How stem cells age and why

8/7/2019 How stem cells age and why

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Dirs acqird and gntic factors dri th com-plx clllar and organismal procss of mammalianaging. Th procss appars to hastnd y ni-ronmntal and haioral factors inclding osity,diats, nd-stag rnal disas and xposr tomtagns sch as chmothrapy, ltraiolt light andtoacco smok. Likwis, arios gntic lsions thataltr DNA mtaolism and nclar architctr han associatd with progroid syndroms in hmanssch as ataxia tlangictasia, Wrnr syndromand HtchinsonGilford syndrom1. Most comp-lling ha n gntic stdis in yast, Drosophilamelanogaster, Caenorhabditis elegans and mic, whichha stalishd crcial rols for th inslininslin-lik growth factor-1 (IGF1)AKTforkhad trancriptionfactor cla O (FOXO) pathway (s th Riw yRssll and Kahn in this iss) and oxygn-radicalrglators (s th Opinion articl y Plicci andcollags in this iss) as dtrminants of lifspan

in ths modl systms. Althogh ths disparatxprimntal osrations sggst common molclarthms, hman aging in physiological trms rmainsan nigma.

In this Riw, w sggst that som aspcts ofmammalian aging rslt from an ag-associatddclin in th rplicati fnction of crtain tiss-spcific rgnrati clls adlt stm clls (FIG. 1).Ths rar and spcializd clls ar rqird fortiss rplacmnt throghot th hman lifspan,and appar to charactrizd y a fw spcificphysiological and iochmical proprtis (riwdin ReFs 24), particlarly th capacity for lf-rnwal.

Rcnt idnc spports th modl that stm cllsin sral tisss ar largly rtaind in a qiscnt statt can coaxd ack into th cll cycl in rsponsto xtraclllar cs, n aftr prolongd priodsof dormancy. Onc stimlatd to diid, stm cllsyild ndiffrntiatd progny, which in trn prodcdiffrntiatd ffctor clls throgh ssqnt rondsof prolifration (BOX 1). This hirarchical diffrntia-tion schm maks sns from th prspcti of organ-ismal longity it prmits th prodction of largnmrs of diffrntiatd clls from a singl stm clly comining ssqnt stps in diffrntiation withprolifration5,6. Thrfor, this approach alancs thhigh rats of homostatic prolifration that ar rqirdin tisss lik th on marrow and intstin with thlong-trm nd to protct stm clls from mtagnicinslt and carcinognsis. Indd, ndr homostaticconditions, thr is limitd prolifrati dmand onth slf-rnwing stm clls thmsls and so ths

clls diid infrqntly, sparing stm clls th prilsof DNA rplication and mitosis. Additionally, as stmclls appar to lss mtaolically acti in thir qi-scnt stat, thy may sjctd to lowr lls ofDNA-damag-indcing mtaolic sid prodcts schas racti oxygn spcis (ROS)7.

Onc lid to rstrictd only to high-trnororgans lik th on marrow and intstin, rsidnt slf-rnwing clls ar now thoght to ha a significant rolin th homostatic maintnanc of many organs, incld-ing organs with lowr trnor rats sch as th rainand pancratic islts8. Althogh thr is disagrmntas to th significanc of sch clls in ths low-trnor

*Departments of Medicine

and Genetics, The Lineberger

Comprehensive Cancer Center,

The University of North

Carolina, Chapel Hill, NorthCarolina 275997295, USA.Center for Applied Cancer

Science of the Belfer Institute

for Innovative Cancer Science,

and Department of Medical

Oncology, DanaFarber

Cancer Institute; Departments

of Medicine and Genetics,

Harvard Medical School,

Boston, Massachusetts

02115, USA.

emails:

[email protected].

edu; [email protected]

doi:10.1038/nrm2241

Forkhead transcription

factor class O

(FOXO). On of a family of

volutionarily conrvd

trancription factor that ar

linkd to lifpan rgulation in

lowr ytm and to tm-cllmaintnanc in mic. Th

FOXO protin ar thought to

xrt th ffct by

rgulating th xprion of

gn involvd in apoptoi,

prolifration, gluco

mtabolim, DNA rpair,

rgulation of ractiv oxygn

pci and othr divr

cllular proc.

