/Users/andrea/_magisterarbeit/korpus/clean/trainkorpus/1/file3.html NN ----------------------------------------- : Skip NP to TO content VV . SENT HomeCurrent NP IssueNew NP ArticlesArchiveSubmit NP PaperContent NP AlertsPLoSPLoS NP Medicine NP Order NP Print NP Issues NPS Contact NP Us NP Author NN Info NP Reviewer NN Info NP Journal NP Info NP Ed NP Board NP Help NN Volume NN 3 CD Issue NN 9 CD SEPTEMBER NP 2005 CD Previous JJ article NN Next JJ article NN SEARCH NN PLoS NP Biology NN Advanced NP Search NP Research NP Article NP Aging VVG and CC Gene NP Expression NN in IN the DT Primate NN Brain NP Hunter NP B NP . SENT Fraser NP 1 CD , , Philipp NP Khaitovich NP 2 CD , , Joshua NP B NP . SENT Plotkin NP 3 CD , , Svante NP P NN bo NP 2 CD , , Michael NP B NP . SENT Eisen NP 1 CD , , 4 CD 1 CD Department NP of IN Molecular JJ and CC Cell NN Biology NN , , University NP of IN California NP , , Berkeley NP , , California NP , , United NP States NPS of IN America NP , , 2 CD Max NP Planck NP Institute NP for IN Evolutionary JJ Anthropology NN , , Leipzig NP , , Germany NP , , 3 CD Society NP of IN Fellows NP , , Harvard NP University NP , , Cambridge NP , , Massachusetts NP , , United NP States NPS of IN America NP , , 4 CD Genome NN Sciences NPS Department NP , , Genomics NP Division NP , , Lawrence NP Berkeley NP National NP Laboratory NP , , Berkeley NP , , California NP , , United NP States NPS of IN America NP It PP is VBZ well RB established VVN that IN gene NN expression NN levels NNS in IN many JJ organisms NNS change VVP during IN the DT aging VVG process NN , , and CC the DT advent NN of IN DNA NN microarrays NNS has VHZ allowed VVN genome NN wide JJ patterns NNS of IN transcriptional JJ changes NNS associated VVN with IN aging VVG to TO be VB studied VVN in IN both DT model NN organisms NNS and CC various JJ human JJ tissues NNS . SENT Understanding VVG the DT effects NNS of IN aging VVG on IN gene NN expression NN in IN the DT human JJ brain NN is VBZ of IN particular JJ interest NN , , because IN of IN its PP$ relation NN to TO both DT normal JJ and CC pathological JJ neurodegeneration NN . SENT Here RB we PP show VVP that IN human JJ cerebral JJ cortex NN , , human JJ cerebellum NN , , and CC chimpanzee NN cortex NN each DT undergo VVP different JJ patterns NNS of IN age NN related JJ gene NN expression NN alterations NNS . SENT In IN humans NNS , , many JJ more JJR genes NNS undergo VVP consistent JJ expression NN changes NNS in IN the DT cortex NN than IN in IN the DT cerebellum NN . SENT in IN chimpanzees NNS , , many JJ genes NNS change VVP expression NN with IN age NN in IN cortex NN , , but CC the DT pattern NN of IN changes NNS in IN expression NN bears VVZ almost RB no DT resemblance NN to TO that DT of IN human JJ cortex NN . SENT These DT results NNS demonstrate VVP the DT diversity NN of IN aging VVG patterns NNS present JJ within IN the DT human JJ brain NN , , as RB well RB as IN how WRB rapidly RB genome NN wide JJ patterns NNS of IN aging VVG can MD evolve VV between IN species NNS . SENT they PP may MD also RB have VH implications NNS for IN the DT oxidative JJ free JJ radical JJ theory NN of IN aging VVG , , and CC help VV to TO improve VV our PP$ understanding NN of IN human JJ neurodegenerative JJ diseases NNS . SENT Academic NP Editor NP . SENT Thomas NP Kirkwood NP , , University NP of IN Newcastle NP upon IN Tyne NP , , United NP Kingdom NP Received VVD . SENT February NP 18 CD , , 2005 CD . SENT Accepted VVN . SENT June NP 7 CD , , 2005 CD . SENT Published VVN . SENT August NP 2 CD , , 2005 CD DOI NP . SENT 10 CD . SENT 1371 CD journal NN . SENT pbio NN . SENT 0030274 CD Copyright NN . SENT 2005 CD Fraser NP et NP al NP . SENT This DT is VBZ an DT open JJ access NN article NN distributed VVN under IN the DT terms NNS of IN the DT Creative JJ Commons NP Attribution NN License NN , , which WDT permits VVZ unrestricted JJ use NN , , distribution NN , , and CC reproduction NN in IN any DT medium NN , , provided VVD the DT original JJ work NN is VBZ properly RB cited VVN . SENT Abbreviations NNS . SENT GO VV , , Gene NP Ontology NN . SENT ROS NP , , reactive JJ oxygen NN species NNS To TO whom WP correspondence NN should MD be VB addressed VVN . SENT E SYM mail NN . SENT hunter NN alum NN . SENT mit NP . SENT edu NP Citation NP . SENT Fraser NP HB NP , , Khaitovich NP P NN , , Plotkin NP JB NP , , P NN bo NP S NP , , Eisen NP MB NP 2005 CD Aging NN and CC Gene NP Expression NN in IN the DT Primate NN Brain NP . SENT PLoS NP Biol NP 3 CD 9 CD . SENT e SYM 274 CD View NN this DT article NN by IN . SENT FiguresPrint NP PDF NP 2053 CD K NP Screen NP PDF NP 182 CD K NP Download NP Citation NP Options NPS . SENT Read NP SynopsisRead NP Related NP ArticlesSee NP Articles NNS Citing VVG This DT ArticleE NP mail NN this DT ArticleSearch NP PubMed NP for IN . SENT Related NP ArticlesPubMed NP CitationHunter NP B NP . SENT FraserPhilipp NP KhaitovichJoshua NP B NP . SENT PlotkinSvante NP P NN boMichael NP B NP . SENT Eisen NP Introduction NN Despite IN its PP$ ubiquity NN and CC importance NN , , aging NN remains VVZ a DT poorly RB understood VVN process NN . SENT This DT lack NN of IN understanding NN is VBZ due JJ in IN part NN to TO the DT complexity NN of IN aging NN , , which WDT is VBZ characterized VVN by IN the DT gradual JJ and CC progressive JJ decline NN of IN numerous JJ physiological JJ processes NNS and CC homeostasis NN , , eventually RB leading VVG to TO death NN 1 CD 6 CD . SENT However RB , , recent JJ progress NN in IN aging VVG research NN has VHZ made VVN it PP clear JJ that IN aging VVG processes NNS are VBP amenable JJ to TO biochemical JJ and CC genetic JJ dissection NN , , in IN both DT humans NNS and CC model NN organisms NNS 3 CD 6 CD . SENT Both DT environmental JJ and CC genetic JJ alterations NNS in IN model NN organisms NNS have VHP been VBN found VVN to TO have VH profound JJ effects NNS on IN aging VVG and CC lifespan NN . SENT In IN particular JJ , , dietary JJ restriction NN has VHZ been VBN found VVN to TO dramatically RB increase VV the DT lifespan NN of IN organisms NNS including VVG yeast NN , , flies VVZ , , nematodes NNS , , and CC mammals NNS 4 CD , , 5 CD . SENT the DT mechanism NN by IN which WDT this DT intervention NN reduces VVZ mortality NN rates NNS is VBZ still RB under IN investigation NN . SENT Additionally RB , , inactivating VVG myriad JJ single JJ genes NNS has VHZ been VBN found VVN to TO be VB able JJ to TO significantly RB increase VV the DT average JJ lifespan NN of IN model NN organisms NNS 4 CD , , 5 CD , , and CC the DT identification NN of IN the DT pathways NNS to TO which WDT these DT genes NNS belong VVP is VBZ beginning VVG to TO shed VV light NN on IN their PP$ possible JJ modes NNS of IN action NN . SENT For IN example NN , , many JJ genes NNS implicated VVN in IN regulating VVG lifespan NN in IN the DT nematode NN Caenorhabditis NN elegans NNS belong VVP to TO the DT insulin NN IGF NN insulin NN like IN growth NN factor NN signaling VVG pathway NN , , indicating VVG possible JJ connections NNS to TO metabolism NN and CC a DT state NN of IN arrested VVN development NN known VVN as IN dauer NP 4 CD , , 5 CD . SENT Another DT class NN of IN genes NNS found VVN to TO be VB involved VVN in IN the DT aging VVG process NN is VBZ related VVN to TO the DT production NN and CC scavenging VVG of IN molecules NNS known VVN as IN reactive JJ oxygen NN species NN ROS NP , , thus RB providing VVG genetic JJ evidence NN in IN support NN of IN a DT mechanistic JJ theory NN of IN aging VVG known VVN as IN the DT free JJ radical JJ theory NN 2 CD , , 3 CD . SENT The DT free JJ radical JJ theory NN of IN aging VVG was VBD first RB introduced VVN by IN Harman NP almost RB half PDT a DT century NN ago IN 2 CD . SENT This DT theory NN , , as RB well RB as IN the DT related JJ rate NN of IN living VVG theory NN proposed VVN earlier RBR by IN Pearl NP 1 CD , , holds VVZ that DT aging NN is VBZ at IN least JJS in IN part NN due JJ to TO deleterious JJ side NN effects NNS of IN aerobic JJ respiration NN . SENT Specifically RB , , mitochondrial JJ activity NN leads VVZ to TO the DT production NN of IN ROS NP that WDT can MD damage VV many JJ cellular JJ components NNS , , including VVG DNA NN , , lipids NNS , , and CC proteins VVZ 3 CD . SENT These DT ROS NP , , such JJ as IN the DT hydroxyl NN radical NN OH UH and CC hydrogen NN peroxide NN H NP 2 CD O NN 2 CD , , are VBP produced VVN in IN large JJ part NN by IN the DT mitochondrial JJ electron NN transport NN chain NN . SENT The DT free JJ radical JJ theory NN has VHZ garnered VVN widespread JJ support NN in IN recent JJ years NNS . SENT in IN addition NN to TO the DT genetic JJ evidence NN mentioned VVN above IN , , studies NNS from IN a DT number NN of IN model NN organisms NNS showing VVG that IN decreasing VVG ROS NP levels NNS leads VVZ to TO an DT increase NN in IN lifespan NN indicate VVP that IN ROS NP can MD strongly RB modulate VV the DT aging VVG process NN 3 CD 5 CD . SENT Exactly RB how WRB macromolecules NNS damaged VVN by IN ROS NP may MD lead VV to TO aging NN has VHZ been VBN studied VVN in IN detail NN in IN recent JJ years NNS , , and CC the DT human JJ brain NN has VHZ been VBN intensively RB examined VVN in IN this DT regard NN because IN of IN its PP$ overall JJ importance NN in IN human JJ senescence NN . SENT For IN example NN , , up RB to TO one CD third NN of IN the DT proteins NNS in IN the DT brains NNS of IN elderly JJ individuals NNS may MD be VB oxidatively RB damaged VVN , , and CC these DT damaged JJ proteins NNS have VHP been VBN shown VVN to TO sometimes RB have VHP diminished VVN catalytic JJ function NN 3 CD , , 6 CD . SENT One CD recent JJ study NN of IN aging VVG in IN the DT human JJ brain NN demonstrated VVN that IN oxidative JJ damage NN to TO DNA NP can MD be VB caused VVN by IN mitochondrial JJ dysfunction NN , , and CC tends VVZ to TO accumulate VV preferentially RB in IN some DT areas NNS of IN the DT genome NN that WDT include VVP promoters NNS , , resulting VVG in IN lower JJR levels NNS of IN transcription NN 7 CD possibly RB due JJ to TO loss NN of IN transcription NN factor NN or CC other JJ protein NN binding VVG 8 CD 10 CD . SENT In IN this DT same JJ study NN , , genome NN wide JJ patterns NNS of IN aging VVG associated VVN gene NN expression NN change NN in IN one CD region NN of IN the DT human JJ brain NN cortex NN the DT frontal JJ pole NN . SENT Figure NN 1 CD were VBD measured VVN using VVG DNA NN microarrays NNS , , and CC genes NNS that WDT had VHD decreased VVN transcription NN with IN age NN were VBD shown VVN to TO be VB the DT ones NNS that WDT are VBP most RBS susceptible JJ to TO oxidative JJ damage NN 7 CD . SENT Since IN different JJ regions NNS of IN the DT human JJ brain NN have VHP been VBN shown VVN to TO accumulate VV DNA NN damage NN at IN different JJ rates NNS 11 CD , , 12 CD , , it PP is VBZ reasonable JJ to TO suppose VV that IN these DT different JJ regions NNS may MD show VV different JJ gene NN expression NN changes NNS with IN age NN as IN a DT result NN . SENT Figure NN 1 CD . SENT The DT Seven CD Regions NNS of IN the DT Human NP Brain NP Analyzed VVD in IN This DT WorkThe NP seven CD regions NNS anterior JJ cingulate JJ cortex NN , , Broca's NP area NN , , caudate JJ nucleus NN , , cerebellum NN , , frontal JJ pole NN , , prefrontal JJ cortex NN , , and CC primary JJ visual JJ cortex NN are VBP indicated VVN in IN red NN . SENT Complementing VVG studies NNS of IN aging VVG differences NNS in IN various JJ tissues NNS within IN a DT single JJ species NN , , research NN into IN the DT evolution NN of IN aging VVG has VHZ begun VVN to TO shed VV light NN on IN the DT similarities NNS and CC differences NNS between IN species NNS , , although IN the DT expectation NN for IN how WRB well RB conserved VVN the DT effects NNS of IN aging VVG will MD be VB on IN a DT gene NN by