仓鼠的寿命有多长支链氨基酸延长小白鼠寿命全文CellMetabolismBranched-ChainAminoAcidSupplementationPromotesSurvivalandSupportsCardiacandSkeletalMuscleMitochondrialBiogenesisinMiddle-AgedMiceGiuseppeDAntona,1,2MaurizioRagni,3AnnalisaCardile,3LauraTedesco,3,4MartaDossena,3,5FlaviaBruttini,1,2FrancescaCaliaro,1,2GiovanniCorsetti,6RobertoBottinelli,1,2MicheleO.Carruba,3,4AlessandraValerio,3,5andEnzoNisoli3,4,*ofPhysiology,HumanPhysiologyUnitInstituteofMyologyPaviaUniversity,Pavia27100,Italy3CenterforStudyandResearchonObesity,DepartmentofPharmacology,ChemotherapyandMedicalToxicology,SchoolofMedicine,MilanUniversity,Milan20129,Italy4IstitutoAuxologicoItaliano,Milan20145,Italy5PharmacologyUnit6HumanAnatomyUnitDepartmentofBiomedicalSciencesandBiotechnologies,BresciaUniversity,Brescia25123,Italy*Correspondence:enzo.nisoli@unimi.itDOI10.1016/j.cmet.2010.08.0162Interuniversity1DepartmentSUMMARYRecentevidencepointstoastrongrelationshipbetweenincreasedmitochondrialbiogenesisandincreasedsurvivalineukaryotes.Branched-chainaminoacids(BCAAs)havebeenshowntoextendchronologicallifespaninyeast.However,theroleoftheseaminoacidsinmitochondrialbiogenesisandlongevityinmammalsisunknown.Here,weshowthataBCAA-enrichedmixture(BCAAem)increasedtheaveragelifespanofmice.BCAAemsupplementationincreasedmitochondrialbiogen-esisandsirtuin1expressioninprimarycardiacandskeletalmyocytesandincardiacandskeletalmuscle,butnotinadiposetissueandliverofmiddle-agedmice,andthiswasaccompaniedbyenhancedphysicalendurance.Moreover,thereac-tiveoxygenspecies(ROS)defensesystemgeneswereupregulated,andROSproductionwasreducedbyBCAAemsupplementation.AlloftheBCAAem-mediatedeffectswerestronglyattenuatedinendo-thelialnitricoxidesynthasenullmutantmice.ThesedatarevealanimportantantiagingroleofBCAAsmediatedbymitochondrialbiogenesisinmammals.INTRODUCTIONAgingisanaturalprocessthataffectsmostbiologicalfunctionsandresultsinreducedresistancetostress,increasedvulnera-bilitytodiseases(includingcardiovasculardisease,cancer,diabetes,sarcopenia,osteoporosis,andkidneydisease),andincreasedprobabilityofdeath.Amongtheplethoraofbiologicalphenomenaaffectedbyaging,themalfunctionofmitochondriaandthedecreaseofmitochondrialbiogenesis,togetherwithincreasedoxidativedamage,seemtoexertsomeofthemostpez-deleteriouseffectsontheorganism(Guarente,2008;LoLluchetal.,2008).Avarietyofstrategiesthatalleviateagerelatedde?citsinmitochondrialbiogenesisandactivity,includingcalorierestriction(CR)andmoderatephysicalexercise,promotesurvivalinmammals.Theseinterventionsincreasetheexpressionofperoxisomeproliferator-activatedreceptorgcoactivator-1a(PGC-1a,amasterregulatorofmito-chondrialbiogenesisandreactiveoxygenspecies[ROS]defensesystem)andofsirtuin1(SIRT1,amemberofthesirtuinfamilylinkedtolifespanextension,enhancedmitochondrialbiogenesis,anddecreasedROSproduction),thusreducingoxidativedamageinmetabolicallyactivetissuesofmiceandhumans(Civitareseetal.,2007;Nisolietal.,2005;Ristowetal.,2009).TheCReffectsonmitochondrialbiogenesisaredue,atleastinpart,toinductionofendothelialnitricoxidesynthase(eNOS)expression(Nisolietal.,2005).Indeed,eNOSnullmutant(eNOSa/a)micearecharacterizedbyareducedlifespan(Lietal.,2004),duetoage-relateddiseases(Cooketal.,2003),andbyareducedmitochondrialbiogenesis(Nisolietal.,2003,2004)andSIRT1expression(Nisolietal.,2005).AlthoughCRhasbene?cialeffectsinhumans(Heilbro...