TothosewhoinsistthatBela,8,hasturnedbackintoapuppy—“Lookhowfastshe’sgettingthatball!”—Ms.Gemmellhastriedtoturnadeafear.Bela,aBordercollie-Australianshepherdmix,mayhavebeengivenaplacebo,foronething.
8岁的贝拉是博德牧羊犬和澳大利亚牧羊犬杂交的后代。有些人坚称它又变成了小狗——“看她接球接得多快啊!”——格默尔尽量不去听信。一来，贝拉接受的药物或许只是安慰剂。
Thedrug,rapamycin,whichimprovedhearthealthandappearedtodelaytheonsetofsomediseasesinoldermice,maynotworkthesamemagicindogs,foranother.Thereisalsoachanceitcoulddomoreharmthangood.“Thisisjusttolookforsideeffects,indogs,”Ms.GemmelltoldBela’smanywell-wishers.
Technicallythatistrue.Butthetrialalsorepresentsanewfrontierintestingapropositionforimprovinghumanhealth:Ratherthanonlyseekingtreatmentsfortheindividualmaladiesthatcomewithage,wemightdobettertotargetthebiologythatunderliesagingitself.
从技术层面讲，这是事实。但这项试验代表着测试改善人类健康方案的新阵地：与其只为随着衰老会患上的各种疾病寻求治疗方案，不如将目标放在有关衰老本身的生物学研究上。
Whilethediseasesthatnowkillmostpeopleindevelopednations—heartdisease,stroke,Alzheimer’s,diabetes,cancer—havedifferentimmediatecauses,ageisthemajorriskfactorforallofthem.Thatmeansthateventreatmentbreakthroughsintheseareas,nomatterhowvitaltoindividuals,wouldyieldonaveragefourorfivemoreyearsoflife,epidemiologistssay,andsomeofthemlikelyshadowedbyillness.
尽管在发达国家夺取最多生命的那些疾病——心脏病、脑卒中、阿尔茨海默病、糖尿病、癌症——有各种不同的直接起因，但衰老是罹患所有这些疾病的主要风险因素。流行病学家表示，这意味着，即便这些疾病的治疗出现突破，哪怕对个人而言有多么重大，也只会平均延长四五年的寿命，其中有些年还很可能会生活在疾病的阴影下。
Adrugthatslowsaging,thelogicgoes,mightinsteadservetodelaytheonsetofseveralmajordiseasesatonce.Ahandfulofdrugstestedbyfederallyfundedlaboratoriesinrecentyearsappeartoextendthehealthylivesofmice,withrapamycinanditsderivatives,approvedbytheFoodandDrugAdministrationfororgantransplantpatientsandtotreatsometypesofcancer,sofarprovingthemosteffective.Ina2014studybythedrugcompanyNovartis,thedrugappearedtobolstertheimmunesysteminolderpatients.Andtheearlyresultsinagingdogssuggestthatrapamycinishelpingthem,too,saidMattKaeberlein,abiologyofagingresearcherattheUniversityofWashingtonwhoisrunningthestudywithacolleague,DanielPromislow.
这里的逻辑是，可以减缓衰老的药物或许能同时延迟好几种重大疾病的发生。最近几年，由美国联邦政府资助的实验室测试的几种药物似乎可以延长小鼠的健康寿命，其中雷帕霉素及其衍生物目前被证明效果最好。这种药物经过了美国食品与药品管理局(FoodandDrugAdministration)的批准，可以给接受器官移植的病人使用，或用来治疗某些癌症。制药公司诺华(Novartis)在2014年进行的一项研究显示，它似乎可以增强老年病人的免疫系统。在华盛顿大学(UniversityofWashington)从事衰老生物学研究的马特·克贝尔莱茵(MattKaeberlein)表示，针对老年狗的早期实验结果也显示，雷帕霉素对它们有帮助。克贝尔莱茵在和同事丹尼尔·普罗米斯洛(DanielPromislow)一起牵头进行这项研究。
Butscientistswhochampionthestudyofaging’sbasicbiology—theycallit“geroscience”—saytheirfieldhasreceivedshortshriftfromthebiomedicalestablishment.AnditwasnotlostontheUniversityofWashingtonresearchersthatexposingdogloverstotheideathatagingcouldbedelayedmightgeneratepopularsupportinadditiontonewdata.