IN gene NN basis NN is VBZ still RB unclear JJ . SENT One NN the DT one CD hand NN , , if IN aging NN is VBZ largely RB caused VVN by IN the DT deleterious JJ effects NNS of IN many JJ alleles NNS late JJ in IN life NN as RB is VBZ often RB the DT interpretation NN of IN two CD widely RB held VVN models NNS for IN the DT evolution NN of IN aging NN , , known VVN as IN antagonistic JJ pleiotropy NN and CC mutation NN accumulation NN 4 CD , , 5 CD , , 13 CD then RB rapid JJ evolutionary JJ change NN of IN the DT aging VVG process NN , , at IN least JJS at IN a DT mechanistic JJ level NN , , should MD be VB impossible JJ . SENT This DT reasoning NN is VBZ supported VVN by IN empirical JJ observations NNS that IN many JJ aging VVG related JJ factors NNS such JJ as IN ROS NP induced VVD damage NN and CC pathways NNS such JJ as IN insulin NN IGF NP signaling VVG appear VVP to TO be VB highly RB conserved VVN 4 CD , , 5 CD , , 13 CD . SENT However RB , , even RB if IN the DT mechanistic JJ underpinnings NN of IN aging VVG are VBP indeed RB relatively RB constant JJ , , the DT phenotypic JJ effects NNS may MD be VB subject JJ to TO dramatic JJ change NN . SENT This DT is VBZ best RBS demonstrated VVN by IN the DT observation NN that IN artificial JJ selection NN on IN model NN organisms NNS in IN the DT lab NN can MD lead VV to TO dramatic JJ changes NNS in IN lifespan NN in IN a DT very RB small JJ number NN of IN generations NNS 5 CD , , 13 CD , , implying VVG that IN the DT consequences NNS of IN aging VVG could MD be VB subject JJ to TO rapid JJ evolutionary JJ change NN in IN the DT wild JJ as RB well RB . SENT Clearly RB , , this DT issue NN cannot NN be VB resolved VVN solely RB by IN laboratory NN evolution NN experiments NNS or CC theoretical JJ work NN . SENT One CD promising JJ approach NN to TO answering VVG this DT question NN of IN evolutionary JJ conservation NN lies VVZ at IN the DT level NN of IN gene NN expression NN . SENT Do VV orthologous JJ genes NNS tend VVP to TO undergo VV the DT same JJ patterns NNS of IN expression NN changes NNS with IN age NN in IN diverse JJ species NNS , , or CC can MD a DT common JJ factor NN such JJ as IN ROS NP lead NN to TO different JJ gene NN expression NN patterns NNS in IN different JJ organisms NNS . SENT Using VVG DNA NN microarrays NNS , , this DT question NN can MD now RB be VB addressed VVN in IN a DT systematic JJ , , genome NN wide JJ manner NN . SENT One CD such JJ study NN found VVN that IN a DT small JJ but CC significant JJ portion NN of IN aging VVG related JJ gene NN expression NN changes NNS are VBP shared VVN by IN the DT very RB distantly RB related VVN nematode NN and CC fruit NN fly VVP 14 CD . SENT another DT study NN comparing VVG aging VVG patterns NNS in IN muscle NN cells NNS of IN two CD more JJR closely RB related VVN species NNS , , mouse NN and CC human JJ , , also RB found VVD a DT great JJ deal NN of IN divergence NN in IN aging VVG patterns NNS 15 CD . SENT Although IN both DT of IN these DT studies NNS are VBP informative JJ , , neither CC addresses VVZ the DT questions NNS of IN how WRB quickly RB age NN related JJ gene NN expression NN patterns NNS can MD evolve VV over IN short JJ periods NNS of IN time NN , , and CC if IN humans NNS in IN particular JJ show NN unique JJ patterns NNS of IN aging VVG not RB shared VVN by IN closely RB related VVN primates NNS . SENT The DT human JJ brain NN is VBZ of IN particular JJ interest NN for IN studying VVG the DT divergence NN in IN phenotypes NNS that WDT have VHP changed VVN rapidly RB during IN evolution NN such JJ as IN aging VVG . SENT Brain NN specific JJ genes NNS have VHP undergone VVN accelerated JJ evolution NN in IN the DT lineage NN leading VVG to TO human JJ since IN the DT split NN with IN chimpanzee NN at IN the DT levels NNS of IN both DT protein NN sequence NN and CC gene NN expression NN 16 CD , , 17 CD , , pointing VVG to TO the DT numerous JJ functional JJ differences NNS that WDT have VHP accumulated VVN between IN these DT two CD species NNS since IN their PP$ divergence NN only RB 5 CD to TO 7 CD million CD years NNS ago RB . SENT Aging VVG in IN the DT human JJ brain NN is VBZ also RB of IN interest NN because IN ROS NP induced VVD damage NN and CC age NN are VBP both DT major JJ risk NN factors NNS in IN many JJ neurodegenerative JJ diseases NNS such JJ as IN Alzheimer's NP , , Parkinson's JJ , , and CC Amyotrophic JJ Lateral JJ Sclerosis NN 18 CD . SENT In IN this DT study NN we PP addressed VVD two CD questions NNS about IN the DT relationship NN between IN gene NN expression NN and CC aging VVG . SENT First RB , , using VVG published VVN data NNS , , we PP asked VVD whether IN the DT pattern NN of IN gene NN expression NN change NN with IN age NN previously RB observed VVD in IN the DT frontal JJ pole NN 7 CD is VBZ representative JJ of IN other JJ regions NNS of IN the DT human JJ brain NN . SENT Then RB , , using VVG data NNS generated VVN for IN this DT project NN , , we PP asked VVD how WRB similar JJ the DT aging VVG associated VVN changes NNS in IN gene NN expression NN observed VVD in IN human JJ brain NN 7 CD are VBP to TO those DT observed VVN in IN our PP$ closest JJS living NN relative NN , , the DT chimpanzee NN . SENT TopIntroductionResultsDiscussionMaterials NP and CC MethodsSupporting NP InformationAcknowledgmentsReferences NP Results NNS In IN order NN to TO test VV whether IN different JJ regions NNS of IN the DT human JJ brain NN show VVP similar JJ patterns NNS of IN change NN with IN age NN , , we PP utilized VVD three CD independently RB published VVN microarray NN expression NN datasets NNS . SENT These DT were VBD . SENT Lu NP et NP al NP . SENT 7 CD , , mentioned VVN above IN , , in IN which WDT the DT frontal JJ pole NN regions NNS of IN 30 CD individuals NNS aged VVN 26 CD 106 CD y NN were VBD used VVN to TO identify VV hundreds NNS of IN genes NNS with IN clear JJ up RB or CC down RB regulation NN associated VVN with IN age NN . SENT Khaitovich NP et NP al NP . SENT 19 CD , , in IN which WDT gene NN expression NN patterns NNS of IN six CD brain NN regions NNS Figure NP 1 CD . SENT prefrontal JJ cortex NN , , primary JJ visual JJ cortex NN , , anterior JJ cingulate JJ cortex NN , , Broca's NP area NN , , caudate JJ nucleus NN , , and CC cerebellum NN were VBD studied VVN in IN three CD individuals NNS aged VVN 45 CD , , 45 CD , , and CC 70 CD y NN . SENT and CC Evans NP et NP al NP . SENT 20 CD , , in IN which WDT three CD brain NN regions NNS Figure NP 1 CD . SENT prefrontal JJ cortex NN , , anterior JJ cingulate JJ cortex NN , , and CC cerebellum NN from IN seven CD individuals NNS aged VVN 18 CD 70 CD y NN were VBD studied VVN . SENT The DT latter JJ two CD studies NNS were VBD conducted VVN to TO examine VV gene NN expression NN differences NNS between IN regions NNS of IN human JJ brain NN . SENT the DT data NNS were VBD not RB previously RB analyzed VVN with IN respect NN to TO aging VVG . SENT All DT three CD studies NNS used VVD the DT same JJ microarray NN platform NN Affymetrix NP HG NP U NP 95 CD Av NP 2 CD , , facilitating VVG comparison NN between IN them PP . SENT Aging VVG Is VBZ Heterogeneous JJ within IN the DT Human NP Brain NP To TO achieve VV the DT most RBS comprehensive JJ picture NN of IN brain NN aging VVG possible JJ with IN these DT data NNS , , we PP first RB sought VVD to TO study VV the DT patterns NNS of IN aging VVG in IN all DT six CD brain NN regions NNS from IN Khaitovich NP et CC al NP . SENT 19 CD . SENT Because IN only RB three CD samples NNS of IN two CD ages NNS were VBD available JJ for IN each DT brain NN region NN in IN this DT dataset NN , , only RB three CD general JJ aging NN patterns NNS were VBD possible JJ . SENT up IN regulation NN the DT old JJ sample NN is VBZ more RBR highly RB expressed VVN than IN either DT young JJ sample NN , , down RB regulation NN the DT old JJ sample NN is VBZ more RBR weakly RB expressed VVN , , or CC neither RB the DT old JJ sample NN is VBZ in IN between IN the DT young JJ samples NNS . SENT Because IN thousands NNS of IN genes NNS would MD be VB expected VVN to TO show VV each DT of IN these DT three CD patterns NNS even RB in IN the DT absence NN of IN any DT genuine JJ aging VVG related VVN changes NNS in IN gene NN expression NN , , we PP were VBD unable JJ to TO use VV the DT three CD samples NNS on IN their PP$ own JJ to TO accurately RB identify VV genes NNS changing VVG expression NN with IN age NN . SENT However RB , , with IN the DT available JJ data NNS we PP could MD ask VV whether IN the DT genes NNS whose WP$ expression NN changes NNS with IN age NN in IN frontal JJ pole NN 7 CD showed VVD the DT same JJ direction NN of IN change NN in IN each DT of IN six CD other JJ brain NN regions NNS 19 CD . SENT In IN order NN to TO do VV this DT , , we PP reanalyzed VVD the DT data NN of IN Lu NP et CC al NP . SENT 7 CD , , and CC identified VVD 841 CD genes NNS that WDT showed VVD a DT significant JJ p NN 0 CD . SENT 01 CD Spearman NP rank NN correlation NN between IN age NN and CC expression NN level NN in IN frontal JJ pole NN , , irrespective RB of IN their PP$ fold NN change NN in IN expression NN . SENT most JJS of IN these DT were VBD expected VVN to TO be VB true JJ positives NNS , , because IN only RB approximately RB 126 CD genes NNS would MD be VB expected VVN to TO pass VV this DT significance NN threshold NN by IN chance NN corresponding JJ to TO an DT estimated JJ false JJ discovery NN rate NN 21 CD of IN 126 CD 841 CD 15 CD . SENT 0 CD . SENT We PP classified VVD these DT 841 CD genes NNS as IN having VHG either DT increasing VVG or CC decreasing VVG expression NN with IN age NN in IN frontal JJ pole NN , , and CC then RB as IN either RB increasing VVG , , decreasing VVG , , or CC constant JJ in IN each DT of IN the DT six CD other JJ brain NN regions NNS . SENT After IN discarding VVG genes NNS with IN no DT direction NN of IN change NN within IN each DT of IN the DT six CD brain NN regions NNS , , because IN these DT lack NN any DT information NN about IN aging VVG changes NNS , , we PP tested VVD how WRB well RB the DT frontal JJ pole NN data NNS agree VVP with IN the DT data NNS from IN each DT of IN the DT six CD other JJ regions NNS . SENT For IN example NN , , comparing VVG prefrontal JJ cortex NN to TO frontal JJ pole NN , , we PP asked VVD how WRB many JJ genes NNS belong VVP to TO each DT of IN four CD categories NNS . SENT 1 LS up RB regulated VVN in IN frontal JJ pole NN and CC down RB regulated VVN in IN prefrontal JJ cortex NN . SENT 2 LS down RB regulated VVN in IN frontal JJ pole NN and CC up RB regulated VVN in IN prefrontal JJ cortex NN . SENT 3 LS up RB regulated VVN in IN both DT regions NNS . SENT and CC 4 CD down RB regulated VVN in IN both DT regions NNS . SENT If IN the DT datasets NNS showed VVD similar JJ aging VVG patterns NNS , , we PP would MD expect VV an DT excess NN of IN genes NNS in IN the DT latter JJ two CD categories NNS , , whereas IN no DT such JJ excess NN would MD be VB expected VVN in IN the DT absence NN of IN a DT shared VVN pattern NN . SENT There EX are VBP a DT number NN of IN statistical JJ tests NNS that WDT can MD be VB used VVN to TO quantify VV these DT patterns NNS . SENT we PP chose VVD to TO use VV the DT nonparametric JJ Spearman NP rank NN correlation NN coefficient NN abbreviated VVN as IN r NN . SENT Values NNS of IN r NN close JJ to TO one PP indicate VVP good JJ agreement NN between IN aging VVG patterns NNS , , whereas IN those DT close NN to TO zero VV indicate VV a DT lack NN of IN agreement NN . SENT To TO assess VV the DT significance NN of IN these DT correlations NNS , , we PP randomly RB permuted VVD the DT ages NNS of IN the DT samples NNS , , and CC calculated VVN the DT probability NN of IN observing VVG a DT random JJ correlation NN as IN strong JJ as IN that WDT found VVD in IN the DT real JJ data NNS see VVP Materials NNS