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1、Sirtuinsasregulatorsofage-relateddiseaseandmetabolismIntroductionSincethediscoveryoftheyeastsirtuinsilenceinformationregulator2(Sir2)beingabletoextendsyeastlifespan,Sirtuinshavereceivedsignificantattentionandwasoriginallydescribedasaregulatoroftranscriptionalsilengcingo
2、fmating-typeloci,telomeresandribosomalDNA[1,2].Inmammals,thesirtuinfamilywhichinvolves7proteins(SIRT1-SIRT7)canbedividedinto4classes,andvaryintissuespecificity,subcellularlocalization,enzymaticactivityandtargets(TABLE1).Studieshaveprovedthekeyrolesofsirtuinsincaloricres
3、triction,age-relateddiseaseandmetabolichomeostasis.Someotherresearchesalsodiscoveredthattheactivationofsirtuinscanreliefdiseaserelatingtometabolismorneurodenegeration,suchastype2diabetesandParkinson’sdisease.Asaconsequence,regulationofsirtuinscanbeapotentialmethodforage
4、-relateddiseaseormetabolicdisorder.Inthisarticle,Ipresentmycurrentknowledgeabouttheregulationofsirtuins,namelySIRT1,SIRT5andSIRT7inage-relateddiseaseandmetabolichomeostasis.NAD+asarate-limitingsubstrateforsirtuindeacylasesThedeacetylaseactivityofthesirtuinproteinsrequir
5、esNAD+asasubstrate,thedensityofwhichisdeterminedbythenutritionalstateofthecell[3].Therefor,NAD+hasapowerfulmetabolicimpactbymodulatingtheactivityofsirtuinsandtheirdownstreameffectors.Itiswellknownthatnicotinamidemononucleotide(NM)andnicotinamideriboside(NR)areNAD+precur
6、sors,andDNArepairproteins,poly(ADP-ribose)polymeraseproteins(PARP)-withPARP1andPARP2representingthemainPARPactivitiesinmammalsareNAD+-consumingproteins[4].BothactivationofNM/NRandinactivationofPARPincreasedtissueNAD+levelsandactivatedmitochondrialmetabolism[5-7].Inthere
7、searchofLaurentMouchiroud,etal.[8],theyshowthatNAD+iscausallyreducedinaging,andPARPinhibitorsorNAD+precursorsareabletoincreasemitochondrialfunction,thuspreventage-associatedmetabolicdeclineandpromotelongevityinworms.Theseeffectsaredependentuponthesirtuinsdeacetylazition
8、,whichinvolvetheinductionofmitonuclearproteinimbalance,activationofstresssignalingviathemitochondrialunfoldedp
