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Cea seescece as fomay descied moe thafo decades ago he Hayfick ad coeages shoedthat oma ces had a imited aiity to oifeate icte1(see BOX 1 fo descitios of diffeet tyesof seescece). These cassic exeimets shoed thathma fioasts iitiay deet ost ce diisioi cte. Hoee, gaday oe may ce do-igs ce oifeatio (sed hee itechageayith ce goth) decied. Eetay, a ces i thecte ost the aiity to diide. The o-diidig cesemaied iae fo may eeks, t faied to godesite the esece of ame sace, tiets adgoth factos i the medim.

Soo afte this discoey, the fidig that omaces do ot idefiitey oifeate saed toimotat hyotheses. At the time, oth ee highysecatie ad seemigy cotadictoy. The fisthyothesis stemmed fom the fact that may caceces oifeate idefiitey i cte. Cea sees-cece as oosed to e a ati-cace o tmo-sessie mechaism. I this cotext, the seesceceesose as cosideed eeficia ecase it otected

ogaisms fom cace, a majo ife-theateig disease.The secod hyothesis stemmed fom the fact thattisse egeeatio ad eai deteioate ith age.Cea seescece as oosed to ecaitate theageig, o oss of egeeatie caacity, of ces in vivo.I this cotext, cea seescece as cosideeddeeteios ecase it cotited to decemets itisse eea ad fctio. Fo may yeas, thesehyotheses ee sed moe o ess ideed-ety. Hoee, as a destadig of the seesceceesose ge, these hyotheses coaesced, igige isights to the fieds of cace ad ageig. Hee,e eie ecet ogess i destadig the cases

of cea seescece, ad the eidece that it is imo-tat fo sessig cace ad a ossie cotitoto ageig.

Senescence in an evolutionary context

To destad ho cea seescece ca e oth ee-ficia ad detimeta, ad the oigis of its egatio,it is imotat to destad the ate of cace adthe eotioay theoy of ageig. Cace is ofte fataad theefoe oses a majo chaege to the ogeityof ogaisms ith rnwabl tiu. Tisse eea isessetia fo the iaiity of comex ogaisms schas mammas. Hoee, ce oifeatio is essetiafo tmoigeesis, ad eeae tisses ae at isk ofdeeoig cace2. Moeoe, cace iitiates ad, toa age extet, ogesses oig to somatic mtatios3,ad oifeatig ces acqie mtatios moe eadiytha o-diidig ces4. The dage that cace osedto ogeity as mitigated y the eotio of tmo-sesso mechaisms. Oe sch mechaism ascea seescece, hich stos iciiet cace cesfom oifeatig57.

The eiomet i hich cea seesceceeoed as eete ith extisic hazads sch asifectio, edatio ad staatio. Hece, ogaismaifesas ee eatiey shot oig to death fomthese hazads. Theefoe, tmo-sesso mecha-isms eeded to e effectie fo oy a eatiey shotitea (a fe decades fo hmas, seea mothsfo mice). Shod sch mechaisms e deeteiosate (fo exame, if the egeeatie caacity eeto decie o if dysfctioa seescet ces ee toaccmate), thee od e itte seectie esseto eimiate the hamf effects. Theefoe, sometmo-sesso mechaisms ca e oth eeficia

*Life Sciences Division,

Lawrence Berkeley

National Laboratory,

1 Cyclotron Road, Berkeley,California 94720, USA;

and Buck Institute for

Age Research, 8001

Redwood Boulevard, Novato,

California 94945, USA.IFOM Foundation,

FIRC Institute of Molecular

Oncology, Via Adamello 16,

20139 Milan, Italy.

e-mails:[email protected];

fabrizio.dadda@ifom-ieo-

campus.it

doi:10.1038/nrm2233

Publihd onlin

1 Augut 2007

Renewable tissue

A tiu in which cll

prolifration i important for

tiu rpair or rgnration.

Rnwabl tiu typically

contain, but omtim rcruit,

mitotic cll upon injury or cll

lo.

Cellular senescence: when bad thingshappen to good cells

Judith Campisi* and Fabrizio dAdda di Fagagna

Abstract | Cells continually experience stress and damage from exogenous and endogenous

sources, and their responses range from complete recovery to cell death. Proliferating cells

can initiate an additional response by adopting a state of permanent cell-cycle arrest that is

termed cellular senescence. Understanding the causes and consequences of cellular

senescence has provided novel insights into how cells react to stress, especially genotoxicstress, and how this cellular response can affect complex organismal processes such as the

development of cancer and ageing.

nATurE rEvIEwS |molecular cell biology vOluME 8 | SEpTEMbEr 2007 |729

REVIEWS
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Antagonistic pleiotropy

Th hypothi that gn or

proc that wr lctd

to bnfit th halth and

fitn of young organim can

hav unlctd dltriou

ffct that manift in oldr

organim and thrby

contribut to aging.

Mitotic cell

A cll that ha th ability to

prolifrat. In vivo, mitotic cll

oftn xit in a rvribl

growth-arrtd tat that i

trmd quicnc or G0

pha, but uch cll can b

timulatd to prolifrat in

rpon to appropriat

phyiological ignal.

Post-mitotic cell

A cll that ha prmanntly

lot th ability to prolifrat,

uually du to diffrntiation.

ad deeteios, deedig o the age of the oga-ism8. This cocet that a ocess ca e eeficiato yog ogaisms t hamf to od ogaisms isthe essece ofantagonitic pliotropy, a imotat eo-tioay theoy of ageig9. Thee is o sstatiaeidece that cea seescece is ideed a otettmo-sesso mechaism6,7,10,11, ad thee is asomotig t sti agey cicmstatia eidece

that cea seescece omotes ageig1214.

Characteristics of senescent cells

Comex ogaisms sch as mammas cotai othmitotic cll ad pot-mitotic cll(BOX 2). Cea sees-cece is cofied to mitotic ces, fom hich cace caaise. Athogh mitotic ces ca oifeate, they ca asosed og iteas i a eesiy aested state temedquicnc o G0. Qiescet ces esme oifeatio iesose to aoiate sigas, icdig the eed fotisse eai o egeeatio. by cotast, ost-mitoticces emaety ose the aiity to diide oig todiffeetiatio.

Mitotic ces ca seesce he they ecote ote-tiay ocogeic eets (discssed eo). whe thisoccs, the ces cease oifeatio (ko as gothaest), i essece ieesiy. They ofte ecome esis-tat to ce-death sigas (aotosis esistace) ad theyacqie idesead chages i gee exessio (ateedgee exessio). Togethe, these feates comise thencnt phnotyp(FIG. 1).

Growth arrest. The hamak of cea seescece is aiaiity to ogess thogh the ce cyce. Seescet cesaest goth, say ith a DnA cotet that is tyicaof G1 hase, yet they emai metaoicay actie1518.Oce aested, they fai to iitiate DnA eicatio desiteadeqate goth coditios. This eicatio faie isimaiy cased y the exessio of domiat ce-cyce ihiitos (see eo). I cotast to qiescece,the seescece goth aest is essetiay emaet(i the asece of exeimeta maiatio) ecaseseescet ces caot e stimated to oifeate yko hysioogica stimi.