and CC Methods NNS . SENT Strikingly RB , , all DT four CD regions NNS of IN cerebral JJ cortex NN for IN which WDT we PP had VHD expression NN data NNS prefrontal JJ cortex NN , , Broca's NP area NN , , primary JJ visual JJ cortex NN , , and CC anterior JJ cingulate JJ cortex NN showed VVD excellent JJ agreement NN with IN the DT aging VVG pattern NN in IN frontal JJ pole NN Figure NP 2 CD A NP . SENT r SYM 0 CD . SENT 8 CD and CC p NN 0 CD . SENT 02 CD for IN each DT . SENT We PP note VVP that IN the DT true JJ similarity NN of IN aging VVG patterns NNS in IN these DT regions NNS is VBZ likely JJ to TO be VB even RB stronger JJR than IN is VBZ indicated VVN by IN the DT correlations NNS because IN , , as IN mentioned VVN above IN , , approximately RB 15 CD of IN our PP$ genes NNS are VBP expected VVN to TO be VB false JJ positives NNS with IN no DT true JJ aging VVG related JJ changes NNS . SENT In IN sharp JJ contrast NN to TO cortex NN , , the DT cerebellum NN and CC caudate JJ nucleus NN showed VVD far RB less JJR agreement NN with IN frontal JJ pole NN Figure NP 2 CD A NP . SENT r SYM 0 CD . SENT 1 CD and CC p NN 0 CD . SENT 4 CD for IN each DT . SENT These DT results NNS have VHP several JJ implications NNS . SENT First RB , , the DT agreement NN between IN frontal JJ pole NN and CC four CD regions NNS of IN cortex NN indicates VVZ that IN we PP were VBD able JJ to TO accurately RB measure VV the DT direction NN of IN gene NN expression NN changes NNS with IN age NN for IN most JJS genes NNS , , even RB with IN only RB three CD samples NNS from IN each DT region NN . SENT thus RB the DT age NN range NN , , number NN of IN samples NNS , , etc FW . SENT , , are VBP all RB sufficient JJ to TO reflect VV the DT pattern NN of IN gene NN expression NN changes NNS previously RB reported VVD in IN frontal JJ pole NN 7 CD . SENT Second JJ , , we PP can MD have VH even RB greater JJR confidence NN in IN the DT results NNS from IN frontal JJ pole NN 7 CD , , because IN they PP have VHP been VBN independently RB reproduced VVD albeit IN in IN different JJ brain NN regions NNS . SENT Third JJ , , and CC most RBS importantly RB , , the DT human JJ brain NN appears VVZ to TO have VH different JJ aging VVG patterns NNS in IN cerebellum NN and CC caudate JJ nucleus NN than IN in IN cortex NN . SENT The DT fact NN that IN our PP$ four CD cortex NN samples NNS all RB show VVP strong JJ correlations NNS with IN frontal JJ pole NN is VBZ akin JJ to TO having VHG a DT positive JJ control NN , , and CC it PP allows VVZ us PP to TO interpret VV the DT lack NN of IN correlation NN in IN cerebellum NN and CC caudate JJ nucleus NN as IN evidence NN suggesting VVG a DT difference NN in IN aging VVG patterns NNS , , as RB opposed VVN to TO several JJ more JJR trivial JJ explanations NNS e NN . SENT g NN . SENT , , too RB few JJ samples NNS . SENT Figure NN 2 CD . SENT Aging VVG in IN the DT Human NP BrainThe NP abbreviations NNS used VVN are VBP as RB follows VVZ . SENT ACC NP , , anterior JJ cingulate JJ cortex NN . SENT BA NP , , Broca's NP area NN . SENT C NP , , cerebellum NN . SENT CN NP , , caudate JJ nucleus NN . SENT PFC NP , , prefrontal JJ cortex NN . SENT PVC NP , , primary JJ visual JJ cortex NN . SENT A DT Correlations NNS of IN aging VVG gene NN expression NN patterns NNS between IN human JJ frontal JJ pole NN 7 CD and CC each DT of IN the DT six CD regions NNS of IN the DT human JJ brain NN from IN 19 CD from IN left VVN to TO right NN , , number NN of IN genes NNS used VVN are VBP 656 CD , , 733 CD , , 684 CD , , 710 CD , , 690 CD , , and CC 603 CD . SENT The DT strong JJ correlation NN for IN all DT four CD cerebral JJ cortex NN samples NNS indicates VVZ a DT reproducible JJ aging VVG pattern NN across IN all DT tested VVN regions NNS of IN cortex NN . SENT this DT pattern NN does VVZ not RB hold VV for IN caudate JJ nucleus NN or CC cerebellum NN . SENT B SYM Correlations NNS of IN aging VVG gene NN expression NN patterns NNS between IN human JJ prefrontal JJ cortex NN 20 CD and CC each DT of IN the DT six CD regions NNS of IN the DT human JJ brain NN from IN 19 CD from IN left VVN to TO right NN , , number NN of IN genes NNS used VVN are VBP 704 CD , , 832 CD , , 697 CD , , 784 CD , , 759 CD , , and CC 674 CD . SENT The DT strong JJ correlations NNS for IN all DT four CD cortex NN samples NNS indicates VVZ a DT reproducible JJ aging VVG pattern NN across IN all DT tested VVN regions NNS of IN cortex NN but CC not RB caudate JJ nucleus NN or CC cerebellum NN , , confirming VVG the DT result NN of IN A DT . SENT C SYM Correlations NNS of IN aging VVG gene NN expression NN patterns NNS between IN cerebellum NN 20 CD and CC each DT of IN the DT six CD regions NNS of IN the DT brain NN from IN 19 CD from IN left VVN to TO right NN , , number NN of IN genes NNS used VVN are VBP 213 CD , , 241 CD , , 204 CD , , 241 CD , , 244 CD , , and CC 204 CD . SENT The DT lack NN of IN any DT significant JJ correlation NN , , even RB when WRB comparing VVG the DT two CD cerebellum NN aging VVG patterns NNS to TO each DT other JJ , , suggests VVZ that DT human JJ cerebellum NN lacks VVZ a DT reproducible JJ aging NN pattern NN . SENT In IN order NN to TO further RBR test VV the DT similarity NN of IN aging VVG patterns NNS within IN the DT brain NN , , we PP compared VVD a DT third JJ independent JJ dataset NN to TO the DT data NN from IN Lu NP et CC al NP . SENT 7 CD and CC Khaitovich NP et NP al NP . SENT 19 CD . SENT As IN described VVN above IN , , Evans NP et CC al NP . SENT 20 CD sampled VVN three CD brain NN regions NNS from IN each DT of IN seven CD individuals NNS . SENT We PP first RB tested VVD whether IN the DT aging VVG patterns NNS in IN the DT two CD cortex NN regions NNS from IN Evans NP et CC al NP . SENT 20 CD correlated VVD more RBR highly RB with IN the DT frontal JJ pole NN aging VVG changes NNS 7 CD than IN did VVD the DT cerebellum NN samples NNS , , as RB would MD be VB expected VVN from IN Figure NP 2 CD A NP . SENT Classifying VVG the DT same JJ 841 CD genes NNS showing VVG significant JJ change NN with IN age NN in IN the DT frontal JJ pole NN as IN either DT up RB regulated VVN or CC down RB regulated VVN with IN age NN in IN each DT brain NN region NN of IN this DT new JJ dataset NN , , we PP found VVD the DT same JJ general JJ pattern NN of IN correlations NNS as IN with IN the DT data NN from IN Khaitovich NP et CC al NP . SENT 19 CD . SENT Cerebellum NN showed VVD a DT weaker JJR correlation NN with IN frontal JJ pole NN than IN did VVD either DT cortex NN sample NN prefrontal JJ cortex NN , , r NN 0 CD . SENT 70 CD . SENT anterior JJ cingulate JJ cortex NN , , r NN 0 CD . SENT 61 CD . SENT cerebellum NN , , r NN 0 CD . SENT 38 CD . SENT Although IN the DT cerebellum NN correlation NN is VBZ stronger JJR here RB than IN in IN Figure NP 2 CD A DT , , it PP is VBZ still RB not RB significantly RB different JJ from IN zero CD p NN 0 CD . SENT 17 CD , , even RB though IN the DT two CD cortex NN samples NNS are VBP both DT significant JJ p NN 0 CD . SENT 01 CD each DT . SENT This DT finding NN supports VVZ our PP$ conclusion NN that IN cerebellum NN ages NNS differently RB than IN cortex NN . SENT For IN a DT third JJ test NN of IN aging VVG patterns NNS throughout IN the DT human JJ brain NN , , we PP determined VVD the DT correlation NN of IN aging VVG patterns NNS between IN a DT single JJ cortex NN region NN from IN Evans NP et CC al NP . SENT 20 CD with IN all DT six CD of IN the DT brain NN regions NNS from IN Khaitovich NP et CC al NP . SENT 19 CD . SENT We PP used VVD the DT prefrontal JJ cortex NN samples NNS from IN Evans NP et CC al NP . SENT 20 CD because RB , , as IN mentioned VVN above IN , , this DT brain NN area NN shows VVZ a DT better JJR agreement NN of IN aging VVG patterns NNS with IN frontal JJ pole NN than IN does VVZ anterior JJ cingulate JJ cortex NN . SENT To TO facilitate VV comparison NN with IN cerebellum NN see VVP below RB , , we PP extended VVD this DT analysis NN to TO all DT 12 CD , , 558 CD probe NN sets NNS present JJ on IN the DT microarray NN . SENT however RB in IN order NN to TO increase VV the DT signal NN noise NN ratio NN , , we PP then RB excluded VVD genes NNS with IN no DT apparent JJ aging NN changes NNS age NN vs NP . SENT expression NN r SYM 0 CD . SENT 5 CD in IN either DT dataset NN . SENT This DT comparison NN showed VVD the DT expected VVN reproducibility NN of IN aging VVG patterns NNS across IN all DT four CD regions NNS of IN the DT cortex NN . SENT r NN 0 CD . SENT 76 CD for IN all DT four CD Figure NN 2 CD B NN . SENT p NN 0 CD . SENT 03 CD for IN each DT except IN for IN prefrontal JJ cortex NN , , for IN which WDT p NN 0 CD . SENT 067 CD . SENT In IN contrast NN , , neither DT cerebellum NN nor CC caudate JJ nucleus NN showed VVD a DT significant JJ correlation NN Figure NP 2 CD B NP . SENT r SYM 0 CD . SENT 04 CD and CC p NN 0 CD . SENT 4 CD for IN each DT , , as RB expected VVN from IN their PP$ lack NN of IN correlation NN with IN the DT frontal JJ pole NN data NNS shown VVN in IN Figure NP 2 CD A NP . SENT In IN addition NN to TO providing VVG further JJR support NN for IN our PP$ finding NN of IN an DT aging VVG pattern NN common JJ to TO all DT tested VVN regions NNS of IN cortex NN , , this DT result NN demonstrated VVN that IN even RB when WRB comparing VVG aging VVG patterns NNS from IN the DT two CD smaller JJR microarray NN studies NNS used VVD here RB 19 CD , , 20 CD , , the DT age NN range NN , , number NN of IN samples NNS , , etc FW . SENT , , were VBD sufficient JJ to TO reveal VV a DT correlation NN when WRB one PP exists VVZ . SENT The DT lack NN of IN correlation NN between IN the DT aging VVG pattern NN in IN cerebral JJ cortex NN with IN those DT in IN cerebellum NN and CC caudate JJ nucleus NN might MD arise VV if IN the DT quality NN of IN data NNS in IN the DT cerebellum NN and CC caudate JJ nucleus NN samples NNS was VBD lower JJR than IN that DT of IN the DT cortex NN samples NNS from IN both DT Khaitovich NP et NP al NP . SENT 19 CD and CC Evans NP et NP al NP . SENT 20 CD , , because IN lower JJR quality NN of IN data NNS would MD lead VV to TO weaker JJR correlations NNS . SENT To TO address VV this DT possibility NN , , we PP first RB compared VVD the DT expression NN levels NNS of IN the DT 841 CD genes NNS used VVN in IN Figure NP 2 CD A DT in IN the DT two CD 45 CD y NN olds NNS from IN Khaitovich NP et CC al NP . SENT 19 CD , , because IN their PP$ equal JJ age NN controls NNS for IN the DT fact NN that IN we PP expect VVP these DT genes NNS not RB to TO have VH a DT very RB high JJ correlation NN between IN sample NN of IN different JJ ages NNS such JJ as IN between IN the DT 45 CD and CC 70 CD y NN olds NNS . SENT All DT six CD brain NN regions NNS had VHD highly RB reproducible JJ expression NN levels NNS . SENT the DT lowest JJS correlation NN among IN all DT six CD was VBD for IN anterior JJ cingulate JJ cortex NN , , with IN r NN 0 CD . SENT 952 CD . SENT The DT cerebellum NN data NNS from IN Evans NP et CC al NP . SENT 20 CD was VBD of IN similarly RB high JJ quality NN . SENT Among IN five CD replicates VVZ of IN the DT same JJ cerebellum NN samples NNS analyzed VVD in IN two CD different JJ laboratories NNS , , the DT lowest JJS correlation NN of IN expression NN levels NNS among IN all DT genes NNS was VBD r NN 0 CD . SENT 964 CD . SENT Thus RB differing VVG data NN quality NN could MD not RB explain VV the DT lack NN of IN correlation NN in IN cerebellum NN and CC caudate JJ nucleus NN . SENT Human JJ Cerebellum NN Ages NPS Less JJR than IN Cortex NN There EX are VBP two CD possible JJ explanations NNS for IN the DT difference NN in IN the DT aging VVG patterns NNS between IN cerebellum NN caudate JJ nucleus NN and CC cerebral JJ cortex NN . SENT One PP is VBZ that DT cerebellum NN and CC caudate JJ nucleus NN have VHP their PP$ own JJ aging VVG patterns NNS