不过，支持衰老基础生物学——他们称为“老年科学”——研究的科学家表示，这一领域遭到了生物医学界权威人士的漠视。但华盛顿大学的研究人员注意到，向爱狗人士展示可以延缓宠物的衰老这样一种观念，或许可以为他们赢得公众的支持，也可能带来新的数据。
“Manyofusinthebiologyofagingfieldfeellikeitisunderfundedrelativetothepotentialimpactonhumanhealththiscouldhave,”saidDr.Kaeberlein,whohelpedpayforthestudywithfundshereceivedfromtheuniversityforturningdownacompetingjoboffer.“Iftheaveragepetownerseesthere’sawaytosignificantlydelayagingintheirpet,maybeitwillbegintoimpactpolicydecisions.”
Theideathatresourcesmightbebetterspenttryingtodelayagingratherthantocurediseasesfliesinthefaceofmostdisease-relatedphilanthropyandtheObamaadministration’sproposaltospend$1billionona“cancermoonshot.”Andmanyscientistssayitisstilltoounproventomeritmoreinvestment.
Researchersinthefield,inturn,saytheymighthavemoretoshowforthemselvesiftheycouldbetterexplaintoCongressandthepublicwhybasicresearchonagingcouldbeuseful.
该领域的研究人员则表示，如果他们能更清晰地向国会和大众解释有关衰老的基础研究为何很有用，或许便能更好地证明自己。
“Peopleunderstand‘myrelativediedofaheartattack,soI’mgoingtogivemoneytothat,’”saidDr.JamesL.Kirkland,aMayoClinicresearcher.“It’shardertograsp‘myrelativewasolder,thatpredisposesthemtohaveaheartattack,soIshouldgivemoneytoresearchonaging.’”
“人们可以理解‘我的亲人死于心梗，所以我要给这方面的研究捐钱，’”梅奥诊所(MayoClinic)的研究员詹姆斯·L·柯克兰博士(JamesL.Kirkland)说。“更难被人理解的是，‘我的亲人年纪大了，就会更容易心梗，所以我应该捐钱让他们做有关衰老的研究。’”
Mostofusharbortheintuitionthatweagebecauseourbodies,likeourcars,ourfurniture,ourpatience,justwearout.Butthebestargumentthatlifespanisnothard-wired,biologistssay,haslongbeenevident:Livingthingsageatsignificantlydifferentrates.
我们大多数人怀着这样一种直觉：我们之所以衰老，只是因为身体遭到了损耗，就像我们的汽车、家具和我们的耐心一样。但生物学家表示，能最好反驳生命周期不可改变这种观念的证据一直都显而易见：生物衰老的速度可以是天差地别的。
“Thesquirrelsinmyneighborhoodhavea25-yearlifespan,buttheylooklikeratsthatlivetwoyears,”saidGaryRuvkun,apioneerinagingbiologyatHarvardMedicalSchool.“Ifyoulookatwhatnaturehasselectedforandallowed,itsuggeststhatyoumightbeabletogetyourhandsonthevariousleversthatchangethings.”
“在我家附近生活的松鼠有25年的寿命，但和它们看起来长得差不多的老鼠只能活两年，”衰老生物学研究领域的先驱、来自哈佛医学院的加里·鲁夫库恩(GaryRuvkun)说。“如果看看自然界选择了什么，容许什么，就能明白你或许可以获得各种能够改变现状的杠杆。”
Thataspirationgainedtractioninthe1990sand2000s,whenscientists,armedwithnewtoolsofmolecularbiology,homedinonthecomplexcellularpathwaysthatregulatelifespaninmanyspecies.Byremovinggenesthatproducedcertainproteins,oraddinggenesthatproducedothers,researchersfoundtheycouldsignificantlyextendthelivesofsimplelaboratoryorganismslikebuddingyeast,roundwormsandflies.
