letters782VOLUME23|NUMBER6|JUNE2017naturemedicineThebalancebetweendetrimental,pro-aging,oftenstochasticprocessesandcounteractinghomeostaticmechanismslargelydeterminestheprogressionofaging.Thereissubstantialevidencesuggestingthattheendocannabinoidsystem(ECS)ispartofthelattersystembecauseitmodulatesthephysiologicalprocessesunderlyingaging1,2.TheactivityoftheECSdeclinesduringaging,asCB1receptorexpressionandcouplingtoGproteinsarereducedinthebraintissuesofolderanimals3–5andthelevelsofthemajorendocannabinoid2-arachidonoylglycerol(2-AG)arelower6.However,adirectlinkbetweenendocannabinoidtoneandagingsymptomshasnotbeendemonstrated.HereweshowthatalowdoseofD9-tetrahydrocannabinol(THC)reversedtheage-relateddeclineincognitiveperformanceofmiceaged12and18months.Thisbehavioraleffectwasaccompaniedbyenhancedexpressionofsynapticmarkerproteinsandincreasedhippocampalspinedensity.THCtreatmentrestoredhippocampalgenetranscriptionpatternssuchthattheexpressionprofilesofTHC-treatedmiceaged12monthscloselyresembledthoseofTHC-freeanimalsaged2months.ThetranscriptionaleffectsofTHCwerecriticallydependentonglutamatergicCB1receptorsandhistoneacetylation,astheirinhibitionblockedthebeneficialeffectsofTHC.Thus,restorationofCB1signalinginoldindividualscouldbeaneffectivestrategytotreatage-relatedcognitiveimpairments.TodeterminewhetherprolongedexposuretoalowdoseofTHChaslastingeffectsonlearningandmemoryperformanceinmiceaged2,12and18months(termedyoung,matureandold,respectively),weimplantedosmoticminipumpsreleasing3mgperkgbodyweightperdayofTHCorvehiclefor28d.TheeffectsofageandtreatmentonspatiallearningandmemorywerefirstassessedintheMorriswatermaze(MWM)teststartingonday33afterpumpimplantation,thusallowingawashoutperiodof5d(Fig.1a).Thematureandoldvehicle-treatedanimalslearnedthetaskmoreslowlythantheyounganimals,whichisindicativeofanage-relateddeficitinspatiallearning(Fig.1b).TreatmentwithTHCimprovedtaskacquisitioninmatureandoldanimals.Thedifferencebetweenthegroupspersistedinthereversalphaseofthetest,whichass...