distinct JJ from IN that DT in IN cortex NN . SENT The DT other JJ possibility NN is VBZ that IN cerebellum NN and CC caudate JJ nucleus NN are VBP different JJ from IN cortex NN because IN they PP each DT have VHP far RB fewer JJR genes NNS changing VVG expression NN with IN age NN than IN cortex NN does VVZ , , and CC they PP thus RB lack VVP a DT reproducible JJ pattern NN of IN aging VVG associated VVN gene NN expression NN changes NNS altogether RB . SENT To TO distinguish VV between IN these DT possibilities NNS , , one PP could MD attempt VV to TO calculate VV exactly RB how WRB many JJ genes NNS change VVP expression NN with IN age NN in IN each DT region NN . SENT if IN cerebellum NN and CC or CC caudate JJ nucleus NN have VHP aging VVG related JJ changes NNS in IN as RB many JJ but CC a DT different JJ set NN of IN genes NNS than IN cortex NN , , then RB the DT number NN of IN genes NNS identified VVN as IN changing VVG in IN cerebellum NN and CC or CC caudate JJ nucleus NN should MD be VB comparable JJ to TO any DT region NN of IN cortex NN . SENT Unfortunately RB , , as RB mentioned VVN above RB , , there EX is VBZ not RB enough RB statistical JJ power NN to TO pursue VV this DT approach NN , , given VVN only RB three CD samples NNS per IN region NN or CC seven CD , , as RB in IN Evans NP et CC al NP . SENT 20 CD . SENT Another DT way NN to TO differentiate VV between IN the DT two CD possibilities NNS listed VVN above RB would MD be VB to TO compare VV two CD datasets NNS of IN cerebellum NN and CC or CC caudate JJ nucleus NN aging VVG patterns NNS to TO one CD another DT . SENT If IN these DT regions NNS have VHP a DT reproducible JJ pattern NN of IN many JJ genes NNS changing VVG expression NN with IN age NN as IN in IN the DT cortex NN samples NNS of IN Figure NP 2 CD A NP and CC 2 CD B NN , , we PP should MD find VV a DT significant JJ correlation NN . SENT A DT comparison NN between IN the DT data NN from IN Evans NP et CC al NP . SENT 20 CD and CC Khaitovich NP et NP al NP . SENT 19 CD is VBZ suitable JJ for IN this DT purpose NN because IN both DT datasets NNS contain VVP cerebellum NN samples NNS and CC we PP already RB have VHP a DT positive JJ control NN that WDT demonstrated VVD our PP$ ability NN to TO find VV a DT correlation NN between IN aging VVG patterns NNS in IN these DT datasets NNS when WRB one PP exists VVZ Figure NP 2 CD B NN . SENT We PP thus RB expected VVD to TO see VV a DT strong JJ positive JJ correlation NN between IN cerebellum NN aging VVG patterns NNS in IN our PP$ two CD datasets NNS if IN and CC only RB if IN a DT large JJ number NN of IN genes NNS change VVP expression NN with IN age NN in IN cerebellum NN . SENT Because IN this DT analysis NN was VBD carried VVN out RP on IN all DT informative JJ genes NNS age NN vs NP . SENT expression NN r SYM 0 CD . SENT 5 CD , , as RB in IN Figure NP 2 CD B NN , , instead RB of IN just RB the DT 841 CD with IN expression NN changes NNS in IN the DT frontal JJ pole NN , , any DT reproducible JJ changes NNS in IN cerebellum NN should MD be VB found VVN . SENT Comparison NN of IN cerebellum NN aging VVG from IN Evans NP et CC al NP . SENT 20 CD with IN all DT six CD regions NNS from IN Khaitovich NP et CC al NP . SENT 19 CD gave VVD an DT unambiguous JJ result NN . SENT Not RB a DT single JJ region NN had VHD a DT significant JJ correlation NN Figure NP 2 CD C NP . SENT r SYM 0 CD . SENT 2 CD and CC p NN 0 CD . SENT 4 CD for IN each DT , , including VVG the DT cerebellum NN cerebellum NN comparison NN . SENT From IN these DT results NNS , , we PP conclude VVP that DT cerebellum NN has VHZ a DT different JJ pattern NN of IN aging VVG than IN cortex NN because IN significantly RB fewer JJR genes NNS appear VVP to TO change VV expression NN with IN age NN in IN cerebellum NN . SENT In IN order NN to TO further RBR characterize VV the DT differences NNS in IN aging VVG patterns NNS between IN cortex NN and CC cerebellum NN , , we PP calculated VVD the DT average JJ expression NN levels NNS in IN one CD representative NN region NN of IN cortex NN prefrontal JJ cortex NN for IN the DT 841 CD genes NNS changing VVG strongly RB with IN age NN in IN frontal JJ pole NN , , in IN both DT young JJ 45 CD y NN old JJ and CC old JJ 70 CD y NN old JJ samples NNS from IN Khaitovich NP et CC al NP . SENT 19 CD . SENT As IN expected VVN , , when WRB separated VVN into IN two CD groups NNS by IN their PP$ direction NN of IN change NN with IN age NN , , clear JJ differences NNS were VBD seen VVN between IN the DT young JJ and CC old JJ samples NNS Figure NP 3 CD . SENT When WRB the DT same JJ genes NNS were VBD subjected VVN to TO this DT analysis NN using VVG their PP$ cerebellum NN expression NN levels NNS , , an DT interesting JJ trend NN emerged VVD . SENT Although IN the DT genes NNS that WDT are VBP up RB regulated VVN in IN cortex NN are VBP also RB slightly RB up RB regulated VVN in IN cerebellum NN , , those DT that WDT are VBP down RB regulated VVN in IN cortex NN show VVP almost RB no DT change NN at IN all DT in IN cerebellum NN Figure NP 3 CD . SENT Thus RB , , the DT difference NN in IN aging VVG patterns NNS between IN these DT two CD brain NN regions NNS arises VVZ mainly RB from IN genes NNS down RB regulated VVN in IN the DT cortex NN . SENT The DT reason NN for IN this DT may MD be VB related VVN to TO metabolic JJ differences NNS between IN cerebral JJ cortex NN and CC cerebellum NN see VVP Discussion NN . SENT Figure NN 3 CD . SENT Expression NN Levels NP in IN Human NP Cortex NN and CC CerebellumAverage NN expression NN levels NNS base JJ two CD logarithm NN expression NN intensity NN . SENT error NN bars NNS indicate VVP plus IN or CC minus IN one CD standard JJ error NN in IN prefrontal JJ cortex NN were VBD calculated VVN for IN four CD sets NNS of IN genes NNS in IN both DT young JJ two CD 45 CD y NN old JJ and CC old JJ one CD 70 CD y NN old JJ human JJ samples NNS . SENT Red NP indicates VVZ cortex NN expression NN levels NNS . SENT blue JJ , , cerebellum NN expression NN levels NNS . SENT solid JJ lines NNS , , genes NNS down RB regulated VVN in IN frontal JJ pole NN . SENT and CC dashed VVN lines NNS , , genes NNS up RB regulated VVN in IN frontal JJ pole NN connecting VVG lines NNS are VBP not RB meant VVN to TO imply VV linear JJ changes NNS in IN gene NN expression NN with IN age NN . SENT The DT genes NNS up RB regulated VVN with IN age NN in IN cortex NN are VBP somewhat RB up RB regulated VVN in IN cerebellum NN , , whereas IN those DT down RB regulated VVN in IN cortex NN do VVP not RB change VV at IN all DT with IN age NN in IN cerebellum NN . SENT Chimpanzee NN Cortex NN Ages NPS Differently RB than IN Human JJ Cortex NN In IN order NN to TO study VV the DT relationship NN between IN brain NN aging VVG patterns NNS in IN humans NNS and CC chimpanzees NNS , , we PP required VVD gene NN expression NN data NNS from IN the DT chimpanzee NN brain NN . SENT Although IN four CD studies NNS have VHP already RB produced VVN such JJ data NNS , , three CD of IN these DT 16 CD , , 22 CD , , 23 CD examined VVD only RB a DT single JJ brain NN area NN , , and CC the DT fourth JJ 19 NP had VHD an DT insufficient JJ number NN of IN samples NNS of IN appropriate JJ age NN for IN our PP$ purposes NNS . SENT Therefore RB , , we PP generated VVD new JJ data NNS by IN measuring VVG gene NN expression NN levels NNS in IN three CD regions NNS of IN the DT chimpanzee NN brain NN . SENT prefrontal JJ cortex NN , , anterior JJ cingulate JJ cortex NN , , and CC cerebellum NN see VVP Materials NNS and CC Methods NNS . SENT We PP had VHD samples NNS of IN all DT five CD regions NNS from IN five CD individuals NNS aged VVN 7 CD to TO approximately RB 45 CD y NN . SENT see VV Materials NNS and CC Methods NNS , , as RB well RB as IN one CD additional JJ cerebellum NN sample NN and CC two CD additional JJ prefrontal JJ cortex NN samples NNS although IN excluding VVG the DT three CD extra JJ samples NNS made VVD little JJ difference NN in IN the DT analysis NN . SENT see VV Materials NNS and CC Methods NNS . SENT Because IN of IN the DT very RB high JJ sequence NN similarity NN between IN humans NNS and CC chimpanzees NNS 24 CD , , we PP were VBD able JJ to TO use VV microarrays NNS designed VVN for IN human JJ sequences NNS . SENT Because IN we PP are VBP only RB comparing VVG chimpanzee NN samples NNS directly RB with IN one NN another DT comparisons NNS with IN human JJ are VBP using VVG only RB aging VVG patterns NNS , , not RB actual JJ expression NN levels NNS , , masking VVG of IN microarray NN probes NNS containing VVG DNA NP sequence NN differences NNS between IN human JJ and CC chimpanzee NN was VBD not RB necessary JJ and CC did VVD not RB affect VV the DT analysis NN when WRB tested VVN . SENT We PP compared VVD the DT aging VVG patterns NNS of IN different JJ regions NNS within IN chimpanzee NN brains NNS by IN applying VVG the DT same JJ methods NNS as IN for IN comparison NN between IN aging VVG patterns NNS of IN different JJ regions NNS within IN the DT human JJ brain NN . SENT As RB in IN Figure NP 2 CD B NP and CC 2 CD C NP , , we PP used VVD all DT informative JJ genes NNS age NN vs NP . SENT expression NN r SYM 0 CD . SENT 5 CD present NN on IN the DT microarray NN . SENT Although IN we PP found VVD no DT significant JJ correlation NN when WRB comparing VVG cerebellum NN to TO either DT cortex NN region NN Figure NP 4 CD A NP . SENT r SYM 0 CD . SENT 07 CD and CC p NN 0 CD . SENT 3 CD for IN both DT comparisons NNS , , we PP found VVD a DT very RB strong JJ agreement NN when WRB comparing VVG aging VVG patterns NNS of IN prefrontal JJ cortex NN to TO anterior JJ cingulate JJ cortex NN Figure NP 4 CD A NP . SENT r SYM 0 CD . SENT 894 CD , , p NN 0 CD . SENT 005 CD . SENT This DT result NN is VBZ precisely RB analogous JJ to TO our PP$ findings NNS in IN human JJ , , where WRB the DT entire JJ cerebral JJ cortex NN shares NNS a DT single JJ pattern NN of IN gene NN expression NN changes NNS with IN age NN that WDT is VBZ not RB found VVN in IN the DT cerebellum NN see VVP Figure NP 2 CD A NP and CC 2 CD B NN . SENT Importantly RB , , this DT also RB demonstrates VVZ that IN our PP$ chimpanzee NN samples NNS are VBP of IN sufficient JJ number NN , , quality NN , , and CC age NN range NN to TO detect VV a DT correlation NN of IN aging VVG patterns NNS when WRB one PP exists VVZ . SENT Figure NN 4 CD . SENT Aging VVG in IN the DT Chimpanzee NN BrainThe NN abbreviations NNS used VVN are VBP as RB follows VVZ . SENT ACC NP , , anterior JJ cingulate JJ cortex NN . SENT C NP , , cerebellum NN . SENT PFC NP , , prefrontal JJ cortex NN . SENT A DT Correlations NNS of IN aging VVG gene NN expression NN patterns NNS between IN all DT three CD possible JJ pairs NNS of IN the DT three CD regions NNS of IN the DT chimpanzee NN brain NN used VVN in IN this DT work NN from IN left VVN to TO right NN , , number NN of IN genes NNS used VVN are VBP 1 CD , , 343 CD , , 2 CD , , 235 CD , , and CC 1 CD , , 328 CD . SENT The DT strong JJ correlation NN when WRB comparing VVG cortex NN regions NNS indicates VVZ a DT reproducible JJ pattern NN of IN aging VVG in IN chimpanzee NN cortex NN . SENT B SYM Correlations NNS of IN aging VVG gene NN expression NN patterns NNS between IN human JJ frontal JJ pole NN 7 CD and CC each DT of IN the DT three CD regions NNS of IN the DT chimpanzee NN brain NN used VVN in IN this DT work NN 841 CD genes NNS used VVN in IN each DT comparison NN . SENT The DT lack NN of IN any DT significant JJ correlation NN suggests VVZ that IN human JJ and CC chimpanzee NN brain NN aging VVG patterns NNS differ VVP . SENT We PP then RB tested VVD whether IN brain NN aging VVG in IN chimpanzee NN is VBZ similar JJ to TO that DT of IN human JJ . SENT Using VVG the DT 841 CD genes NNS that IN change NN expression NN with IN age NN in IN human JJ frontal JJ pole NN 7 CD , , we PP tested VVD the