The feates ad stigecy of the seescece gothaest ay deedig o the secies ad the geeticackgod of the ce. Fo exame, most mose fio-asts seesce ith a G1 DnA cotet, athogh a defecti the stess-sigaig kiase MKK7 imaiy idcesa G2M aest19. likeise, some oncogn (see eo)case a factio of ces to seesce ith aDnA cotetthat is tyica of G2 hase2022. Fthemoe, tmo cesca seesce ith G2- o S-hase DnA cotets. Athoghtmo ces say oifeate idefiitey i cte,some of them etai the aiity to dego a seescece-ike aest, eseciay i esose to cetai ati-cacetheaies23. Fiay, hma ad odet ces diffe stik-igy i the stigecy of the seescece goth aest24.like hma ces, may mose ad at ces hae a fiiteoifeatie caacity i cte, athogh, as discssedeo, the mechaisms that imit this oifeatiooay diffe. Hoee, odet ce ctes feqetyacqie sotaeos aiats that ca diide idefiitey.Sch aiats ae exceedigy ae i hma ctes.

Apoptosis resistance. Aotosis etais the cotoeddestctio of cea costitets ad thei timateegfmet y othe ces25. like seescece, aotosis isa exteme esose to cea stess ad is a imotattmo-sessie mechaism26. bt, heeas sees-cece eets the goth of damaged o stessed ces,

aotosis qicky eimiates them.May (t ot a) ce tyes acqie esistace to

cetai aototic sigas he they ecome seescet.Fo exame, seescet hma fioasts esist ceamide-idced aotosis t edotheia ces do ot27. Seescethma fioasts aso esist aotosis cased y goth-facto deiatio ad oxidatie stess, t do ot esistaotosis cased y egagemet of the Fas death ece-to28,29. resistace to aotosis might aty exai hyseescet ces ae so stae i cte. This attitemight aso exai hy the me of seescet cesiceases ith age, athogh, as discssed eo, seeafactos oay cotite to this heomeo.

Box 1 | A hitchhikers guide to senescence nomenclature

Senescence derives from senex, a Latin word meaning old man or old age.

In organismal biology, senescence describes deteriorative processes that follow

development and maturation, and the term is used interchangeably with ageing.

The term senescence was applied to cells that ceased to divide in culture1, based on

the speculation that their behaviour recapitulated organismal ageing. Consequently,

cellular senescence is sometimes termed cellular ageing or replicative senescence.

Cells that are not senescent are termed pre-senescent, early passage, proliferating or,

sometimes, young.

Telomere shortening provided the first molecular explanation for why many cells

cease to divide in culture61,68. Dysfunctional telomeres trigger senescence through

the p53 pathway. This response is often termed telomere-initiated cellular

senescence.

Some cells undergo replicative senescence independently of telomere

shortening16,53,101. This senescence is due to stress, the nature of which is poorly

understood. It increases p16 expression and engages the p16retinoblastoma protein

(pRB) pathway. This response is termed stress-induced or premature senescence,

stasis or M0 (mortality phase 0).

Certain mitogenic oncogenes or the loss of anti-mitogenic tumour-suppressor genes

induce senescence in normal cells83,92,93,95. This is known as oncogene-induced

senescence.

Cells that do not divide indefinitely are said to have a finite or limited replicative

(or proliferative) lifespan and are (replicatively) mortal. Cells that proliferate

indefinitely are termed (replicatively) immortal.

Immortal cells are not necessarily transformed (tumorigenic) cells. Although

historically the terms immortalization and transformation have been used

interchangeably, the replicative lifespan of cells can be expanded indefinitely by the

expression of telomerase without the phenotypic changes that are associated with

malignant transformation138.

Telomere-initiated senescence is sometimes termed M1 (mortality phase 1)153.

Some cells (for example, fibroblasts) undergo telomere-initiated senescence with few

signs of genomic instability. Other cells (for example, some epithelial cells) arrest with

obvious signs of genomic instability and are termed agonescent154.

Human cells that escape telomere-initiated senescence (M1) or agonescence owing

to the loss of p53 function can proliferate until they enter a state that is termed crisis,

mitotic catastrophe or M2 (mortality phase 2)153. This state is characterized by

extensive genomic instability and cell death.

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Quiescence

A rvribl non-dividing tat

from which cll can b

timulatd to prolifrat in

rpon to phyiological

ignal.

Senescent phenotype

Th combination of chang in

cll bhaviour, tructur and

function that occur upon

cllular ncnc. For mot

cll typ, th chang

includ an ntially

irrvribl growth arrt,

ritanc to apoptoi and

many altration in gn

xprion.

Oncogene

A gn that contribut to th

malignant tranformation of

cll. Oncogn can b

cllular or viral in origin.

Cllular oncogn ar uuallymutant or ovrxprd form

of normal cllular gn. Viral

oncogn can alo originat

from cllular gn, acquiring

mutation during viral captur,

but thy can alo b ditinctly

viral in origin.

Chromatin

Th DNA and complx of

aociatd protin that

dtrmin th accibility of

larg DNA rgion to th

trancription machinry and

othr larg protin complx.

It is ot cea hat detemies hethe ces degoseescece o aotosis. Oe detemiat is ce tye; foexame, damaged fioasts ad eitheia ces ted toseesce, heeas damaged ymhocytes ted to degoaotosis. The ate ad itesity of the damage ostess may aso e imotat30,31. Most ces ae caaeof oth esoses. Moeoe, maiatio of o- adati-aototic oteis ca case ces that ae destiedto die y aotosis to seesce ad, coesey, case cesthat ae destied to seesce to dego aotosis3032.The seescece ad aotosis egatoy systems thee-foe commicate oay thogh thei commoegato, the 53 tmo sesso otei31. Themechaisms y hich seescet ces esist aotosis aeooy destood. I some ces, esistace might e deto exessio chages i oteis that ihiit, omote oimemet aototic ce death33,34. I othes, 53 mightefeetiay tasactiate gees that aest oifeatio,athe tha those that faciitate aotosis35.

Altered gene expression. Seescet ces sho stikigchages i gee exessio, icdig chages i koce-cyce ihiitos o actiatos3541. To ce-cyceihiitos that ae ofte exessed y seescet ces aethe cyci-deedet kiase ihiitos (CDKIs) 21

(aso temed CDKn1a, 21Ci1, waf1 o SDI1) ad16(aso temed CDKn2a o 16InK4a)6,7. These CDKIsae comoets of tmo-sesso athays that aegoeed y the 53 ad etioastoma (rb) oteis,esectiey. 53 ad rb ae tascitioa egatos,ad the athays they goe ae feqety distedi cace42. both athays ca estaish ad maitaithe goth aest that is tyica of seescece. 21 isidced diecty y 53 (ReFs 35,43) t the mechaismsthat idce 16, a tmo sesso i its o ight, aeicometey destood44. utimatey, 21 ad 16 mai-tai rb i a hyohoshoyated ad actie state t, asdiscssed eo, thei actiities ae ot eqiaet.

Seescet ces aso eess gees that ecode oteisthat stimate o faciitate ce-cyce ogessio (foexame, eicatio-deedet histoes, c-FOS, cyci A,cyci b ad pCnA (oifeatig ce cea ati-ge))4548. Some of these gees ae eessed ecaseE2F,the tascitio facto that idces them, is iactiatedy rb. I some seescet ces, E2F taget gees aesieced y a rb-deedet eogaizatio ofchromatinito discete foci that ae temed seescece-associatedheteochomati foci (SAHFs)45.