“It’snotjustwearingout,it’saprogram,”Dr.Ruvkunsaid.“Thegeneticstoldusthat.Ifyoucanmodulateitwithafewsimpleperturbations,that’sthedefinitionofaprogram.”
“不只是逐渐损耗，而是一个程序，”鲁夫库恩说，“遗传学向我们表明了这一点。我们能施加一些简单的干预，从而对它进行调节——这就是程序。”
Sincegenescannotbesoeasilymanipulatedinhumans,itwassignificantin2006whenDr.Kaeberleinandothersdemonstratedthatrapamycin,thedrugnowbeingtestedindogs,suppressedoneofthecrucialproteinsinyeast,resultinginalongerlifespanwithoutremovingagene.Theproteinisknowntobeinvolvedincellgrowth.Butjusthowitssuppressionworkstoextendlifeisstillunclear,raisingquestionsaboutpotentialunknowndownsides.
由于人类的基因不易操纵，2006年的一项发现就显得很重要：克贝尔莱因等人发现，雷帕霉素能抑制酵母中的一种关键蛋白质，从而在不移除基因的前提下延长寿命。人们知道这种蛋白质参与细胞生长，但不清楚为什么抑制它能延长生命，因此让人担心它可能存在未知的负面作用。这种药目前正在狗身上试验。
Dogsagefasterthanhumans,andbiggerdogsagefasterthansmallerdogs.The40dogsthatparticipatedintherapamycintrial,whichjustconcludeditspilotruninSeattle,hadtobeatleast6yearsoldandweighatleast40pounds.
狗比人衰老得更快，大型狗比小型狗衰老得更快。参与雷帕霉素试验的40只狗都是至少6岁，体重至少40磅。这项研究刚在西雅图完成了初试阶段。
LikeLynnGemmell’sBela,whosecholesterolwashigh,manyofthemwereshowingsignsofaging:looseskin,grayingmuzzles,astiffnessinthejoints.Soweresomeoftheirowners.
林恩·格默尔的贝拉胆固醇偏高。参与实验的其他很多狗也像贝拉一样，表现出衰老的迹象：皮肤松弛，鼻口发灰，关节僵硬。它们的主人中有些也是这样。
“Howareyougoingtobesurepeoplearegoingtobegivingthistotheirdogratherthantakingitthemselves”Ms.Gemmell,58,jokedwithDr.Kaeberleinonherfirstvisittotheveterinaryclinic,whereBelawasgivenacheckupandanechocardiogramtomeasureheartfunction,amarkerthatcouldconceivablyregisteranimprovementoverthe10weeksthatshewouldbegiventhedrug.
“你怎么能确保主人把药喂给狗了，而不是自己吃了”58岁的格默尔第一次去这家兽医诊所时跟克贝尔莱因博士开玩笑说。贝拉在那里进行体检，还做了超声心动图，以检查心脏功能。这是一个标记，可以直观显示用药10周后的改善情况。
Aresearchcoordinatorforhumanclinicaltrialsatahospital,Ms.GemmelladoptedBelaasa12-week-oldrescuewithoutrealizinghowmuchoutdoortimeshewouldneedwithher.Nowdivorcedwithtwogrowndaughters,Ms.Gemmelldonsaheadlampwhenshereturnshomeinthedark,andtakesBelaoutwithaglow-in-the-darkballandacollarlight.“Iwishshecouldliveforever,”shesaid.
Over1,500dogownersappliedtoparticipateinthetrialofrapamycin,whichhasitsrootsinaseriesofstudiesinmice,thefirstofwhichwaspublishedin2009.Madebyatypeofsoilbacterium,rapamycinhasextendedthelifespansofyeast,fliesandwormsbyabout25percent.