DT agreement NN between IN the DT aging VVG related JJ changes NNS in IN frontal JJ pole NN and CC the DT changes NNS in IN each DT of IN our PP$ three CD chimpanzee NN brain NN regions NNS . SENT As RB can MD be VB seen VVN in IN Figure NP 4 CD B NP , , none NN of IN the DT three CD regions NNS showed VVD any DT significant JJ correlations NNS with IN human JJ frontal JJ pole NN r SYM 0 CD . SENT 13 CD , , p NN 0 CD . SENT 4 CD for IN all DT three CD . SENT Similar JJ results NNS were VBD found VVN when WRB comparing VVG chimpanzee NN aging VVG changes NNS in IN any DT brain NN region NN to TO the DT patterns NNS from IN either DT of IN our PP$ other JJ two CD human JJ expression NN datasets NNS 19 CD , , 20 CD for IN either RB the DT 841 CD genes NNS or CC all DT aging VVG informative JJ genes NNS on IN the DT microarray NN not RB shown VVN . SENT Therefore RB , , we PP conclude VVP that DT chimpanzee NN cortex NN has VHZ a DT reproducible JJ pattern NN of IN aging VVG associated VVN gene NN expression NN changes NNS , , but CC this DT pattern NN is VBZ completely RB different JJ from IN that DT of IN human JJ cortex NN . SENT Alternative JJ explanations NNS such JJ as IN lower JJR chimpanzee NN data NNS accuracy NN , , insufficient JJ chimpanzee NN age NN range NN , , and CC very RB few JJ age NN related VVN changes NNS in IN chimpanzee NN cortex NN as IN in IN human JJ cerebellum NN can MD all RB be VB eliminated VVN because IN they PP would MD all RB preclude VV the DT strong JJ correlation NN between IN aging VVG patterns NNS of IN the DT two CD chimpanzee NN cortex NN regions NNS shown VVN in IN Figure NP 4 CD A DT other JJ possible JJ artifactual JJ explanations NNS for IN the DT difference NN are VBP discussed VVN in IN Materials NNS and CC Methods NNS . SENT Given VVN this DT difference NN in IN aging VVG patterns NNS between IN humans NNS and CC chimpanzees NNS , , we PP examined VVD the DT expression NN levels NNS of IN the DT chimpanzee NN orthologs NNS of IN the DT 841 CD human JJ genes NNS that WDT change VVP expression NN with IN age NN in IN frontal JJ pole NN in IN order NN to TO see VV if IN the DT expression NN levels NNS of IN the DT chimpanzee NN orthologs NNS of IN these DT genes NNS resemble VVP young JJ humans NNS , , old JJ humans NNS , , or CC neither RB . SENT To TO test VV this DT , , we PP first RB reanalyzed VVD the DT expression NN data NNS by IN masking VVG all DT microarray NN probes NNS with IN sequence NN differences NNS between IN humans NNS and CC chimpanzees NNS 19 CD . SENT We PP then RB calculated VVN , , for IN both DT human JJ and CC chimpanzee NN prefrontal JJ cortex NN , , the DT average JJ expression NN level NN for IN the DT set NN of IN genes NNS that IN increase NN expression NN with IN age NN in IN frontal JJ pole NN , , as RB well RB as IN the DT average NN for IN the DT genes NNS that WDT decrease VVP expression NN with IN age NN . SENT The DT result NN is VBZ that IN in IN chimpanzee NN cortex NN , , the DT orthologs NNS of IN both DT sets NNS of IN human JJ genes NNS up RB regulated VVN and CC down RB regulated VVN are VBP expressed VVN at IN the DT levels NNS of IN their PP$ young JJ human JJ counterparts NNS Figure NP 5 CD . SENT In IN other JJ words NNS , , chimpanzee NN cortex NN expression NN levels NNS strongly RB resemble VVP expression NN levels NNS in IN young JJ but CC not RB old JJ humans NNS , , at IN least JJS among IN the DT set NN of IN genes NNS tested VVN here RB . SENT Humans NNS then RB diverge VV from IN these DT average JJ expression NN levels NNS as IN they PP age VVP , , whereas IN chimpanzee NN gene NN expression NN levels NNS change VVP in IN an DT almost RB entirely RB different JJ set NN of IN genes NNS . SENT Figure NN 5 CD . SENT Expression NN Levels NP in IN Human NP and CC Chimpanzee NN CortexAverage NN expression NN levels NNS base JJ two CD logarithm NN expression NN intensity NN . SENT error NN bars NNS indicate VVP plus IN or CC minus IN one CD standard JJ error NN in IN prefrontal JJ cortex NN were VBD calculated VVN for IN four CD sets NNS of IN genes NNS in IN both DT young JJ two CD 45 CD y NN old JJ human NN , , or CC five CD 7 CD to TO 12 CD y NN old JJ chimpanzee NN and CC old JJ one CD 70 CD y NN old JJ human NN , , or CC two CD older JJR than IN 40 CD y NN old JJ chimpanzee NN samples NNS . SENT Red NP indicates VVZ human JJ genes NNS . SENT blue JJ , , chimpanzee NN genes NNS . SENT solid JJ lines NNS , , genes NNS or CC orthologs NNS of IN genes NNS down RB regulated VVN in IN human JJ frontal JJ pole NN . SENT and CC dashed VVN lines NNS , , genes NNS or CC orthologs NNS up RB regulated VVN in IN human JJ frontal JJ pole NN connecting VVG lines NNS are VBP not RB meant VVN to TO imply VV linear JJ changes NNS in IN gene NN expression NN with IN age NN . SENT The DT chimpanzee NN expression NN levels NNS resemble VVP young JJ , , but CC not RB old JJ , , human JJ . SENT The DT high JJ correlation NN of IN gene NN expression NN aging VVG patterns NNS between IN the DT two CD regions NNS of IN chimpanzee NN cortex NN implied VVN that IN the DT genes NNS for IN which WDT both DT regions NNS show VVP the DT same JJ direction NN of IN change NN that WDT passed VVD our PP$ cutoff NN of IN age NN vs NP . SENT expression NN r SYM 0 CD . SENT 5 LS are VBP nearly RB all RB genuinely RB up RB or CC down RB regulated VVN with IN age NN . SENT Using VVG this DT list NN of IN genes NNS with IN a DT consistent JJ aging VVG pattern NN in IN the DT two CD cortex NN regions NNS , , there EX were VBD 1 CD , , 252 CD down RB regulated VVN and CC 700 CD up RB regulated VVN genes NNS . SENT Note NN that IN although IN the DT false JJ positive JJ rate NN is VBZ likely JJ to TO be VB low JJ , , we PP have VHP no DT way NN to TO estimate VV the DT false JJ negative JJ rate NN , , so RB these DT numbers NNS should MD not RB be VB interpreted VVN as IN the DT total JJ number NN of IN genes NNS changing VVG expression NN with IN age NN in IN chimpanzee NN cortex NN . SENT Using VVG this DT list NN of IN aging VVG associated VVN genes NNS , , we PP tested VVD for IN any DT significant JJ enrichments NNS of IN these DT genes NNS in IN Gene NP Ontology NN annotation NN categories NNS 19 CD . SENT We PP did VVD not RB find VV any DT enrichments NNS for IN the DT set NN of IN genes NNS down RB regulated VVN with IN age NN , , although IN we PP found VVD a DT number NN of IN significant JJ enrichments NNS for IN those DT up RB regulated VVN with IN age NN , , including VVG mitochondrial JJ localization NN , , protein NN degradation NN functions NNS , , and CC several JJ metabolic JJ processes NNS see VVP Table NN S NP 1 CD . SENT Interestingly RB , , and CC consistent JJ with IN our PP$ finding NN of IN no DT similarity NN between IN human JJ and CC chimpanzee NN aging VVG patterns NNS , , there EX was VBD little JJ overlap VVP between IN these DT enriched VVN groups NNS and CC those DT previously RB reported VVN for IN human JJ frontal JJ pole NN 7 CD . SENT TopIntroductionResultsDiscussionMaterials NP and CC MethodsSupporting NP InformationAcknowledgmentsReferences NP Discussion NN In IN this DT study NN , , we PP have VHP made VVN three CD main JJ observations NNS . SENT First RB , , aging VVG related JJ gene NN expression NN changes NNS are VBP similar JJ throughout IN all DT five CD tested VVN regions NNS of IN the DT human JJ cerebral JJ cortex NN . SENT Second RB , , this DT pattern NN of IN human JJ cortex NN aging NN is VBZ not RB found VVN in IN cerebellum NN or CC caudate JJ nucleus NN , , and CC at IN least JJS in IN cerebellum NN this DT appears VVZ to TO be VB due JJ to TO far RB fewer JJR genes NNS changing VVG expression NN with IN age NN . SENT Third JJ , , although IN chimpanzee NN cortex NN has VHZ a DT reproducible JJ pattern NN of IN expression NN changes NNS with IN age NN , , it PP shares VVZ no DT detectable JJ similarity NN with IN the DT aging VVG pattern NN in IN human JJ cortex NN . SENT These DT conclusions NNS raise VVP a DT number NN of IN questions NNS . SENT For IN example NN , , why WRB does VVZ human JJ cerebellum NN age NN differently RB than IN human JJ cortex NN . SENT We PP have VHP shown VVN that IN the DT majority NN of IN the DT difference NN is VBZ because IN genes NNS down RB regulated VVN with IN age NN in IN cortex NN are VBP not RB down RB regulated VVN in IN cerebellum NN see VVP Figure NP 3 CD . SENT because IN fewer JJR genes NNS change VVP with IN age NN in IN cerebellum NN than IN in IN cortex NN see VVP Figure NP 2 CD , , it PP therefore RB follows VVZ that IN this DT is VBZ mostly RB due JJ to TO fewer JJR genes NNS being VBG down RB regulated VVN with IN age NN . SENT What WP could MD cause VV fewer JJR genes NNS to TO have VH reduced VVN transcription NN over IN time NN in IN cerebellum NN than IN in IN cerebral JJ cortex NN . SENT Cerebellum NN differs VVZ in IN many JJ important JJ respects NNS from IN cortex NN . SENT in IN particular JJ , , it PP has VHZ a DT lower JJR metabolic JJ rate NN than IN cortex NN in IN both DT human JJ and CC rhesus NN macaque NN , , regardless RB of IN age NN 25 CD 27 CD . SENT These DT observations NNS of IN lower JJR metabolic JJ activity NN in IN cerebellum NN imply VVP that IN if IN a DT consequence NN of IN aerobic JJ respiration NN is VBZ ROS NP induced VVN DNA NN damage NN , , then RB such JJ damage NN should MD be VB greater JJR in IN cortex NN than IN in IN cerebellum NN . SENT Indeed RB , , it PP has VHZ been VBN shown VVN that IN cerebellum NN has VHZ far RB fewer JJR mtDNA NN mitochondrial JJ DNA NN deletions NNS than IN cortex NN , , especially RB in IN old JJ humans NNS 11 CD , , and CC it PP accumulates VVZ less RBR oxidative JJ damage NN to TO both DT mtDNA NN and CC nuclear JJ DNA NN than IN does VVZ cortex NN 12 CD . SENT Therefore RB if IN the DT accumulation NN of IN DNA NP damage NN causes VVZ gene NN expression NN down IN regulation NN 7 CD 10 CD , , 28 CD , , then RB we PP would MD expect VV to TO see VV fewer JJR aging VVG related JJ gene NN expression NN level NN reductions NNS in IN cerebellum NN than IN in IN cortex NN . SENT Our PP$ confirmation NN of IN this DT prediction NN is VBZ quite RB consistent JJ with IN the DT theory NN that IN ROS NP induced VVD damage NN is VBZ responsible JJ for IN gene NN expression NN changes NNS 7 CD , , 28 CD , , as RB well RB as IN the DT more RBR general JJ oxidative JJ free JJ radical JJ theory NN of IN aging VVG 2 CD . SENT Similarly RB , , one PP might MD ask VV why WRB chimpanzee NN cortex NN ages NNS differently RB than IN human JJ cortex NN . SENT If IN ROS NP induced VVD DNA NN damage NN is VBZ indeed RB a DT major JJ cause NN of IN gene NN expression NN changes NNS 7 CD , , 28 CD , , then RB the DT aging VVG differences NNS could MD be VB due JJ to TO differential JJ ROS NP susceptibilities NNS of IN orthologous JJ loci NNS in IN the DT human JJ and CC chimpanzee NN genomes NNS although IN ROS NP damage NN is VBZ unlikely JJ to TO directly RB explain VV the DT difference NN in IN up RB regulated VVN genes NNS as IN seen VVN in IN Figure NP 5 CD , , it PP may MD be VB indirectly RB responsible JJ by IN down RB regulating VVG genes NNS such JJ as IN transcriptional JJ repressors NNS . SENT It PP is VBZ difficult JJ to TO know VV how WRB plausible JJ this DT is VBZ because IN we PP do VVP not RB presently RB understand VV what WP factors NNS lead VVP to TO ROS NP damage NN susceptibility NN . SENT regardless RB of IN the DT factors NNS involved VVD . SENT however RB , , it PP is VBZ quite RB possible JJ that IN even RB the DT relatively RB few JJ genetic JJ or CC epigenetic JJ differences NNS between IN human JJ and CC chimpanzee NN may MD be VB sufficient JJ to TO cause VV drastic JJ changes NNS in IN ROS NP susceptibility NN , , as IN is VBZ the DT case NN for IN other JJ chromosomal JJ properties NNS such JJ as IN DNA NP methylation NN 29 CD and