Iteestigy, may chages i gee exessioaea to e eated to the goth aest. Mayseescet ces oeexess gees that ecode secetedoteis that ca ate the tisse micoeiomet3641.Fo exame, seescet fioasts oeexess oteisthat emode the extacea matix o mediate ocaifammatio. As discssed eo, these fidigs aisethe ossiiity that as seescet ces icease ith age,they might cotite to age-eated decemets itisse stcte ad fctio8,12. The mechaisms thatae esosie fo the seescece-associated secetoy

heotye ae ko.

Senescence markers. Seea makes ca idetify sees-cet ces i cte ad in vivo. Hoee, o makesae excsie to the seescet state. A ooy destoodfeate of these makes is that, aside fom the deciei DnA eicatio, a of them eqie seea daysto deeo.

A oios make fo seescet ces is the ackof DnA eicatio, hich is tyicay detected y theicooatio of 5-omodeoxyidie o 3H-thymidie,o y immostaiig fo oteis sch as pCnA adKi-67. Of cose, these makes do ot distigishetee seescet ces ad qiescet o diffeetiatedost-mitotic ces. The fist make to e sed fo themoe secific idetificatio of seescet ces as theseescece-associated -gaactosidase (SA-ga)49. Thismake is detectae y histochemica staiig i mostseescet ces. Hoee, it is aso idced y stessessch as ooged cofece i cte. The SA-gaoay deies fom the ysosoma -gaactosidasead efects the iceased ysosoma iogeesis thatcommoy occs i seescet ces50. I additio, 16 a imotat egato of seescece is o sedto idetify seescet ces51. 16 is exessed y may,t ot a, seescet ces52,53 ad it is aso exessedy some tmo ces, eseciay those that hae ost

rb fctio44. recety, thee oteis ee ideti-fied i a scee fo gees that ee exessed fooigocogee-idced seescece, ad the oteis eesseqety sed to idetify seescet ces: DEC1(diffeetiated emyo-chodocyte exessed-1),15 (a CDKI) ad DCr2 (decoy death eceto-2)54.The secificity ad sigificace of these oteis foseescet ces ae ot yet cea, t they ae omisigadditioa makes.

Some seescet ces ca aso e idetified ythe cytoogica makes of SAHFs45 ad seescece-associated DnA-damage foci (SDFs)16,20,55,56. SAHFs aedetected y the efeetia idig of DnA dyes, sch as

Box 2 | Mitotic and post-mitotic cells

Mitotic cells are capable of proliferation, and they include the epithelial, stromal

(fibroblastic) and vascular (endothelial) cells that comprise the major renewable tissues

and organs such as the skin, intestines, liver, kidney and so on. They also comprise major

components of the haematopoietic system, and cells such as the glia, which support

the survival and function of non-dividing neurons. Mitotic cells also include the

undifferentiated stem and progenitor cells that provide many of these tissues with the

differentiated cells that are required for their function. Mitotic cells are susceptible tomalignant transformation (that is, transformation into a cancer cell). They are also

susceptible to undergoing cellular senescence when challenged by stimuli that have

the potential to cause cancer.

Post-mitotic cells are incapable of proliferation. They include the differentiated

neurons and muscle cells that comprise the brain, heart and skeletal muscle. Recent

findings suggest that tissues that are composed mainly of post-mitotic cells can

undergo limited repair and regeneration; however, this regeneration is not due to the

proliferation of post-mitotic cells, but rather to the recruitment of mitotic stem cells or

their progeny (progenitor cells)155157. Because they have already lost the ability to

proliferate, post-mitotic cells do notundergo cellular senescence as currently defined.

Post-mitotic and senescent cells are irreversibly blocked from re-entering the cell

cycle. The mechanisms that prevent these cells from undergoing cell division are

incompletely understood, but probably share some common effectors.

R E V I E W S

http://www.expasy.org/uniprot/P04637http://www.expasy.org/uniprot/P38936http://www.expasy.org/uniprot/P42771http://www.expasy.org/uniprot/P06400http://www.expasy.org/uniprot/Q01094http://www.expasy.org/uniprot/Q01094http://www.expasy.org/uniprot/Q01094http://www.expasy.org/uniprot/P06400http://www.expasy.org/uniprot/P42771http://www.expasy.org/uniprot/P38936http://www.expasy.org/uniprot/P04637

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Pre-senescent cell

Senescent phenotype

Strong mitogenicsignals

Chromatin perturbationsand other non-genotoxicstresses

Dysfunctionaltelomeres

Non-telomericDNA damage

Growth arrest

Apoptosisresistance

Altered geneexpression

4,6-diamidio-2-heyidoe (DApI), ad the eseceof cetai heteochomati-associated histoe modifica-tios (fo exame, H3 lys9 methyatio) ad oteis(fo exame, heteochomati otei-1 (Hp1)). SAHFsaso cotai E2F taget gees, hich SAHFs ae thoghtto siece. I mose ces, eicetomeic chomatiaso efeetiay ids DApI, cotais modifiedhistoes ad oteis fod i SAHFs, ad foms cyto-ogicay detectae foci. Hoee, thee is o eidecethat these foci cotai E2F taget gees; ideed, they aeaso eset i oifeatig ces. becase eiceto-meic foci ae mch moe omiet i mose ces thahma ces57,58, they ca e mistake fo SAHFs. SDFs,

y cotast, ae eset i seescet ces fom mice adhmas ad cotai oteis that ae associated ithDnA damage (fo exame, hoshoyated histoeH2AX (-H2AX) ad 53-idig otei-1 (53bp1)).As discssed eo, these foci est fom dysfctioateomees ad othe soces of DnA damage.

Causes of cellular senescence

what cases ces to seesce? The fist ces came fomdestadig hy oma hma ces do ot o-ifeate idefiitey i cte (BOX 1), t sseqetstdies shoed that seescece ca e idced ymay stimi (FIG. 1).

Telomere-dependent senescence. Teomees ae stetchesof eetitie DnA (5-TTAGGG-3 i eteates) adassociated oteis that ca the eds of iea chomo-somes ad otect them fom degadatio o fsio yDnA-eai ocesses59. The ecise teomeic stcte isot ko, t mammaia teomees ae thoght to edi a age cica stcte, temed a t-oo60. becasestadad DnA oymeases caot cometey eicateDnA eds a heomeo caed the ed-eicatiooem ces ose 50200 ase ais of teomeic DnAdig each S hase61(FIG. 2). Hma teomees agefom a fe kioases to 1015 ki egth, so may cediisios ae ossie efoe the ed-eicatio oemedes teomees citicay shot ad dysfctioa. Oyoe o a fe sch teomees ae sfficiet to tigge sees-cece62,63. The ed-eicatio oem is a majo (tot the soe) easo hy oma ces do ot oifeateidefiitey(BOX 1).