How stem cells age and whythis makes us grow oldNorman E. Sharpless* and Ronald A. DePinho

Abstract | Recent data suggest that we age, in part, because our self-renewing stem cells

grow old as a result of heritable intrinsic events, such as DNA damage, as well as extrinsic

forces, such as changes in their supporting niches. Mechanisms that suppress the

development of cancer, such as senescence and apoptosis, which rely on telomere

shortening and the activities of p53 and p16INK4a, may also induce an unwanted consequence:a decline in the replicative function of certain stem-cell types with advancing age.

This decreased regenerative capacity appears to contribute to some aspects of mammalian

ageing, with new findings pointing to a stem-cell hypothesis for human age-associated

conditions such as frailty, atherosclerosis and type 2 diabetes.

s t e m c e l l s

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Young

Old

Stem cell Progenitors Effectors

Physiological ageing, mutagenexposure or forced regeneration

Self-renewal

Th capacity of rplicating

tm cll to gnrat

daughtr cll with th am

biological and molcular profil

that ndow continud rnwal

potntial. Thi can occur ithr

aymmtrically whn a tm

cll produc anothr tm cll

and a mor diffrntiatd

daughtr cll, or ymmtricallywhn tm-cll diviion giv

ri to two idntical tm cll.

Importantly, in matur organ

ytm, mot cll-diviion

activity that i rponibl for

tiu maintnanc and

xpanion i not lf-rnwing.

Progeny

Along with prognitor cll,

th ar rlativly

undiffrntiatd cll typ that

ar drivd from aymmtric

tm-cll diviion and lack th

capacity to lf-rnw.

organs in th adlt hman, thir importanc in rodntshas n dmonstratd xprimntally. It is thrforrasonal to srmis that prhaps som charactristicsof aging onc thoght to dgnrati mightrflct a dclin in th rgnrati capacity of rsidntstm clls across many diffrnt tisss.

Slf-rnwal coms with som dangr for th organ-ism; in particlar, a risk of malignant transformation4,9,10.unrpaird gntic lsions in stm clls ar passd onto thir slf-rnwing daghtrs and accmlat withaging in this way. Fnctional mtations that proid agrowth or srial adantag in trn prodc positislction for th mtant stm-cll clon, with fll-fldgdcancr rslting from th accmlation of mltiplcancr-promoting nts. To offst this possiility, stmclls appar to ha old mltipl rinforcing mcha-nisms that ar aimd at maintaining gnomic intgrityyond that of othr prolifrating clls (riwd inReFs 24). Whn mtations occr dspit ths rror-prntion capacitis, potnt tmor-spprssor mcha-nisms sch as ncnc and apoptosis xist to sns

damagd stm-cll gnoms with malignant potntialand limit rplicati xpansion or cll sch clons. Thisrlationship twn slf-rnwing clls and cancrraiss th possiility that whil carrying ot a nfi-cial, anti-cancr fnction ths tmor-spprssormchanisms may inadrtntly contrit to aging ycasing stm-cll arrst or attrition.

Hr, w discss rcnt rfinmnts of this so-calldcancraging hypothsis, according to which cllswithin a tiss ar compromisd y ths anti-cancrmchanisms (s also th Opinion articl y Srrano andblasco in this iss). Spcifically, w rason that growth-inhiitory molcls sch as th cyclin-dpndnt

kinas inhiitor p16INK4a and th tmor spprssorp53 xrt thir pro-aging ffcts in part throgh thiractiation in spcific slf-rnwing compartmnts schas tiu-pcific tm cll. Frthr, w dscri findingsfrom a sris of rcntly plishd hman associationanalyss that sggst a link twn th INK4/ARFlocs(also calld CDKN2a and CDKN2b) and th onst ofdistinct hman ag-associatd phnotyps. Ths rcntosrations, togthr with th findings in gntic modlsystms, proid xprimntal spport for th concptthat th actiation of tmor-spprssor mchanisms inslf-rnwing compartmnts contrits to th agingprocsss in hmans.