CC recombination NN rate NN 30 CD , , 31 CD . SENT One CD possible JJ explanation NN for IN ROS NP susceptibility NN is VBZ that IN promoters NNS driving VVG high JJ levels NNS of IN transcription NN are VBP more RBR vulnerable JJ to TO ROS NP , , perhaps RB because IN of IN their PP$ more JJR accessible JJ chromatin NN structure NN and CC or CC lower JJR tolerance NN for IN oxidative JJ damage NN . SENT however RB , , although IN highly RB expressed VVN genes NNS are VBP indeed RB more RBR likely JJ to TO be VB down RB regulated VVN with IN age NN in IN human JJ frontal JJ pole NN , , expression NN levels NNS are VBP far RB from IN explaining VVG all DT of IN the DT variation NN in IN aging VVG related JJ changes NNS in IN either DT human JJ or CC chimpanzee NN not RB shown VVN . SENT It PP is VBZ likely JJ that IN ROS NP susceptibility NN will MD have VH to TO be VB measured VVN in IN a DT number NN of IN chimpanzee NN gene NN promoters NNS , , as RB has VHZ been VBN done VVN for IN human JJ 7 CD , , in IN order NN to TO discover VV if IN differential JJ oxidative JJ damage NN can MD explain VV the DT human JJ chimpanzee NN divergence NN in IN aging VVG patterns NNS . SENT Another DT implication NN of IN these DT results NNS is VBZ related VVN to TO the DT use NN of IN model NN organisms NNS such JJ as IN mouse NN , , rat NN , , and CC various JJ primates NNS as IN surrogates NNS for IN human JJ brain NN aging NN and CC neurodegeneration NN . SENT The DT fact NN that IN even RB the DT chimpanzee NN , , our PP$ closest JJS living NN relative JJ , , has VHZ patterns NNS of IN age NN related JJ gene NN expression NN changes NNS almost RB entirely RB different JJ than IN human NN implies VVZ that IN making VVG specific JJ inferences NNS about IN human JJ brain NN aging VVG from IN model NN organisms NNS may MD be VB difficult JJ . SENT This DT conclusion NN is VBZ supported VVN by IN a DT study NN of IN brain NN aging VVG in IN mice NNS , , in IN which WDT in IN contrast NN to TO the DT results NNS reported VVD here RB for IN human JJ , , the DT cerebellum NN was VBD found VVN to TO contain VV more JJR genes NNS changing VVG expression NN with IN age NN than IN cortex NN 32 CD a DT difference NN that WDT may MD be VB due JJ to TO different JJ relative JJ metabolic JJ rates NNS of IN cortex NN and CC cerebellum NN in IN mouse NN compared VVN to TO human JJ . SENT Model NN organisms NNS are VBP probably RB well RB suited VVN for IN studying VVG the DT mechanisms NNS of IN aging VVG such JJ as IN ROS NP induced VVD damage NN , , which WDT are VBP likely JJ to TO be VB conserved VVN over IN great JJ phylogenetic JJ distances NNS , , but CC such JJ conserved VVN mechanisms NNS may MD have VH species NNS specific JJ outcomes NNS at IN the DT level NN of IN individual JJ genes NNS . SENT Thus RB , , caution NN is VBZ warranted VVN when WRB trying VVG to TO extrapolate VV the DT results NNS of IN neurodegeneration NN research NN from IN model NN organisms NNS to TO humans NNS . SENT Many JJ other JJ questions NNS raised VVN by IN this DT work NN are VBP still RB unresolved JJ . SENT First RB , , how WRB diverse JJ are VBP aging VVG patterns NNS of IN gene NN expression NN change NN in IN human JJ tissues NNS outside IN the DT brain NN . SENT A DT recent JJ study NN finding VVG similar JJ aging VVG profiles NNS of IN human JJ kidney NN cortex NN and CC medulla NN regions NNS implies VVZ that IN the DT intra NN organ NN variability NN in IN aging VVG patterns NNS observed VVN in IN the DT present JJ work NN may MD not RB be VB found VVN in IN all DT organs NNS 33 CD . SENT Second RB , , do VVP human JJ and CC chimpanzee NN differ VVP in IN their PP$ aging VVG patterns NNS in IN tissues NNS other JJ than IN brain NN , , or CC is VBZ the DT brain NN a DT special JJ case NN because IN of IN its PP$ recent JJ rapid JJ morphological JJ evolution NN in IN the DT human JJ lineage NN . SENT It PP will MD be VB interesting JJ to TO test VV this DT for IN tissues NNS that WDT have VHP not RB undergone VVN any DT obvious JJ rapid JJ evolution NN such JJ as IN liver NN or CC kidney NN , , as RB well RB as RB for IN tissues NNS that WDT are VBP likely JJ to TO have VH been VBN under IN strong JJ positive JJ selection NN such JJ as IN testes NNS . SENT Third JJ , , does VVZ chimpanzee NN cerebellum NN have VHP fewer JJR gene NN expression NN changes NNS with IN age NN than IN cortex NN , , as IN is VBZ the DT case NN in IN human JJ . SENT More JJR chimpanzee NN data NNS will MD be VB needed VVN to TO address VV this DT question NN , , although IN it PP seems VVZ likely RB that IN the DT answer NN will MD be VB affirmative JJ because IN the DT greater JJR metabolic JJ rate NN of IN cortex NN compared VVN to TO cerebellum NN is VBZ conserved VVN to TO rhesus NN macaque NN 27 CD . SENT Fourth JJ , , does VVZ the DT human JJ or CC chimpanzee NN cortex NN aging VVG pattern NN represent VVP the DT ancestral JJ state NN of IN this DT pattern NN for IN these DT two CD species NNS , , or CC are VBP they PP both CC highly RB diverged VVN from IN that DT state NN . SENT Examination NN of IN brain NN aging VVG patterns NNS in IN an DT outgroup NN species NN , , such JJ as IN rhesus NN macaque NN , , may MD help VV to TO resolve VV this DT question NN . SENT Fifth NP , , is VBZ the DT rapid JJ divergence NN of IN aging VVG patterns NNS along IN the DT human JJ and CC or CC chimpanzee NN lineage NN the DT result NN of IN selection NN on IN the DT aging VVG process NN itself PP , , or CC is VBZ the DT divergence NN an DT indirect JJ consequence NN of IN selection NN on IN other JJ aspects NNS of IN the DT brain NN , , or CC could MD it PP even RB be VB explained VVN by IN random JJ drift NN alone RB . SENT And CC finally RB , , can MD we PP use VV our PP$ understanding NN of IN the DT similarities NNS and CC differences NNS in IN brain NN aging VVG of IN humans NNS and CC chimpanzees NNS to TO gain VV greater JJR insight NN into IN the DT causes NNS of IN , , and CC possible JJ treatments NNS for IN , , human JJ neurodegeneration NN . SENT We PP believe VVP this DT will MD be VB possible JJ because IN investigation NN of IN how WRB a DT phenomenon NN such JJ as IN neurodegeneration NN emerged VVN during IN evolution NN might MD well RB point VV us PP towards IN its PP$ underlying JJ causes NNS TopIntroductionResultsDiscussionMaterials NP and CC MethodsSupporting NP InformationAcknowledgmentsReferences NP Materials NPS and CC Methods NNS Tissue NN samples NNS and CC gene NN expression NN data NNS Human JJ microarray NN data NNS was VBD obtained VVN from IN Pritzker NP Neuropsychiatric JJ Disorders NNS Research NP Consortium NP http NN . SENT www JJ . SENT pritzkerneuropsych NN . SENT org NP and CC the DT National NP Institute NP of IN Mental JJ Health NP NIMH NP Silvio NP O NP . SENT Conte NP Center NP , , and CC from IN ArrayExpress NP and CC GEO NP databases NNS . SENT Only RB the DT seven CD Type NN 1 CD control NN individuals NNS 34 CD , , 35 CD were VBD used VVN from IN the DT Evans NP et NP al NP . SENT 20 CD dataset NN . SENT Chimpanzee NN postmortem NN samples NNS were VBD obtained VVN from IN Yerkes NP Regional NP Primate NN Center NP , , Biomedical JJ Primate NN Research NP Centre NP and CC Anthropologisches NP Institut NP und NN Museum NP , , Universit NP t NN Z NN rich JJ . SENT All DT individuals NNS suffered VVD sudden JJ death NN for IN reasons NNS other JJ than IN their PP$ participation NN in IN this DT study NN and CC without IN any DT relation NN to TO the DT tissues NNS used VVD . SENT time NN between IN death NN and CC preservation NN of IN brain NN tissue NN postmortem NN interval NN did VVD not RB correlate VV with IN expression NN of IN genes NNS that IN changes NNS with IN age NN . SENT Age NN and CC sex NN for IN all DT individuals NNS are VBP listed VVN in IN Table NN S NP 2 CD . SENT Total NP RNA NP was VBD isolated VVN from IN approximately RB 50 CD mg NN of IN frozen JJ tissue NN using VVG the DT TRIZol NP reagent NN according VVG to TO manufacturer's NNS instructions NNS and CC purified VVN with IN QIAGEN NP RNeasy NP kit NN Qiagen NP , , Valencia NP , , California NP , , United NP States NPS following VVG the DT RNA NP cleanup NN protocol NN . SENT RNAs NNS were VBD of IN high JJ and CC comparable JJ quality NN in IN all DT samples NNS as RB gauged VVD by IN the DT ratio NN of IN 28 CD S NP to TO 18 CD S NP ribosomal JJ RNAs NP estimated VVD using VVG the DT Agilent NP 2100 CD Bionalyzer NP system NN Agilent NP , , Palo NP Alto NP , , California NP , , United NP States NPS and CC by IN the DT signal NN ratios NNS between IN the DT probes NNS for IN the DT 3 CD and CC 5 CD ends NNS of IN the DT mRNAs NNS of IN GAPDH NP and CC actin NN genes NNS used VVN as IN quality NN controls NNS on IN Affymetrix NP Affymetrix NP , , Santa NP Clara NP , , California NP , , United NP States NPS microarrays NNS . SENT Labeling VVG of IN 1 CD . SENT 2 CD g NN of IN total JJ RNA NP , , hybridization NN to TO Affymetrix NP HG NP U NP 95 CD v NN 2 CD arrays NNS , , staining VVG , , washing VVG , , and CC array NN scanning VVG were VBD carried VVN out IN following VVG Affymetrix NP protocols NNS . SENT The DT samples NNS were VBD processed VVN in IN random JJ order NN with IN respect NN to TO age NN . SENT All DT primary JJ expression NN data NNS generated VVN for IN this DT study NN are VBP publicly RB available JJ at IN ArrayExpress NP database NN http NN . SENT www JJ . SENT ebi NNS . SENT ac NNS . SENT uk NP arrayexpress NN . SENT Data NNS were VBD normalized VVN using VVG the DT Robust JJ Multichip NP Average NP RMA NP method NN 36 CD . SENT Among IN the DT chimpanzees NNS used VVN for IN this DT work NN , , one PP was VBD of IN indeterminate JJ age NN , , having VHG been VBN caught VVN in IN the DT wild JJ 40 CD y NN before IN its PP$ death NN Table NN S NP 2 CD . SENT However RB , , because IN we PP used VVD nonparametric JJ rank NN statistics NNS for IN all DT analyses NNS , , the DT exact JJ age NN was VBD irrelevant JJ . SENT all PDT that DT mattered VVN was VBD whether IN it PP was VBD older JJR or CC younger JJR than IN our PP$ 44 CD y NN old JJ chimpanzee NN . SENT For IN the DT results NNS shown VVN it PP was VBD assumed VVN to TO be VB older JJR , , although IN assuming VVG it PP to TO be VB younger JJR than IN 44 CD y NN strengthened VVD the DT results NNS of IN the DT analyses NNS the DT correlation NN of IN chimpanzee NN prefrontal JJ cortex NN with IN anterior JJ cingulate JJ cortex NN increased VVN from IN 0 CD . SENT 894 CD to TO 0 CD . SENT 927 CD . SENT Additionally RB , , one CD pair NN of IN chimpanzees NNS used VVN were VBD full JJ siblings NNS , , and CC another DT pair NN were VBD half DT siblings NNS Table NN S NP 2 CD , , which WDT could MD be VB problematic JJ if IN aging VVG patterns NNS are VBP family NN specific JJ . SENT However RB one CD member NN of IN each DT related JJ pair NN could MD be VB excluded VVN from IN the DT analysis NN without IN greatly RB affecting VVG the DT results NNS correlation NN of IN chimpanzee NN prefrontal JJ cortex NN with IN anterior JJ cingulate JJ cortex NN decreased VVD from IN 0 CD . SENT 894 CD to TO 0 CD . SENT 858 CD , , indicating VVG that DT relatedness NN among IN chimpanzees NNS does VVZ not RB alter VV our PP$ conclusions NNS . SENT Excluding VVG one CD member NN of IN each DT related JJ pair NN also RB left VVD the DT same JJ five CD unrelated JJ chimpanzees NNS for IN each DT of IN the DT three CD brain NN regions NNS tested VVD , , controlling VVG for IN any DT possible JJ effects NNS of IN unequal JJ sample NN sizes NNS from IN each DT brain NN region NN . SENT There EX are VBP several JJ possible JJ artifactual JJ explanations NNS for IN our PP$ results NNS not RB addressed VVN in IN the DT main JJ text NN . SENT First RB , , there EX is VBZ the DT possibility NN that IN gene NN expression NN changes NNS correlated VVN