Dysfctioa teomees tigge a cassica DnA-damage esose (DDr)16,55,56,64(FIG. 3). The DDr eaesces to sese damaged DnA, aticay doe-stad

eaks (DSbs), ad to esod y aestig ce-cyce o-gessio ad eaiig the damage if ossie. Athoghthe seeity of the damage is oay a imotat facto,itte is ko aot ho ces choose etee tasietDDr actiatio ad the esistet DDr sigaig that iseidet i may seescet ces. May oteis atici-ate i the DDr, icdig otei kiases (fo exame,ataxia teagiectasia mtated (ATM) ad checkoit-2(CHK2)), adato oteis (fo exame, 53bp1 adMDC1 (mediato of DnA damage checkoit otei-1))ad chomati modifies (fo exame, -H2AX). Mayof these oteis ocaize to the DnA-damage foci that aedetected i seescet ces. I ces that seesce oig todysfctioa teomees, these foci aso cotai a ssetof teomees, sggestig that dysfctioa teomeeseseme DSbs.

The ed-eicatio oem ca e cicmetedy teomease. This ezyme cotais a cataytic oteicomoet (teomease eese tascitase; TErT) ada temate rnA comoet, ad adds teomeic DnAeeats diecty to chomosome eds65. Most omaces do ot exess TErT, o exess it at ees that aetoo o to eet teomee shoteig66,67. by cotast,gem-ie ces ad may cace ces exess TErT.Moeoe, ectoic TErT exessio i oma hmaces simtaeosy eets teomee shoteig adseescece cased y the ed-eicatio oem68.

Hoee, teomease caot eet seescece casedy o-teomeic DnA damage o othe seesceceidces69.

This oit is demostated y the ehaio of maymose ces. I cotast to most hma ces, ces fomaoatoy mice hae og teomees (>20 k) ad mayexess teomease. noetheess, may mose cesseesce afte oy a fe doigs de stadad ctecoditios. This aest is de to the sahysioogicaoxyge ee (20%) that is sed i stadad cteotocos. A 20% oxyge ee, to hich mose ces aemch moe sesitie tha hma ces, cases seeeDnA damage ad, i the asece of efficiet eai

Figure 1 | T snsnt pntp ndd tp

st. Mitotically competent cells respond to various

stressors by undergoing cellular senescence. These

stressors include dysfunctional telomeres, non-telomeric

DNA damage, excessive mitogenic signals including those

produced by oncogenes (which also cause DNA damage),

non-genotoxic stress such as perturbations to chromatinorganization and, probably, stresses with an as-yet-

unknown etiology. The senescence response causes

striking changes in cellular phenotype. These changes

include an essentially permanent arrest of cell

proliferation, development of resistance to apoptosis

(in some cells), and an altered pattern of gene expression.

The expression or appearance of senescence-associated

markers such as senescence-associated -galactosidase,p16, senescence-associated DNA-damage foci (SDFs) and

senescence-associated heterochromatin foci (SAHFs) are

neither universal nor exclusive to the senescent state and

therefore are not shown.

R E V I E W S

http://www.expasy.org/uniprot/Q13315http://www.expasy.org/uniprot/O96017http://www.expasy.org/uniprot/O96017http://www.expasy.org/uniprot/Q13315

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Telomerelength

Normal somatic cells(telomerase-negative)

Chromosome

Telomeric DNA

Germline cells,cancer cells(telomerase-positive)

Normal cells +

telomerase,cancer cells

Cell division

Senescence

Euchromatin

Chromatin that i in an opn

conformation and hnc

accibl. Alo trmd activ

chromatin.

Heterochromatin

Chromatin that i in a clod

conformation and hnc

inaccibl. Alo trmd ilnt

or inactiv chromatin.

Chromatin probably xit in

many form btwn th

xtrm of uchromatin and

htrochromatin.

mechaisms, DSbs. both the damage ad eicatiefaie ae mitigated y ctig mose ces at a (oe)hysioogica oxyge ee70.

DNA-damage-initiated senescence. Seee DnA damagethat occs ayhee i the geome eseciay damagethat ceates DSbs cases may ce tyes to degoseescece15,70. I cte, sch ces hao SDFs fomay eeks o oge (J.C. ad F.dA.d.F., ishedoseatios). Thee is as yet o fim eidece that theseesistet foci cotai ieaae DSbs. whatee theiate, they may oide costittie sigas to 53 tomaitai the seescece goth aest.

both damage- ad teomee-iitiated seescece

deed stogy o 53 ad ae say accomaiedy exessio of 21 (ReFs 15,16,55)(FIG. 4). Hoee,i may ces, DnA damage ad dysfctioa teo-mees aso idce 16, aeit ith deayed kietics.16,the, oides a secod aie to eet the gothof ces ith seeey damaged DnA o dysfctioateomees52,71,72.

May chemotheaetic dgs case seee DnAdamage. As exected, sch dgs idce seescece ioma ces. Sisigy, they aso idce seescecei some tmo ces, oth i cte ad in vivo73.Tmo ces ith id-tye, as oosed to mtat, 53ae moe ikey to seesce i esose to chemotheay, at

east i ce cte ad cace-oe mose modes7476,cosistet ith a iota oe fo 53 i damage-idcedseescece. Of actica imotace, DnA-damagigtheaies ae moe ikey to e efficacios i tmosthat seesce, comaed ith those that do ot7376.

Senescence caused by chromatin perturbation. Thechomati state detemies the extet to hich geesae actie (uchromatin) o siet (htrochromatin), addeeds maiy o histoe modificatios (fo exame,acetyatio ad methyatio). Iteestigy, chemicahistoe deacetyase ihiitio (HDAi), hich omotesechomati fomatio, idces seescece17,77. Themechaism y hich this occs is ooy destood,ad may diffe deedig o the secies ad ce tye.Fo exame, i hma fioasts, HDAi seqetiayidces 21 ad 16 exessio, ad the seescecegoth aest citicay deeds o the esece of rb.by cotast, i mose fioasts, the 53 athay ismoe imotat fo the seescece esose to HDAi(ReF. 77). becase HDAi ca idce ATM kiase actiity78,

HDAi might case seescece i some ces y iitiatiga 53-deedet DDr.

The fidig that HDAi cases seescece aeasto cofict ith the oe of heteochomati ad SAHFsi estaishig ad maitaiig the seescet gothaest45. likeise, HDAi-idced seescece seems toe i cofict ith the fidig that doegatio of ahistoe acety tasfease, hich omotes heteochom-ati fomatio, idces seescece79. It is ot ko hoseescece ca e tiggeed oth y heteochomatidistio ad y actiities that ae associated ithheteochomati fomatio. both maiatios caseextesie t icomete chages i chomati oga-izatio, so each may ate the exessio of diffeetcitica gees, ad the esose may e ce-tye secific.udestadig this aadox cod e imotat, ecaseHDAi hods omise fo teatig cetai caces80.

Oncogene-induced senescence. Ocogees ae mtatesios of oma gees that hae the otetia to tas-fom ces i cojctio ith additioa mtatios.noma ces esod to may ocogees y degoigseescece. This heomeo as fist oseed hea ocogeic fom of rAS, a cytoasmic tasdceof mitogeic sigas, as exessed i oma hmafioasts18. Sseqety, othe memes of the rASsigaig athay (fo exame, rAF, MEK, MOS ad

brAF), as e as o-oifeatie cea oteis (foexame, E2F-1), ee sho to case seescece heoeexessed o exessed as ocogeic esios22,8183.

becase ocogees that idce seescece stimatece goth, the seescece esose may coteactexcessie mitogeic stimatio, hich ts ces at isk ofocogeic tasfomatio. This idea is soted y thefidig that mose ces that ae cted i sem-feemedim (hich edces the high mitogeic esse ofsem) esist rAS-idced seescece84. likeise, someodet ces do ot eicatiey seesce (BOX 1) i sem-fee medim, hich sggests that excessie mitogeicstimatio is esosie fo thei seescece85,86.