Do ag?

A dclin in rplicati fnction with ag is apprcialin many mammalian tisss. In most mammalian tisss,howr, th inaility to prify th rsidnt stm cll tohomognity, as wll as th lack of adqat modlsto tst th fnction of ths clls, has mad it difficlt todtrmin if a dclin in stm-cll fnction is indd a

cas of th dgradation of th rgnrati capacitisthat is sn in many organs with aging.

Ageing of haematopoietic stem cells. In th hamato-poitic systm, it is possil to prify hamatopoiticstm clls (HSCs) to nar-homognity and assay thirfnction sing alidatd assays. Thrfor, th qs-tions of whthr and how stm clls ag ar prsntlyst addrssd in this systm, with th caat that stm-cll aging may diffr mchanistically in othr tisss.Sral ffcts of aging on th lood organ ar dscridin hmans: dcrasd immnity11, incrasd incidnc ofon marrow failr and hamatological noplasia12, andmodrat anamia13,14. Oldr indiidals ar mor liklyto sffr toxicity sch as prolongd mylospprssion inrspons to traditional cytotoxic chmothrapy drgs,sggsting a rdcd marrow rgnrati capacity1517.Particlarly tlling is th clinical osration thatincrasd donor ag in on marrow transplantation is aprdictor of transplant-rlatd mortality1822, sggstingthat th diminishd rconstitting aility of HSCs fromldrly donors is partly cll-atonomos. Ths osra-tions sggst a clinically ort dcay in HSC fnctionwith normal hman aging.

Ths corrlati findings in hmans ar ttrssdy rlatd stdis in rodnts. A srprising findinghas n that althogh HSC fnction clarly dclins

with ag, th nmr of HSCs dos not ncssarilyalso dclin. In som strains of mic, th HSC nmractally xpands with adancing ag7,2327 and thisag-dpndnt xpansion of HSCs is a transplantal,cll-atonomos proprty of HSCs7,25. Moror, asdmonstratd y Harrison and collags, HSCs can srially transplantd into sqntial rcipints and showprsistnt fnction for >8 yars, ths xcding th lif-tim of th original donor animal28. Ths xprimntsha stalishd that cll-atonomos, rplicati HSCxhastion dos not ncssarily occr dring priods ofnormal aging in som strains of inrd mic that armaintaind ndr laoratory conditions.

Figure 1 | Hw s s . Stem-cell number and self-renewal (curved arrow) does

not necessarily decline with ageing, but function the ability to produce progenitors

(blue) and differentiated effector cells (depicted in different colours) does decline.

Stem-cell ageing can result in some systems from the heritable accumulation of DNA

damage, which can engage tumour-suppressor activation as the stem cell attempts to

divide asymmetrically. DNA damage can occur stochastically with normal ageing as a

result of exposure to external mutagens, or from increased proliferation as in forced

regeneration (see main text).

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Stem cells

Self-renewal

Multipotent

progenitors

Oligopotentprogenitors

Lineage-restricted

progenitors

Effectorcells

LT-HSC(LIN KIT+ SCA1+ CD34Lo FLK2Lo)

ST-HSC(LIN KIT+ SCA1+ CD34Hi FLK2Lo)

MPP(LIN KIT+ SCA1+ CD34Hi FLK2Hi)