with IN age NN were VBD caused VVN by IN an DT unknown JJ factor NN unrelated JJ to TO the DT normal JJ aging NN process NN . SENT For IN example NN , , if IN in IN the DT study NN by IN Khaitovich NP et CC al NP . SENT 19 RB the DT 70 CD y NN old JJ had VHD a DT disease NN that WDT made VVD his PP$ cerebellum NN and CC caudate JJ nucleus NN appear VVP young JJ in IN their PP$ gene NN expression NN , , but CC did VVD not RB affect VV his PP$ cortex NN because IN all DT four CD of IN his PP$ cortex NN regions NNS showed VVD the DT same JJ reproducible JJ pattern NN , , then RB this DT could MD account VV for IN the DT results NNS of IN Figure NP 2 CD A DT . SENT However RB in IN order NN for IN this DT explanation NN to TO also RB account VV for IN the DT similar JJ results NNS of IN Figure NP 2 CD B NP , , several JJ elderly JJ individuals NNS from IN the DT Evans NP et NP al NP . SENT 20 CD study NN would MD all RB have VH to TO be VB similarly RB afflicted VVN in IN their PP$ cerebella NN as RB well RB . SENT We PP found VVD this DT to TO be VB extremely RB unlikely JJ , , because IN all DT ten CD individuals NNS from IN these DT two CD studies NNS were VBD chosen VVN in IN part NN for IN their PP$ lack NN of IN any DT known VVN brain NN related VVD diseases NNS 19 CD , , 20 CD . SENT Similarly RB , , one CD possible JJ explanation NN for IN the DT results NNS in IN Figure NP 4 CD A DT is VBZ that IN the DT cortexes NNS but CC not RB cerebella NN of IN both DT of IN our PP$ old JJ chimpanzees NNS had VHD a DT large JJ number NN of IN gene NN expression NN differences NNS compared VVN to TO the DT young JJ chimpanzees NNS for IN a DT reason NN other JJ than IN aging VVG , , such JJ as IN a DT cortex NN specific JJ brain NN disease NN distinct JJ from IN the DT normal JJ aging NN process NN . SENT As RB for IN the DT human JJ subjects NNS discussed VVN above IN , , this DT is VBZ extremely RB unlikely JJ to TO be VB the DT case NN , , because IN none NN of IN these DT chimpanzees NNS had VHD any DT apparent JJ brain NN disease NN and CC both DT old JJ chimpanzees NNS who WP are VBP unrelated JJ to TO each DT other JJ would MD have VH to TO be VB similarly RB afflicted VVN to TO observe VV this DT effect NN . SENT If IN gene NN expression NN changes NNS in IN primates NNS tend VVP to TO be VB dependent JJ on IN chronological JJ age NN so RB that IN , , for IN example NN , , gene NN expression NN levels NNS in IN a DT 45 CD y NN old JJ chimpanzee NN are NN most JJS similar JJ to TO those DT in IN a DT 45 CD y NN old JJ human NN , , then RB the DT different JJ patterns NNS of IN expression NN changes NNS with IN age NN seen VVN in IN humans NNS and CC chimpanzees NNS could MD be VB caused VVN by IN the DT different JJ age NN ranges NNS of IN the DT human JJ 18 CD 106 CD y NN and CC chimpanzee NN 7 CD to TO approximately RB 45 CD y NN samples NNS . SENT To TO control VV for IN this DT possibility NN , , we PP truncated VVD the DT data NN of IN Lu NP et CC al NP . SENT 7 CD to TO contain VV only RB the DT 11 CD individuals NNS with IN age NN 45 CD y NN . SENT Recalculating VVG the DT age NN expression NN correlations NNS for IN each DT gene NN and CC comparing VVG them PP to TO the DT chimpanzee NN data NNS , , we PP found VVD no DT more JJR similarity NN in IN which WDT genes NNS change VVP expression NN with IN age NN than IN when WRB using VVG any DT of IN our PP$ three CD full JJ human JJ expression NN datasets NNS 7 CD , , 19 CD , , 20 CD . SENT Therefore RB , , we PP find VVP it PP unlikely JJ that IN brain NN aging VVG of IN chimpanzees NNS is VBZ any DT more RBR similar JJ to TO that DT of IN humans NNS when WRB controlling VVG for IN chronological JJ age NN . SENT Another DT possible JJ explanation NN for IN the DT difference NN between IN human JJ and CC chimpanzee NN aging VVG patterns NNS Figure NN 4 CD B NN is VBZ that IN the DT difference NN is VBZ actually RB due JJ to TO the DT different JJ environments NNS experienced VVN by IN the DT humans NNS and CC chimpanzees NNS during IN their PP$ lifetimes NNS , , and CC is VBZ not RB due JJ to TO any DT intrinsic JJ differences NNS between IN these DT species NN . SENT Because IN there EX is VBZ no DT way NN to TO possibly RB control VV for IN this DT for IN both DT practical JJ and CC ethical JJ reasons NNS a DT human JJ cannot NN be VB raised VVN in IN precisely RB the DT same JJ environment NN as IN a DT chimpanzee NN or CC even RB another DT human JJ all RB that IN we PP can MD rigorously RB conclude VV is VBZ that IN the DT humans NNS and CC chimpanzees NNS used VVN for IN the DT analyses NNS herein RB did VVD experience VV different JJ patterns NNS of IN gene NN expression NN change NN with IN age NN . SENT We PP note VVP that IN this DT general JJ concern NN extends VVZ to TO all DT studies NNS comparing VVG any DT human's JJ phenotype NN with IN that DT of IN another DT organism NN . SENT One CD caveat NN concerning VVG our PP$ interpretation NN of IN fewer JJR genes NNS having VHG aging NN associated VVN changes NNS in IN expression NN in IN cerebellum NN than IN in IN cortex NN is VBZ that IN the DT two CD human JJ cerebellum NN datasets NNS , , although IN both DT consisting VVG of IN grey JJ matter NN of IN the DT cerebellum NN , , were VBD from IN different JJ regions NNS of IN the DT cerebellum NN Khaitovich NP et NP al NP . SENT 19 CD sampled VVN the DT Vermis NN cerebelli NN , , whereas IN Evans NP et CC al NP . SENT 20 CD used VVD the DT left JJ lateral JJ portion NN of IN the DT cerebellum NN . SENT therefore RB it PP is VBZ technically RB possible JJ that IN these DT regions NNS of IN cerebellum NN each DT have VHP their PP$ own JJ reproducible JJ aging NN pattern NN , , which WDT if IN both DT shared VVN no DT similarity NN either RB to TO each DT other JJ or CC to TO cortex NN would MD not RB be VB revealed VVN by IN this DT analysis NN . SENT We PP find VVP this DT to TO be VB quite RB unlikely JJ , , given VVN the DT very RB close JJ proximity NN and CC functionally RB similar JJ properties NNS of IN these DT two CD regions NNS , , together RB with IN the DT finding NN that IN far RB more JJR heterogeneous JJ regions NNS throughout IN the DT cerebral JJ cortex NN share NN nearly RB identical JJ aging VVG patterns NNS . SENT And CC even RB if IN this DT improbable JJ case NN were VBD to TO be VB true JJ , , our PP$ conclusion NN of IN cerebellum NN grey NN matter NN as IN a DT whole NN lacking VVG any DT reproducible JJ aging NN pattern NN would MD still RB hold VV . SENT Statistics NP All NP correlation NN coefficients NNS reported VVD here RB were VBD calculated VVN by IN Spearman NP rank NN correlation NN , , a DT nonparametric JJ method NN that WDT is VBZ robust JJ to TO the DT presence NN of IN any DT outliers NNS . SENT The DT correlation NN coefficients NNS from IN comparisons NNS of IN aging VVG profiles NNS between IN two CD tissues NNS or CC species NNS as IN in IN Figures NNS 2 CD and CC 4 CD were VBD calculated VVN on IN coordinates NNS assigned VVN to TO genes NNS in IN each DT of IN the DT following VVG categories NNS . SENT up RB regulated VVN in IN both DT regions NNS 1 CD , , 1 CD , , up RB regulated VVN in IN one CD region NN and CC down RB in IN another DT 1 CD , , 1 CD or CC 1 CD , , 1 CD , , or CC down RB regulated VVN in IN both DT regions NNS 1 CD , , 1 CD . SENT The DT correlation NN coefficients NNS can MD be VB interpreted VVN as IN scores NNS directly RB proportional JJ to TO the DT fraction NN of IN genes NNS with IN the DT same JJ direction NN of IN expression NN change NN with IN age NN . SENT Probability NN values NNS were VBD calculated VVN by IN randomization NN of IN ages NNS , , given VVN the DT specific JJ genes NNS used VVN in IN any DT particular JJ comparison NN . SENT the DT fraction NN of IN randomizations NNS with IN a DT correlation NN coefficient NN greater JJR than IN or CC equal JJ to TO the DT observed JJ value NN is VBZ the DT p NN value NN given VVN . SENT Therefore RB this DT is VBZ a DT one NN sided VVD test NN , , appropriate JJ for IN the DT question NN of IN whether IN we PP could MD have VH agreement NN between IN aging VVG patterns NNS as IN strong JJ as IN those DT observed JJ , , just RB by IN random JJ chance NN . SENT The DT only JJ exceptions NNS to TO our PP$ using VVG this DT one NN sided VVD test NN were VBD when WRB we PP stated VVD we PP were VBD testing VVG whether IN the DT correlation NN coefficient NN was VBD significantly RB different JJ from IN zero CD as RB opposed VVN to TO greater JJR than IN zero CD . SENT in IN these DT cases NNS the DT test NN was VBD two CD sided VVN . SENT This DT randomization NN test NN is VBZ somewhat RB conservative JJ . SENT for IN example NN , , analyzing VVG the DT leftmost JJ bar NN prefrontal JJ cortex NN of IN Figure NP 2 CD A NP with IN Fisher's NP exact JJ test NN yields NNS a DT p NN value NN of IN approximately RB 10 CD 99 CD , , as RB opposed VVN to TO approximately RB 0 CD . SENT 015 CD from IN randomization NN . SENT This DT large JJ difference NN is VBZ due JJ to TO the DT nonrandom NN structure NN of IN the DT expression NN data NNS , , which WDT makes VVZ it PP more RBR likely JJ to TO observe VV strong JJ correlations NNS than IN would MD be VB expected VVN in IN a DT set NN of IN random JJ data NNS . SENT Finally RB , , we PP note VVP that IN our PP$ finding NN of IN significant JJ agreement NN between IN aging VVG patterns NNS in IN datasets NNS containing VVG various JJ numbers NNS of IN microarrays NNS does VVZ not RB imply VV that IN these DT numbers NNS of IN microarrays NNS will MD always RB yield VV sufficient JJ power NN to TO find VV such PDT a DT correlation NN if IN one PP exists VVZ . SENT TopIntroductionResultsDiscussionMaterials NP and CC MethodsSupporting NP InformationAcknowledgmentsReferences NP Supporting VVG Information NP Table NN S NP 1 CD . SENT Gene NN Ontology NN Groups NNS Enriched VVN in IN the DT List NP of IN Genes NPS Up RB Regulated VVN with IN Age NP in IN Chimpanzee NN Cerebral JJ Cortex NN All DT detected VVN is VBZ the DT number NN of IN genes NNS on IN the DT microarray NN that WDT had VHD an DT annotation NN in IN each DT of IN the DT three CD Gene NP Ontology NN GO VVP categories NNS . SENT Detected VVN group NN is VBZ the DT number NN of IN genes NNS on IN the DT microarray NN that WDT belong VVP to TO the DT specific JJ GO NN group NN listed VVN . SENT All DT selected VVN is VBZ the DT number NN of IN genes NNS up RB regulated VVN with IN age NN in IN chimpanzee NN cortex NN that WDT have VHP annotations NNS in IN each DT of IN the DT three CD GO NN categories NNS . SENT Selected JJ group NN is VBZ the DT number NN of IN genes NNS up RB regulated VVN with IN age NN in IN chimpanzee NN cortex NN that WDT belong VVP to TO the DT specific JJ GO NN group NN listed VVN . SENT The DT uncorrected JJ p NN value NN cutoff NN for IN each DT GO NN group NN is VBZ 0 CD . SENT 005 CD . SENT 21 CD KB NP XLS NNS . SENT Table NN S NP 2 CD . SENT Sample NN Information NP 18 CD KB NP XLS NNS . SENT TopIntroductionResultsDiscussionMaterials NP and CC MethodsSupporting NP InformationAcknowledgmentsReferences NP AcknowledgmentsWe NP would MD like VV to TO thank VV the DT Pritzker NP Neuropsychiatric JJ Disorders NNS Research NP Consortium NP , , the DT National NP Institute NP of IN Mental JJ Health NP NIMH NP Silvio NP O NP . SENT Conte NP Center NP , , and CC J NP . SENT Li NP personally RB for IN sharing VVG the DT data NN from IN Evans NP et CC al NP . SENT 20 CD . SENT I PP . SENT Hellmann NP for IN providing VVG the DT sequence NN mask NN file NN for IN chimpanzee NN microarray NN data NNS analysis NN . SENT W NP . SENT Enard NP and CC A NP . SENT Chen NP for IN helpful JJ discussions NNS . SENT and CC the DT Bundesministerium NN f SYM r NN Bildung NP und NN Forschung NP for IN financial JJ support NN . SENT JBP NP acknowledges VVZ support NN from IN