Disruption of Protein Kinase A in Mice Enhances Healthy Aging 英文参考文献.docVIP

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Disruption of Protein Kinase A in Mice Enhances Healthy Aging 英文参考文献.doc

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Disruption of Protein Kinase A in Mice Enhances Healthy Aging 英文参考文献

DisruptionofProteinKinaseAinMiceEnhancesHealthy Aging LindaC.Enns,JohnF.Morton,PiperR.Treuting,MaryJ.Emond,NormanS.Wolf,G.S.McKnight,PeterS. Rabinovitch,WarrenC.Ladiges* DepartmentsofComparativeMedicine,Biostatistics,Pharmacology,andPathology,SchoolofMedicine,UniversityofWashington,Seattle,Washington,UnitedStatesof America Abstract MutationsthatcauseareductioninproteinkinaseA(PKA)activityhavebeenshowntoextendlifespaninyeast.Lossof functionofmammalianRIIb,aregulatorysubunitofPKAexpressedinbrainandadiposetissue,resultsinmicethatarelean andinsulinsensitive.ItwasthereforehypothesizedthatRIIBnull(RIIb2/2)micewouldexpressanti-agingphenotypes.We conductedlifespanstudiesusing40mutantand40wildtype(WT)littermatesofequalgendernumbersandfoundthat boththemedianandmaximumlifespansweresignificantlyincreased inmutantmalescomparedtoWTlittermates. The median lifespan was increased from 884 days to 1005 days (p=0.006 as determined by the log rank test) and the 80% lifespan(definedhereas80%deaths)wasincreasedfrom941daysto1073days(p=0.004asdeterminedbytheWang- Allison test). There was no difference in either median or 80% lifespan in female genotypes. WT mice of both genders becameincreasinglyobesewithage,whilemutantmicemaintainedtheirleanphenotypeintooldage.Adipositywasfound tocorrelatewithlifespanformalesonly.50%ofmalemicebetween30and35g,correspondingtoabout5%bodyfat,for eithergenotypelivedover1000days.Nomalemouseoutsideofthisweightrangeachievedthislifespan.Duringtheirlast month of life, WT mice began losing weight (a total of 8% and 15% of body weight was lost for males and females, respectively),butRIIb2/2malemicemaintainedtheirleanbodymasstoendoflife.Thisattenuationofdeclinewasnotseen infemalemutantmice.Oldmalemutantmicewereinsulinsensitivethroughouttheirlife.Bothgendersshowedmodestly lowerbloodglucoselevelsinoldmutantscomparedtoWT.Malemutantswerealsoresistanttoage-inducedfattyliver. Pathologicalassessmentoftissuesfromendoflifemalemutantmiceshowedadecreaseintumorincidence,