CMP

MEP GMP

CLP

Erythrocytes Platelets Granulocytes Macrophages T cells B cells

This is not to say, howr, that th rplicati fnc-tion of HSCs is not limitd y anti-cancr mchanismswith aging. It is ntirly possil that snscnt HSCschang thir srfac immnophnotyp (and thrforar no longr idntifid as HSCs y flow cytomtry) orthat th snscnc and apoptosis mchanisms ar notngagd ntil old HSCs attmpt to diid asymmtri-cally. In th lattr modl, snscnc or apoptosis coldlimit HSC fnction withot dcrasing th HSC nm-r. Moror, it is important to not that HSC nmrs

appar to dclin with ag in othr inrd strains ofmic26,27,2931, and that sral xtrnal stimli (forxampl, chmothrapy, ionizing radiation and so on)hastn stm-cll xhastion in hmans and mic3238.Ths, gntically otrd mammals in th wild mayor may not xprinc HSC xhastion with aging,and xposr to nironmntal strsss that ar notnormally ncontrd in th laoratory stting mayfrthr indc HSC xhastion. Finally, indpndntlyof rplicati fnction, HSCs xhiit cll-intrinsic,fnctional signs of aging. Nmros stdis hashown that aging altrs HSC fnction with rgard tomoilization39, homing7,23,24,31,39 and linag choic7,24,31.In particlar, thr is a loss of lymphoid linag potn-tial with a skwing toward myloid linags in HSCsfrom old mic, and old HSCs dmonstrat rprodc-il changs in gn xprssion with ag, incldingincrasd xprssion of myloid linag transcripts7.Thrfor, th prpondranc of idnc sggststhat HSCs ndrgo cll-intrinsic aging, althoghthr is also mrging idnc that th aging HSC

micronironmnt may inflnc HSC fnction in anxtrinsic mannr (s low).

Ageing in other self-renewing compartments. Srallins of idnc sggst that stm clls from othrtisss sffr prolifrati dclin with adancingag (FIG. 1). For xampl, in rodnts, a dclin in thnmr of nw nrons prodcd y nral stm clls(NSCs) with ag or tlomr dysfnction has n doc-mntd40,41, as has th in vivo prolifration of NSCs4143.This dclin in th capacity for mrin nrognsishas n associatd with a progrssi Parkinsoniandisas41 and with an impairmnt of olfactory discrimin-ation with aging44. Likwis, hair grying has nlinkd to dcrasd mlanocyt stm-cll maintnanc,possily in association with mlanolast snscnc45.

Th capacity of th inslin-prodcing -cll of thpancratic islt to rplicat in adlt rodnts throghotlif has n known for dcads, althogh th importancof this rgnrati capacity with rgard to th dlop-mnt oftyp 2 diats mllits (also calld adlt-onstdiats mllits) has only rcntly n apprciatd.Th prailing iw had n that typ 2 diats mll-its was a mtaolic disas rslting largly from anag-associatd dclin in th aility of mscl and lir torspond to inslin (inslin rsistanc), t rcnt carflanalyss of islt mass ha challngd this iw. Stdis

in th immdiat post-mortm priod ha shown sig-nificant rats of-cll prodction and apoptosis, nin agd adlts, with an incrasd -cll mass notd inos indiidals and a rlatily rdcd -cll massamong adlts with diats46,47. Thrfor, th de novosynthsis of-clls throgh slf-rnwal appars to th prdominant sorc of islt mass in adlt hmans.Islt rplication appars to dclin with hman aging47,althogh -cll rplication has n rportd in hmanpatints p to 89 yars of ag48. Consistnt with thsfindings in hmans, a sharp dclin in -cll prolifra-tion with aging in mic has n rcntly dscrid49.Mor than 1% of islt clls from yong mic prolifrat

Box 1 | th hirarhy of haaopoii

Multipotnt tissue-specific stem cells produce differentiated effector cells through a

series of increasingly more committed progenitor intermediates. This tissue stem-cell-

derived differentiation process has been best characterized in the haematopoietic

system (see figure). Here, long-term haematopoietic stem cells (LT-HSCs) represent the

true stem cells that self-renew and produce multipotent progenitors (short-term (ST)-

HSCs and, subsequently, multipotent progeny (MPP)) with no self-renewal capacity.