1500多名狗主人申请参与雷帕霉素试验，这项试验基于一系列对小鼠做的研究，第一项研究结果发表于2009年。雷帕霉素是用一种土壤细菌做成的，能将酵母、苍蝇和蠕虫的寿命延长约25%。
Butinwhatprovedafortuitousaccident,theresearcherswhosetouttotestitinmicehadtroubleformulatingitforeasyconsumption.Asaresult,themicewere20monthsold—theequivalentofabout60humanyears—whenthetrialbegan.Thatthelongest-livedmicesurvivedabout12percentlongerthanthecontrolgroupswasthefirstindicationthatthedrugcouldbegivenlaterinlifeandstillbeeffective.
Still,drugsthatworkinmiceoftenfailinhumans.Itisalsohardtoaskrodentsabouttheirqualityoflife.Thesideeffects,dependingonthedoseandduration,includemouthsores,cataracts,insulinresistanceand,formales,problemswithtesticularfunction.Nooneknowsifpeople,whoalreadylivealotlongerthanmice,wouldseeaproportionalincreaseinlifespan.Andsomeresearcherssaytherewouldbeseriousconcernsintestingrapamycin,oranydrug,inhealthypeoplejusttoslowaging.WhatifadruglengthenedlifeforsomeandshorteneditforothersCouldanyoneethicallyputahealthypersonintoatestthatmightactuallyshortenlifespan
“It’snotassimpleascancer,wherepatientsaregoingtodieanywayiftheydon’tgetthedrug,”saidAndrewDillin,abiologyofagingresearcherattheUniversityofCalifornia,Berkeley,whorecentlyraisedthequestionsinNature,ascientificjournal.
“它不像癌症那么简单，病人不试这种药也会死，”加州大学伯克利分校(UniversityofCalifornia,Berkeley)的衰老生物学研究员安德鲁·迪林(AndrewDillin)说。前不久，他在科学期刊《自然》(Nature)上提出了这些问题。
Ethicalconcernsaside,suchatrialwouldtakedecades.Butwhatdoglovershavelongconsideredthesadfactthattheirpetsageaboutseventimesasfastastheydo,Dr.Kaeberleinknew,wouldbeaboonforastudyofrapamycinthatwouldhaveimplicationsforbothspecies.Anowneroftwodogshimself,hewasdeterminedtoscroungeupthemoneyforthepilotphaseofwhatheandDr.PromislowcalledtheDogAgingProject.
Lastmonth,hereportedatascientificmeetingthatnosignificantsideeffectshadbeenobservedinthedogs,evenatthehighestofthreedoses.Andcomparedwiththeheartsofdogsinthecontrolgroup,theheartsofthosetakingthedrugpumpedbloodmoreefficientlyattheend.Theresearcherswouldliketoenroll450dogsforamorecomprehensivefive-yearstudy,butdonotyethavethemoney.
上个月，他在一次科学会议上报告称，在狗身上没有观察到明显的副作用，即使是三种剂量中最高的那一种，也没有。试验结束时，与对照组的狗的心脏相比，服药狗的心脏泵血功能更强。这些研究者想招募450只狗进行更全面的五年期研究，但目前经费不够。
Evenifthestudyprovidedpositiveresultsonallfronts,ahumantrialwouldcarryrisks.
即使这项研究在各方面的结果都是积极的，在人身上试验仍然可能有风险。
Dr.Kaeberlein,forone,saidtheywouldbeworthit.
但作为一个支持者，克贝尔莱因博士说这值得一试。
“Iwouldargueweshouldbewillingtotoleratesomelevelofriskifthepayoffis20to30percentincreaseinhealthylongevity,”hesaid.“Ifwedon’tdoanything,weknowwhattheoutcomeisgoingtobe.You’regoingtogetsick,andyou’regoingtodie.”
“我要说，我们应该愿意容忍一定程度的风险，如果回报是能延长20%至30%的健康寿命，”他说，“如果我们什么都不做，我们知道结果是什么。我们会生病，会死去。”