Figure 2 | T-dpndnt snsn. Telomeres are stretches of a repetitiveDNA sequence and associated proteins (magenta) that are located at the termini of

linear chromosomes (blue). The telomeric ends form a circular protective cap termed the

t-loop, which may help to prevent the termini from triggering a full DNA-damage

response (DDR). Telomere lengths are maintained by the enzyme telomerase, which is

expressed by cells that comprise the germline as well as many cancer cells. Most normal

somatic cells do not express this enzyme, or express it only transiently or at levels that are

too low to prevent telomere shortening caused by the end-replication problem. In such

cells, telomere lengths decline with each cell cycle. Eventually, one or a few telomeres

become sufficiently short and malfunction, presumably owing to loss of the protective

proteinDNA structure. Dysfunctional telomeres trigger a DDR, to which cells respond

by undergoing senescence.

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DNA-damagesensors

Upstream kinases

Downstream kinases

DNA-damagemediators(adaptors)

Effectors

Transient cell-cycle arrest Apoptosis Senescence

RFC2H2AX

P

H2AXP

NBS1RAD50 RPA

ATM

MDC1 53BP1

CHK2 CHK1

SMC1CDC25

BRCA1 Claspin

ATR

HUS1

MRE11

RAD17

RAD1RA

D9

RFC3RFC4

RFC5

p53

Is ocogee-idced seescece distict fomchomati o teomee/damage-idced seescece?pehas ot; fo exame, ocogeic rAS idces 16ad the fomatio of SAHFs45,87,88. Moeoe, athogh

ocogee-idced seescece does ot etai teomeeshoteig, may ocogees idce a ost DDroig to the DnA damage that is cased y aeatDnA eicatio. This DDr has a casa oe i oth theiitiatio ad maiteace of ocogee-idced sees-cece ecase its exeimeta doegatio eetsseescece, aos ce oifeatio ad edisoses cesto ocogeic tasfomatio20,89.

Ocogee-idced seescece as fist idetifiedi cted ces ad does ot occ i a ces 90,91, so isit hysioogicay eeat? recet fidigs sho thatocogees eicit a seescece esose that ctais thedeeomet of cace83,9295. I mice, stog mitogeic

sigas that ae cased y actiated ocogees, o oss ofthe tmo sesso otei pTEn (hich damesmitogeic sigas), case eig esios that cosist ofseescet ces. likeise, eig aei i hma skicotai ces that exess ocogeic brAF ad aeseescet. These fidigs sggest that ocogee-idcedseescece occs ad sesses tmoigeesis in vivo.Tmoigeesis eqies additioa mtatios otayi 53 o 16 that eet o ehas eese theseescece goth aest92,93,95.

Stress and other inducers of senescence. Sstaied sig-aig y cetai ati-oifeatie cytokies, sch asitefeo-, aso cases seescece. Acte itefeo-stimatio eesiy aests ce goth, t choicstimatio iceases itacea oxyge adicas adeicits a 53-deedet DDr ad seescece96. likeise,choic sigaig y tasfomig goth facto-,a ihiito of eitheia ce oifeatio, idces sees-cece y omotig 16rb-deedet heteochomatifomatio97,98.

Fiay, the oosey defied heomeo efeedto as ce-cte stess, o cte shock, ca idce16-deedet, teomee-ideedet seescece. Foexame, hma keatiocytes ad mammay eitheiaces sotaeosy exess 16 ad seesce ith ogteomees de stadad cte coditios. This doesot occ he the ces ae cted o feede ayes(as of fioasts), t afte may doigs ofeede ayes, the ces eetay dego teomee-deedet seescece99. These fidigs sggest that,i additio to hyehysioogica goth coditios,iadeqate goth coditios aso idce seescece.

Some ces ack a 16-deedet seescece esoseecase the gee ecodig 16 is sieced, ofte y DnAmethyatio100,101. May hma ce ctes, icdigfioasts, ae heteogeeos ad eicatiey seesceas mosaics; some ces seesce de to the exessio of16 ad othes seesce de to teomee shoteig ada 53-deedet DDr16,52,53. The stimi that idce 16ae ooy destood. I some ces, oxidatie stessidces 16 (ReFs 70,102), t this is ot aays the case53.Ocogeic rAS ca idce 16 y hoshoyatig adactiatig ETS tascitio factos87, t exessioof 16 is cotoed y mtie factos, icdig thechomati state44,77,103.

The exessio of 16 ad a oss of 16 idciiityaso occ in vivo. Exessio of 16 iceases ith age

i may mie tisses51,104, ad as ecety sho toicease i mie haematooietic, eoa ad ace-atic stem o ogeito ces in vivo105107. This exessioeets stem-ce oifeatio, ossiy y idcigseescece. Moeoe, hma mammay eitheia cessotaeosy siece 16 ia omote methyatioin vivo108 sch that, as i cte, the adt east eitheiacomatmet is mosaic fo the exessio of 16.

Control by the p53 and p16pRB pathways

The seescece goth aest is estaished ad mai-taied y the 53 ad 16rb tmo sessoathays (FIG. 4). These athays iteact t ca

Figure 3 | T DNa-d spns. DNA damage in the form of DNA double-strand

breaks and other DNA discontinuities is thought to be sensed by a host of factors such as

replication protein A (RPA) and replication factor C (RFC)-like complexes (which contain

the cell-cycle-checkpoint protein RAD17). These complexes recruit the 911 complex

(RAD9HUS1RAD1). Damage is also sensed by the MRN complex (MRE11RAD50

NBS1). Detection of DNA damage then leads to the activation of upstream protein

kinases such as ataxia telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR),

which trigger immediate events such as phosphorylation of the histone variant H2AX.

The modified chromatin recruits multiple proteins. Some of these proteins augment

signalling by the upstream kinases, participate in transducing the damage signal and

optimize repair activities by other proteins, the identity of which depends on the nature

of the damage and position in the cell cycle (for example, the DNA end-stabilizing

heterodimers Ku70/80, DNA ligases such as ligase IV, exonucleases such as MRE11,

DNA helicases such as BLM). Several adaptor proteins, including MDC1, 53BP1, BRCA1

and claspin, orchestrate the orderly recruitment of DNA-damage response proteins, as

well as the function of downstream kinases such as checkpoint-1 (CHK1) and CHK2,

which propagate the damage signal to effector molecules such as SMC1, CDC25 and

the tumour suppressor p53. The effector molecules halt cell-cycle progression, either

transiently or permanently (senescence), or trigger cell death (apoptosis). 53BP1, p53-

binding protein-1; BRCA1, breast cancer type-1 susceptibility protein; HUS1,

hydroxyurea-sensitive-1 protein; MDC1, mediator of DNA damage checkpoint protein-1;

MRE11, meiotic recombination-11 protein; NBS1, Nijmegen breakage syndrome-1

protein; SMC1, structural maintenance of chromosomes protein-1.

