensioninamousemodelwithincreasedbasalautophagy.Todeterminetheeffectsofconstitutivelyincreasedautophagyonmammalianhealth,wegeneratedtargetedmutantmicewithaPhe121Alamutationinbeclin1(Becn1F121A/F121A)thatdecreasesitsinteractionwiththenegativeregulatorBCL2.Wedemonstratethattheinteractionbetweenbeclin1andBCL2isdisruptedinseveraltissuesinBecn1F121A/F121Aknock-inmiceinassociationwithhigherlevelsofbasalautophagicflux.Comparedtowild-typelittermates,thelifespanofbothmaleandfemaleknock-inmiceissignificantlyincreased.Thehealthspanoftheknock-inmicealsoimproves,asphenotypessuchasage-relatedrenalandcardiacpathologicalchangesandspontaneoustumorigenesisarediminished.Moreover,micedeficientintheanti-ageingproteinklotho3haveincreasedbeclin1andBCL2interactionanddecreasedautophagy.Thesephenotypes,alongwithprematurelethalityandinfertility,arerescuedbythebeclin1(F121A)mutation.Together,ourdatademonstratethatdisruptionofthebeclin1–BCL2complexisaneffectivemechanismtoincreaseautophagy,preventprematureageing,improvehealthspanandpromotelongevityinmammals.Autophagy,anevolutionarilyconservedlysosomaldegradationpathway,hasakeyroleintissuehomeostasis,healthanddisease4.In2003,weshowedthattheCaenorhabditiselegansautophagygenebec-1(orthologueofyeastATG6,mammalianbeclin1)wasrequiredforlifespanextensioninnematodeswithalossoffunctionintheinsulinsignallingpathway5.Subsequently,numerousloss-of-functionstudiesinC.elegansandDrosophilahaveconfirmedanessentialroleforthe...