the DT Burroughs NP Wellcome NP Fund NP and CC the DT William NP F NN . SENT Milton NP Fund NP . SENT MBE NP is VBZ a DT Pew NP Scholar NN in IN the DT Biomedical JJ Sciences NPS . SENT HBF NP is VBZ an DT NSF NN predoctoral JJ fellow NN . SENT Competing VVG interests NNS . SENT The DT authors NNS have VHP declared VVN that IN no DT competing JJ interests NNS exist VVP . SENT Author NN contributions NNS . SENT HBF NP , , PK NP , , and CC JBP NP conceived VVD and CC designed VVD the DT experiments NNS and CC analyses NNS . SENT PK NP performed VVD the DT experiments NNS . SENT HBF NP analyzed VVD the DT data NNS . SENT SP NP and CC MBE NP contributed VVD reagents NNS materials NNS analysis NN tools NNS . SENT HBF NP , , PK NP , , JBP NP , , SP NP , , and CC MBE NP wrote VVD the DT paper NN . SENT TopIntroductionResultsDiscussionMaterials NP and CC MethodsSupporting NP InformationAcknowledgmentsReferences NP ReferencesPearl NP R NP 1928 CD The DT rate NN of IN living NN . SENT London NP . SENT University NP of IN London NP Press NP . SENT 185 CD p NN . SENT Harman NP D NP 1956 CD Aging NN . SENT A DT theory NN based VVN on IN free JJ radical JJ and CC radiation NN chemistry NN . SENT J NP . SENT Gerontol NP 2 CD . SENT 298 CD 300 CD . SENT Find VV this DT article NN onlineBeckman NN KB NP , , Ames NP BN NP 1998 CD The DT free JJ radical JJ theory NN of IN aging NN matures VVZ . SENT Physiol NP Rev NP 78 CD . SENT 547 CD 581 CD . SENT Find VV this DT article NN onlineHekimi NP S NP , , Guarente NP L NP 2003 CD Genetics NP and CC the DT specificity NN of IN the DT aging VVG process NN . SENT Science NP 299 CD . SENT 1351 CD 1354 CD . SENT Find VV this DT article NN onlineHughes NNS KA NP , , Reynolds NP RM NP 2005 CD Evolutionary JJ and CC mechanistic JJ theories NNS of IN aging VVG . SENT Annu NP Rev NP Entomol NP 50 CD . SENT 421 CD 445 CD . SENT Find VV this DT article NN onlineStadtman NN ER NP 2001 CD Protein NN oxidation NN in IN aging VVG and CC age NN related JJ diseases NNS . SENT Ann NP N NP Y NP Acad NP Sci NP 928 CD . SENT 22 CD 38 CD . SENT Find VV this DT article NN onlineLu NN T NN , , Pan NP Y NP , , Kao NP SY NP , , Li NP C NP , , Kohane NP I NP 2004 CD Gene NP regulation NN and CC DNA NN damage NN in IN the DT ageing VVG human JJ brain NN . SENT Nature NP 429 CD . SENT 883 CD 891 CD . SENT Find VV this DT article NN onlineGhosh NN R NN , , Mitchell NP DL NP 1999 CD Effect NN of IN oxidative JJ DNA NN damage NN in IN promoter NN elements NNS on IN transcription NN factor NN binding JJ . SENT Nucleic JJ Acids NNS Res NN 27 CD . SENT 3213 CD 3218 CD . SENT Find VV this DT article NN onlineMarietta NN C NP , , Gulam NP H NP , , Brooks NP PJ NP 2002 CD A DT single JJ 8 CD , , 5 CD cyclo NN 2 CD deoxyadenosine NN lesion NN in IN a DT TATA NP box NN prevents VVZ binding VVG of IN the DT TATA NP binding JJ protein NN and CC strongly RB reduces VVZ transcription NN in IN vivo RB . SENT DNA NP Repair NP 1 CD . SENT 967 CD 975 CD . SENT Find VV this DT article NN onlineBrooks NNS PJ NP , , Wise NP DS NP , , Berry NP DA NP , , Kosmoski NP JV NP , , Smerdon NP MJ NP 2000 CD The DT oxidative JJ DNA NN lesion NN 8 CD , , 5 CD S NP cyclo NN 2 CD deoxyadenosine NN is VBZ repaired VVN by IN the DT nucleotide NN excision NN repair NN pathway NN and CC blocks NNS gene NN expression NN in IN mammalian JJ cells NNS . SENT J NP Biol NP Chem NP 275 CD . SENT 22355 CD 22362 CD . SENT Find VV this DT article NN onlineCorral NN Debrinski NP M NP , , Horton NP T NN , , Lott NP MT NP , , Shoffner NP JM NP , , Beal NP MF NP 1992 CD Mitochondrial JJ DNA NN deletions NNS in IN human JJ brain NN . SENT Regional JJ variability NN and CC increase NN with IN advanced JJ age NN . SENT Nat NP Genet NP 2 CD . SENT 324 CD 329 CD . SENT Find VV this DT article NN onlineMecocci NN P NN , , MacGarvey NP U NP , , Kaufman NP AE NP , , Koontz NP D NP , , Shoffner NP JM NP 1993 CD Oxidative JJ damage NN to TO mitochondrial JJ DNA NN shows NNS marked VVD age NN dependent JJ increases NNS in IN human JJ brain NN . SENT Ann NP Neurol NP 34 CD . SENT 609 CD 616 CD . SENT Find VV this DT article NN onlineRose NN MR NP 1991 CD The DT evolutionary JJ biology NN of IN aging VVG . SENT Oxford NP United NP Kingdom NP . SENT Oxford NP University NP Press NP . SENT 240 CD p NN . SENT McCarroll NP SA NP , , Murphy NP CT NP , , Pletcher NP SD NP , , Chin NP CS NP , , Jan NP YN NP 2004 CD Comparing VVG genomic JJ expression NN patterns NNS across IN species NNS identified VVN shared VVD transcriptional JJ profile NN in IN aging VVG . SENT Nat NP Genet NP 36 CD . SENT 197 CD 204 CD . SENT Find VV this DT article NN onlineWelle NP S NP , , Brooks NP A NP , , Thornton NP CA MD 2001 CD Senescence NN related JJ changes NNS in IN gene NN expression NN in IN muscle NN . SENT Similarities NNS and CC differences NNS between IN mice NNS and CC men NNS . SENT Physiol NP Genomics NP 5 CD . SENT 67 CD 73 CD . SENT Find VV this DT article NN onlineEnard NP W NP , , Khaitovich NP P NN , , Klose NP J NP , , Zollner NP S NP , , Heissig NP F NP 2002 CD Intra NP and CC interspecific JJ variation NN in IN primate NN gene NN expression NN patterns NNS . SENT Science NP 296 CD . SENT 340 CD 343 CD . SENT Find VV this DT article NN onlineDorus NN S NP , , Vallender NP EJ NP , , Evans NP PD NP , , Anderson NP JR NP , , Gilbert NP SL NP 2004 CD Accelerated VVD evolution NN of IN nervous JJ system NN genes NNS in IN the DT origin NN of IN Homo NN sapiens JJ . SENT Cell NN 199 CD . SENT 1027 CD 1040 CD . SENT Find VV this DT article NN onlineEmerit NN J NP , , Edeas NP M NP , , Bricaire NP F NP 2003 CD Neurodegenerative JJ diseases NNS and CC oxidative JJ stress NN . SENT Biomed NP Pharmacother NP 58 CD . SENT 39 CD 46 CD . SENT Find VV this DT article NN onlineKhaitovich NN P NN , , Muetzel NP B NP , , She NN X NN , , Lachmann NP M NP , , Hellmann NP I NP 2004 CD Regional JJ patterns NNS of IN gene NN expression NN in IN human JJ and CC chimpanzee NN brains NNS . SENT Genome NN Res NNS 14 CD . SENT 1462 CD 1473 CD . SENT Find VV this DT article NN onlineEvans NNS SJ NP , , Choudary NP PV NP , , Vawter NP MP NN , , Li NP J NP , , Meador NP Woodruff NP JH NP 2003 CD DNA NN microarray NN analysis NN of IN functionally RB discrete JJ human JJ brain NN regions NNS reveals VVZ divergent JJ transcriptional JJ profiles NNS . SENT Neurobiol NP Dis NP 14 CD . SENT 240 CD 250 CD . SENT Find VV this DT article NN onlineBenjamini NP Y NP , , Hochberg NP Y NP 1995 CD Controlling VVG the DT false JJ discovery NN rate NN . SENT A DT practical JJ and CC powerful JJ approach NN to TO multiple JJ testing NN . SENT J NP R NP Stat NP Soc NP Ser NP B NP 57 CD . SENT 289 CD 300 CD . SENT Find VV this DT article NN onlineUddin NN M NP , , Wildman NP DE NP , , Liu NP G NP , , Xu NP W NP , , Johnson NP RM NP 2004 CD Sister NN grouping NN of IN chimpanzees NNS and CC humans NNS as RB revealed VVD by IN genome NN wide JJ phylogenetic JJ analysis NN of IN brain NN gene NN expression NN profiles NNS . SENT Proc NP Natl NP Acad NP Sci NP U NP S NP A NP 101 CD . SENT 2957 CD 2962 CD . SENT Find VV this DT article NN onlineCaceres NNS M NP , , Lachuer NP J NP , , Zapala NP MA NN , , Redmond NP JC NP , , Kudo NP L NP 2003 CD Elevated VVD gene NN expression NN levels NNS distinguish VV human JJ from IN non JJ human JJ primate NN brains NNS . SENT Proc NP Natl NP Acad NP Sci NP U NP S NP A NP 100 CD . SENT 13030 CD 13035 CD . SENT Find VV this DT article NN onlineSakaki NP Y NP , , Watanabe NP H NP , , Taylor NP T NN , , Hattori NP M NP , , Fujiyama NP A NP 2003 CD Human NP versus CC chimpanzee NN chromosome NN wide JJ sequence NN comparison NN and CC its PP$ evolutionary JJ implication NN . SENT Cold NP Spring NP Harb NP Symp NP Quant NP Biol NP 68 CD . SENT 455 CD 460 CD . SENT Find VV this DT article NN onlineSakamoto NP S NP , , Ishii NP K NP 1999 CD Low NP cerebral JJ glucose NN extraction NN rates NNS in IN the DT human JJ medial JJ temporal JJ cortex NN and CC cerebellum NN . SENT J NP Neurol NP Sci NP 172 CD . SENT 41 CD 48 CD . SENT Find VV this DT article NN onlineBentourkia NN M NP , , Bol NN A NP , , Ivanoiu NP A NP , , Labar NP D NP , , Sibomana NP M NP 2000 CD Comparison NN of IN regional JJ cerebral JJ blood NN flow NN and CC glucose NN metabolism NN in IN the DT normal JJ brain NN . SENT Effect NN of IN aging VVG . SENT J NP Neurol NP Sci NP 181 CD . SENT 19 CD 28 CD . SENT Find VV this DT article NN onlineNoda NP A NP , , Ohba NP H NP , , Kakiuchi NP T NN , , Futatsubashi NP M NP , , Tsukada NP H NP 2002 CD Age NP related JJ changes NNS in IN cerebral JJ blood NN flow NN and CC glucose NN metabolism NN in IN conscious JJ rhesus NN monkeys NNS . SENT Brain NN Res NNS 936 CD . SENT 76 CD 81 CD . SENT Find VV this DT article NN onlineEvans NNS MD NP , , Cooke NP MS NN 2004 CD Factors NNS contributing VVG to TO the DT outcome NN of IN oxidative JJ damage NN to TO nucleic JJ acids NNS . SENT Bioessays NP 26 CD . SENT 533 CD 542 CD . SENT Find VV this DT article NN onlineEnard NP W NP , , Fassbender NP A NP , , Model NP F NP , , Adorjan NP P NN , , P NN bo NP S NP 2004 CD Differences NNS in IN DNA NN methylation NN patterns NNS between IN humans NNS and CC chimpanzees NNS . SENT Curr NP Biol NP 14 CD . SENT R SYM 148 CD R NN 149 CD . SENT Find VV this DT article NN onlinePtak NP SE FW , , Hinds NP DA NP , , Koehler NP K NP , , Nickel NP B NP , , Patil NP N NP 2005 CD Fine NP scale NN recombination NN patterns NNS differ VVP between IN chimpanzees NNS and CC humans NNS . SENT Nat NP Genet NP 37 CD . SENT 429 CD 434 CD . SENT Find VV this DT article NN onlineWinckler NN W NP , , Myers NP SR NN , , Richter NP DJ NP , , Onofrio NP RC NP , , McDonald NP GJ NP 2005 CD Comparison NN of IN fine JJ scale NN recombination NN rates NNS in IN humans NNS and CC chimpanzees NNS . SENT Science NP 308 CD . SENT 107 CD 111 CD . SENT Find VV this DT article NN onlineLee NP CK NP , , Weindruch NP R NP , , Prolla NP TA NP 2000 CD Gene NP expression NN profile NN of IN the DT ageing VVG brain NN in IN mice NNS . SENT Nat NP Genet NP 25 CD . SENT 294 CD 297 CD . SENT Find VV this DT article NN onlineRodwell NP GE NP , , Sonu NP R NP , , Zahn NP JM NP , , Lund NP J NP , , Wilhelmy NP J NP 2004 CD A DT transcriptional JJ profile NN of IN aging VVG in IN the DT human JJ kidney NN . SENT PLoS NP Biology NN 2 CD . SENT e SYM 427 CD . SENT Find VV this DT article NN onlineLi NP JZ NP , , Vawter NP MP NN , , Walsh NP DM NP , , Tomita NP H NP , , Evans NP SJ NP 2004 CD Systematic JJ changes NNS in IN gene NN expression NN in IN postmortem JJ human JJ brains NNS associated VVN with IN tissue NN pH NN and CC terminal JJ medical JJ conditions NNS . SENT Hum NP Mol NP Genet NP 13 CD . SENT 609 CD 616 CD . SENT Find VV this DT article NN onlineTomita NP H NP , , Vawter NP MP NN , , Walsh NP DM NP , , Evans NP SJ NP , , Choudary NP PV NP 2004 CD Effect NN of IN agonal JJ and CC postmortem JJ factors NNS on IN gene NN expression NN profile NN . SENT Quality NN control NN in IN microarray NN analyses NNS of IN postmortem JJ human JJ brain NN . SENT Biol NP Psychiatry NP 55 CD . SENT 346 CD 352 CD . SENT Find VV this DT article NN onlineBolstad NP BM NP , , Irizarry NP RA NP , , Astrand NP M NP , , Speed NN TP NP 2003 CD A DT comparison NN of IN normalization NN methods NNS for IN high JJ density NN oligonucleotide NN array NN data NNS based VVN on IN bias NN and CC variance NN . SENT Bioinformatics NP 19 CD . SENT 185 CD 193 CD . SENT Find VV this DT article NN onlineTopIntroductionResultsDiscussionMaterials NNS and CC MethodsSupporting NP InformationAcknowledgmentsReferences NP PLoS NP Biology NN is VBZ an DT open JJ access NN journal NN published VVN by IN the DT nonprofit JJ organization NN Public JJ Library NN of IN Science NP . SENT All DT journal NN content NN , , except IN where WRB otherwise RB noted VVN , , is VBZ licensed VVN under IN a DT Creative JJ Commons NP Attribution NN License NN . SENT