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Senescencegrowth arrest

Senescence signals

ARF

HDM2

p21

p53

p16

CDKs

E2F

pRB

Cellproliferation

ideedety hat ce-cyce ogessio. To someextet, they aso esod to diffeet stimi. I additio,thee ae oth ce-tye-secific ad secies-secificdiffeeces i the oesity ith hich ces egage oeo the othe athay, ad i the aiity of each ath-ay to idce seescece. Fiay, athogh most cesseesce oig to egagemet of the 53 athay, 16rb athay, o oth, thee ae exames of seescecethat aea to e ideedet of these athays21,83.These exames aise the ossiiity of a 53- ad16rb-ideedet seescece athay(s).

The p53 pathway. Stimi that geeate a DDr (foexame, ioizig adiatio ad teomee dysfctio)idce seescece imaiy thogh the 53 athay.This athay is egated at mtie oits y oteissch as the E3 iqiti-otei igase HDM2 (MDM2i mice), hich faciitates 53 degadatio, ad theateate-eadig-fame otei (ArF), hich ihiitsHDM2 actiity42. 21 is a ccia tascitioa tagetof 53 ad mediato of 53-deedet seescece109.

Hoee, 21 aso mediates a tasiet DnA-damage-idced goth aest. So hat detemies hethe cesseesce o aest tasiety? The ase is cetyko. Oe ossiiity is that aid DnA eaiqicky temiates 5321 sigaig, heeas so,icomete o faty eai ests i sstaied siga-ig ad seescece. whatee the case, exeimetaedctio i 53, 21 o DDr oteis (fo exame,ATM o CHK2) eets teomee- o damage-idcedseescece, ad, i some ces (fo exame, those thatexess itte o o 16 o ocogeic rAS), it ca eeeese the seescece goth aest20,52,55,64,109,110. Theoifeatio of damaged ces ith a edced DDr o53 fctio ofte caot e sstaied, hoee, ecaseteomees eetay ecome seeey eoded, eadig toa state of extesie geomic istaiity ad ce death thatis temed cisis o mitotic catastohe (BOX 1). rae mta-tioa o eigeetic eets ca actiate TErT exessioo ecomiatio mechaisms to eogate teomees111.Sch ces ae at a high isk of maigat tasfomatioecase they ca eicate idefiitey ad hao mta-tios ad chomosoma aomaities.

The DDr ad 53 athay oide a fist ie ofdefece agaist cace y eetig the goth of cesith seeey damaged DnA, hich ae at isk of deeo-ig ad oagatig ocogeic mtatios112,113. Hoee,the oss of 53 o a itact DDr eithe efoe ces

exeiece damage o afte damage-idced seescece say eads to mitotic catastohe, hich acts asa secod aie that mst e oecome y teomeestaiizatio111.

The p16pRB pathway. Stimi that odce a DDrca aso egage the 16rb athay, t this sayoccs secoday to egagemet of the 53 athay71,72.noetheess, some seescece-idcig stimi act i-maiy thogh the 16rb athay. This is aticayte of eitheia ces, hich ae moe oe tha fio-asts to idcig 16 ad aestig oifeatio, at east icte. Fthemoe, thee ae secies-secific diffeeces:

fo exame, exeimeta distio of teomees i-maiy egages the 53 athay i mose ces t oththe 53 ad 16rb athays i hma ces114.

Ocogeic rAS idces 16 exessio y actiatigETS tascitio factos; ETS actiity is coteactedy ID oteis87, hich ae doegated i seescetces115. It is ot cea ho othe seescece-casig stimiidce 16 exessio. Oe ossie mechaism is theedced exessio of poycom InK4a eessos sch

Figure 4 | Snsn ntd t p53 nd p16

prb ptws. Senescence-inducing signals, including

those that trigger a DNA-damage response (DDR), as well

as many other stresses (FIG. 1), usually engage either the

p53 or the p16retinoblastoma protein (pRB) tumour

suppressor pathways. Some signals, such as oncogenic

RAS, engage both pathways. p53 is negatively regulated by

the E3 ubiquitin-protein ligase HDM2 (MDM2 in mice),

which facilitates its degradation, and HDM2 is negatively

regulated by the alternate-reading-frame protein (ARF).

Active p53 establishes the senescence growth arrest in

part by inducing the expression of p21, a cyclin-dependent

kinase (CDK) inhibitor that, among other activities,

suppresses the phosphorylation and, hence, the

inactivation of pRB. Senescence signals that engage the

p16pRB pathway generally do so by inducing the

expression of p16, another CDK inhibitor that prevents

pRB phosphorylation and inactivation. pRB halts cell

proliferation by suppressing the activity of E2F, a

transcription factor that stimulates the expression of genes

that are required for cell-cycle progression. E2F can also

curtail proliferation by inducing ARF expression, which

engages the p53 pathway. So, there is reciprocal regulation

between the p53 and p16pRB pathways. Interactions

among ARF, HDM2, p53, p21, CDKs, pRB and E2F also occur

in other cell contexts for example, during the DDR and

reversible or transient growth arrest so it not yet clear

how senescence, as opposed to quiescence or transient

growth arrest, is established. It is noteworthy, however, that

at least in cell-culture studies, upregulation of p16 is not

part of the immediate DDR and does not occur duringtransient growth arrests or quiescence.

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as bMI1 (ReFs 53,116) ad CbX7 (ReF. 117). Cosistet iththis idea, bMI1 o CbX7 oeexessio exteds the ei-catie ifesa of hma ad mose fioasts53,103,117.

16 ad 21 ae oth CDKIs; hece, oth ca keerb i a actie, hyohoshoyated fom, theeyeetig E2F fom tasciig gees that ae eededfo oifeatio42. Hoee, 16 ad 21 ae ceay oteqiaet118. Ces that seesce soey de to 5321actiatio ca esme goth afte iactiatio of the 53athay, ad do so fo may ce doigs ti cisis omitotic catastohe occs20,52,55,64,110 . Hoee, athoghces that seesce de to ocogeic rAS (hich idces16 exessio) ca esme imited oifeatio20,ces that fy egage the 16rb athay fo seeadays say caot esme goth ee afte iactia-tio of 53, rb o 16 (ReF. 52). Moeoe, the oss of16rb actiity egates 53 ad 21 exessio iat ecase E2F aso stimates ArF exessio119,120.Desite ecioca egatio etee the 53 ad16rb athays (FIG. 4), thee ae diffeeces i hoces esod he oe o the othe athay mediates

a seescece esose.The 16rb athay is ccia fo geeatig

SAHFs, hich siece the gees that ae eeded fooifeatio45. SAHFs eqie seea days to deeo,dig hich time thee ae tasiet iteactiosamog chomati-modifyig oteis sch as HIrA(histoe eesso A), ASF1a (ati-siecig fctio-1a)ad Hp1 (ReF. 88). utimatey, each SAHF cotaisotios of a sige codesed chomosome, hich isdeeted fo the ike histoe H1 ad eiched fo Hp1ad the histoe aiat macoH2A121,122. like the gothaest, oce estaished, SAHFs o oge eqie 16o rb fo maiteace45. These fidigs sggest thatthe 16rb athay ca estaish sef-maitaiigseescece-associated heteochomati. This actiitymay e de to the aiity of rb to comex ith histoe-modifyig ezymes that fom eessie chomati123.Athogh SAHFs ae ot eset i a seescet ces,the 16rb athay might estaish chomati statesthat ae fctioay, if ot cytoogicay, eqiaet toSAHFs i ces that do ot deeo these stctes.

Significance of senescence in vivo

Hayficks oseatios1 ee made sig ctedces, ad mch of o cet destadig of thecases ad coseqeces of seescece sti deiesfom ce ctes. Oy dig the ast decade o so

has cea seescece ee sho to occ ad to eimotat in vivo.

Senescent cells in vivo. Seescece-associated makes(see aoe) hae ee sed to idetify seescet cesin vivo, ith the caeat that oe of these makes aeexcsie to the seescet state. I odets, imatesad hmas, seescet ces ae fod i may ee-ae tisses, icdig the ascate, haematooieticsystem, may eitheia ogas ad the stoma12,49,51,124.notay, ces that exess oe o moe seescecemakes ae eatiey ae i yog ogaisms, t theime iceases ith age. Ho adat ae seescet

ces i aged ogaisms? Estimates ay idey deed-ig o the stdy, secies ad tisse, agig fom 15%. It is diffict to ko the case of the sees-cece esose fom these stdies. Hoee, amogthe seescece makes that accmate ith age aeSDFs that co-ocaize ith teomees, sggestig that,at east i some tisses, teomee dysfctio casesseescece in vivo.

Ces that exess seescece makes ae aso fodat sites of choic age-eated athoogy, sch as osteo-athitis ad atheosceosis125127. Ths, seescet cesae associated ith ageig ad age-eated diseasesin vivo, as sggested y Hayficks eay exeimets. Iadditio, seescet ces ae associated ith eig dys-astic o eeoastic esios83,9294 ad eig ostatichyeasia128, t ot ith maigat tmos. Theyae aso fod i oma ad tmo tisses fooigDnA-damagig chemotheay7376. These fidigs s-ot the secod secatio fom Hayficks exeimets that cea seescece sesses the deeometof cace. Seescet ces ae theefoe fod at aoi-

ate times ad aces fo thei oosed oes i tmosessio ad ageig.

why do seescet ces accmate in vivo? Thease to this qestio is ot ko. recet fidigssggest that seescet ces, at east those idced yacte 53 actiatio i mie tmo modes, cae ceaed y host mechaisms sch as the immesystem129,130. vitay othig is ko aot hoseescet ces ae ecogized y the imme system,hethe additioa mechaisms cea them in vivo ohethe ceaace mechaisms chage ith age o iage-eated diseases. likeise, othig is ko aothethe the seescet ces fod in vivo hae escaedceaace o ae i the ocess of eig ceaed.

Cellular senescence and cancer. Seescece-idcigstimi ae otetiay ocogeic, ad cace ces mstacqie mtatios that ao them to aoid teomee-deedet ad ocogee-idced seescece2,93,131133.These mtatios tyicay occ i the 53 ad 16rbathays. Of cose, these athays hae mtie acti-ities, a of hich may cotite to thei tmo s-esso actiities. noetheess, thee ae seea istacesi hich oss of the seescece esose aeas to ea ccia, aeit isfficiet, ste i the deeomet ofcace. Fo exame, geeticay egieeed mice thatae deficiet i a histoe methytasfease o 53 co-

tai ces that fai to seesce i esose to aoiatestimi; these mice ae iaiay cace-oe92,93,134.likeise, ces fom atiets ith li-Famei sydome,hich cay mtatios i 53 o CHK2 (ReFs 135,136),oecome seescece mch moe eadiy tha omaces137; hmas ith these mtatios ae aso cace-oe. Fiay, as oted eaie, some eeoastic esioscotai age mes of ces that exess seescecemakes, hich sggests that a seescece esose hatsthei ogessio to maigacy.

Cea seescece oay sesses tmoigeesisecase cace deeomet eqies ce oifeatio2,so ay mechaism that stigety eets ce goth

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Functional tissue Damaged tissue

Apoptotic cell

Senescent cell

Mutated cell

Senescent cell

Dysfunctional cell

Cancerous cell

i, a ioi, eet cace. Hoee, faie to seesceis say isfficiet fo maigat tasfomatio.This is aticay te fo eicatie seescece; foexame, teomease eets teomee-iitiated sees-cece, t does ot cofe maigat oeties oces138. likeise, the iactiatio of 16, 21 o cetaiDDr gees o ee 53 o rb (fo exame, y iaocogees) iceases the eicatie ifesa of hmaces t does ot tasfom them per se20,109,139. Schces say ete cisis, fom hich ae eicatieyimmota ces (hich hae oecome the ed-eicatiooem) ca aise139. Ee the, the immota ces mayot e tmoigeic ti they acqie mtatios thatactiate mitogeic ocogees sch as rAS o iactiatetmo sessos that dame mitogeic sigas sch

as pTEn83,92,93,140. Ths, geetic o eigeetic eets thataet eicatie seescece ae ecessay t isfficietfo maigat tmoigeesis.

Seescece eesa ca occ if ces seesce ithotfy egagig the 16rb athay ad sseqetyose 53 fctio52. It is ot ko hethe this occsin vivo. Hoee, ces ith sieced (methyated)16 exist i aaety oma tisse108; shod schces seesce (fo exame, i esose to teomeedysfctio o DnA damage) ad sseqety ose53 fctio, they cod, i icie, esme oifea-tio. likeise, seescet 16-egatie ces i dysasticaei83 cod acqie a mtatio that iactiates 53

fctio ad eet to a oifeatig state. no-diidigces ca acqie mtatios4 so these sceaios ae otimossie, t it is ot cea hethe they ae asie.whatee the case, it is aaet that seescece osesa fomidae t ot ismotae aie to caceogessio.

Cellular senescence and ageing.The ik etee ceaseescece ad ageig is moe tetatie tha the ikto cace12. As oted eaie, the me of seescetces iceases ith age, ad seescet ces ae esetat sites of age-eated athoogy. Fthe, ecet fidigsimicate 16-deedet seescece i thee hamaksof ageig decemets i eogeesis, haematooiesisad aceatic fctio105107. 16 exessio iceasesith age i the stem ad ogeito ces of the moseai, oe mao ad aceas, hee it sessesstem-ce oifeatio ad tisse egeeatio. This isei 16-ositie stem ces is aaet i eay midde-age.Stikigy, the age-eated decie i stem-ce gothad tisse egeeatio is sstatiay etaded i mice

that hae ee geeticay egieeed to ack 16 exes-sio. Hoee, as exected, these mice die ematey(i ate midde-age) of cace.

The age-deedet ise i 16-ositie stem adogeito ces is cosistet ith the idea that stem-ceseescece might at east aty exai the age-eateddecie i ai ad oe-mao fctio ad thedeeomet oftye II diaetes. Hoee, it is ot yetko hethe the 16-ositie stem ad ogeitoces ae i fact seescet. So, it is ossie that oth thetmo-sessie ad o-ageig actiities of 16 aeaty de to goth sessio ithot seescece.noetheess, these fidigs sggest that the tmo-sessie actiity of 16 might e iexticay ikedto its o-ageig effects. A simia tade-off eteetmo sessio ad ageig is see i mice ithcostittiey hyeactie foms of 53 aimas thatexess these foms ae emakay tmo-fee, tsho mtie sigs of acceeated ageig141,142, hichae at east aty de to thei iceased sesitiity toseescece-idcig stimi142.

A secod mechaism y hich seescet ces mightcotite to ageig comes fom thei ateed atte ofgee exessio secificay, the egatio of geesthat ecode extacea-matix-degadig ezymes,ifammatoy cytokies ad goth factos, hich caaffect the ehaio of eighoig ces o ee dista

ces ithi tisses12(FIG. 5). These seceted factos cadist the oma tisse stcte ad fctio ice-cte modes (fo exame, the fctioa admohoogica diffeetiatio of mammay eitheiaces o eidema keatiocytes)143,144. Moeoe, factosseceted y seescet ces ca stimate the gothad agiogeic actiity of eay emaigat ces,oth i cte ad in vivo145149. Theefoe, seescetces, hich themsees caot fom tmos, may fethe ogessio of eay emaigat ces, theey ioicay faciitatig the deeomet of cacei ageig ogaisms. Togethe, these fidigs sotthe idea that the seescece esose is atagoisticay

Figure 5 | Ptnt dts ffts f snsnt s. Damage to cells within

tissues can result in several outcomes. Of course, the damage may be completely

repaired, restoring the cell and tissue to its pre-damaged state. Excessive or irreparable

damage, however, can cause cell death (apoptosis), senescence or an oncogenicmutation. The division of a neighbouring cell, or a stem or progenitor cell, usually

replaces apoptotic cells. Cell division, however, increases the risk of fixing DNA damage

as an oncogenic mutation, leaving the tissue with pre-malignant or potentially malignant

cells. Senescent cells, by contrast, may not be readily replaced; in any case, their number

can increase with age. Senescent cells secrete various factors that can alter or inhibit the

ability of neighbouring cells to function, resulting in dysfunctional cells. They can also

stimulate the proliferation and malignant progression of nearby premalignant cells.

Therefore, an accumulation of senescent cells can both compromise normal tissue

function and facilitate cancer progression.

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eiotoic, ad aaces the eefits of sessigcace i yog ogaisms agaist omotig thedeeomet of deeteios ageig heotyes8,12.

Future questions and directions

Desite the tasitio fom ce-cte ciosity tootetia egato of cace ad ageig, cea sees-cece emais eigmatic ad coties to ose a hostof qestios. pecisey ho do the 53 ad 16rbathays estaish ad, eqay imotaty, maitaithe seescet goth aest? both of these tmo-sesso athays aso case tasiet o eesiece-cyce aests, so ho ae thei actiities modifiedy seescece-idcig sigas? Fo that matte, hodo ces decide hethe to dego a tasiet gothaest, seescece o aotosis i esose to damageo stess sigas? The sigas that idce 16, oth icte ad in vivo, ae eseciay osce at eset.

likeise, itte is ko aot the mechaisms thatae esosie fo the aaety deeteios seescetsecetoy heotye. Ho ad hy does this heotye

deeo? Fiay, ho does the seescece esose a-ace tmo sessio, tisse egeeatio ad ageigheotyes? Ceay, it od ot e desiae to eese

the seescece goth aest this od ao dam-aged, stessed o ocogee-exessig ces to oifeatead theefoe icease the isk of cace. bt i it e os-sie to eimiate the deeteios (o-ageig) asects ofcea seescece (fo exame, the seescet secetoyheotye) ithot eesig the tmo-sessiegoth aest? The geeatio of egieeed micethat cay additioa coies of oey egated 53(ReF. 150) o 16 ad ArF151, o hae edced actiityof the egatie 53 egato MDM2 (ReF. 152), edhoe to this ossiiity. These mice deeo itte ca-ce ithot sigs of acceeated ageig. Hoee, theifesas of these mice ee ot sigificaty ogetha coto mice, desite cace eig a majo caseof death i mice. It emais to e see hethe othe,ossiy o-etha, age-eated athoogies ee acce-eated o exaceated. The existece of these mice asoaises the ossiiity that thee is (o ca e) itte o otade-off etee tmo sessio ad ogeity, ifot etee tmo sessio ad ageig heotyeso cetai age-eated athoogies. whatee the case,

it might e ossie, thogh secific iteetios, toameioate ay atagoisticay eiotoic effects thattmo sessos might hae.

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AcknowledgementsThe authors thank colleagues and the members of their labo-

ratories for stimulating discussions. The F.dA.d.F. group is

supported by the Associazione Italiana per la Ricerca sul

Cancro, the Association for International Cancer Research

and the Human Frontier Science Program. The J.C. group is

supported by the US National Institute of Aging, the National

Cancer Institute and the Department of Energy.

Competing interests statementThe authors declare no competing financial interests.

DATABASESOMIM:http://www.ncbi.nlm.nih.gov/entrez/query.

fcgi?db=OMIM

Li-Fraumeni syndrome| type II diabetes

UniProtKB:http://ca.expasy.org/sprot

ATM| CHK2| E2F|HDM2| p16|p21|p53 | pRB|PTEN

FURTHER INFORMATIONJudith Campisis homepages:

http://www.buckinstitute.org/site/index.php?option=com_c

ontent&task=view&id=113&Itemid=100

http://www.lbl.gov/lifesciences/labs/campisi_lab.html

Fabrizio dAdda di Fagagnas homepage:

http://www.ifom-ieo-campus.it/research/dadda.php

all liNkS are acTive iN The oNliNe PDF.

R E V I E W S

740 | SEpTEMbEr 2007 | vOluME 8 / /
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=151623http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=125853http://ca.expasy.org/sprothttp://www.expasy.org/uniprot/Q13315http://www.expasy.org/uniprot/O96017http://www.expasy.org/uniprot/Q01094http://www.expasy.org/uniprot/Q01094http://www.expasy.org/uniprot/Q00987http://www.expasy.org/uniprot/Q00987http://www.expasy.org/uniprot/P42771http://www.expasy.org/uniprot/P38936http://www.expasy.org/uniprot/P38936http://www.expasy.org/uniprot/P38936http://www.expasy.org/uniprot/P04637http://www.expasy.org/uniprot/P04637http://www.expasy.org/uniprot/P06400http://www.expasy.org/uniprot/P06400http://www.expasy.org/uniprot/P60484http://www.expasy.org/uniprot/P60484http://www.buckinstitute.org/site/index.php?option=com_content&task=view&id=113&Itemid=100http://www.buckinstitute.org/site/index.php?option=com_content&task=view&id=113&Itemid=100http://www.lbl.gov/lifesciences/labs/campisi_lab.htmlhttp://www.ifom-ieo-campus.it/research/dadda.phphttp://www.ifom-ieo-campus.it/research/dadda.phphttp://www.lbl.gov/lifesciences/labs/campisi_lab.htmlhttp://www.buckinstitute.org/site/index.php?option=com_content&task=view&id=113&Itemid=100http://www.buckinstitute.org/site/index.php?option=com_content&task=view&id=113&Itemid=100http://www.expasy.org/uniprot/P60484http://www.expasy.org/uniprot/P06400http://www.expasy.org/uniprot/P04637http://www.expasy.org/uniprot/P38936http://www.expasy.org/uniprot/P42771http://www.expasy.org/uniprot/Q00987http://www.expasy.org/uniprot/Q01094http://www.expasy.org/uniprot/O96017http://www.expasy.org/uniprot/Q13315http://ca.expasy.org/sprothttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=125853http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=151623http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

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