These in turn give rise to oligopotent progenitors including the common lymphoid

progenitor (CLP) and common myeloid progenitor (CMP), which then yields the

granulocytemacrophage progenitor (GMP) that differentiates into monocytes,

macrophages and granulocytes, and the megakaryocyteerythrocyte progenitor (MEP)that differentiates into megakaryocytes, platelets and erythrocytes. Similar hierarchies

are also thought to exist in other stem-cell-containing tissues (for example, brain, gut,

liver and lung).

A principal advantage of studies in the haematopoietic system is that stem and

progenitor cells from this organ can be purified to near-homogeneity by surface

markers. For example, LT-HSCs express low levels of lineage markers (LIN), high levels

of the CD117/c-KIT receptor (KIT+), high levels of a surface marker called SCA1 (SCA1 +),

and low levels of another surface marker, CD34 (CD34 Lo). With each asymmetric

division of a LIN KIT+SCA1+CD34Lo LT-HSC, there is the production of another LT-HSC

and a multipotent daughter cell with limited renewal potential, ST-HSC, which has a

similar surface immunophenotype to LT-HSC except that it has higher levels of CD34

(CD34Hi). As ST-HSC in turn proliferate to form more differentiated MPP, they increase

expression of another surface marker, FLK2. Development from oligopotent

progenitors to mature blood cells proceeds through several intermediate progenitors

that are not shown.

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20 40 60 80

Mouse age (weeks)

Proliferatingisletcells

(%oftotalisletcells)

0.2

0.4

0.6

0.8

1.0

1.2

1.4

p16INK4a knockout

p16INK4a transgenic

Wild-type

Senescence

A pcializd form of growth

arrt inducd by variou

trful timuli including lo

of tlomr function, ractiv

oxygn pci, om form of

DNA damag and activation of

crtain oncogn or

ractivation of tumour-

uppror gn. sncnc

i charactrizd by vral

markr uch a ncnc-

aociatd--galactoida,

altration in chromatin

tructur (ncnc-

aociatd htrochromatic

foci) and a markd incra in

th crtion of vral

cytokin and othr bioactiv

molcul (ncnc-aociatd crtory

phnotyp).

Tissue-specific stem cell

A pcializd cll found in

many tiu of adult. Th

cll can rplac thmlv

through lf-rnwal and ar

gnrally multipotnt, in that

thy can giv ri to progny

that can diffrntiat into

multipl diffrnt cll typ of

th aociatd organ.

Multipotency

Th ability to giv ri to

diffrntiatd progny of

diffrnt pcializd ubtyp.

Howvr, om lf-rnwing

cll (for xampl, pancratic

-cll) hav a narrow potntial

for diffrntiation, gnrating

progny imilar to th parntal

cll. Thi typ of lf-rnwing

cll i trmd a unipotnt

prognitor, which can b

viwd a a pcial tm-cll

ubtyp, at lat in trm of

long-trm prolifrativ

capacity. For convninc, in

thi Rviw th trm tm cll

i applid to both typ of

adult lf-rnwing cll.

Telomere

A nucloprotin complx at

th nd of chromoom that

maintain chromoomal

intgrity. It conit of many

doubl-trandd 5-TTAGGG-3

rpat, a 3-ingl-trandd

ovrhang and aociatd

tlomr-binding protin,

which togthr gnrat a

cappd tructur that i

imprviou to th action of

complx that rpair DNA

damag.

ndr stady-stat conditions, t this frqncydclins y narly tnfold aftr a yar of aging (FIG. 2).Thrfor, rathr than ing mrly a disas of inslinrsistanc, typ 2 diats mllits partly rslts from arlati failr of islt rplication.

Cell-extrinsic ageing.Ths osrations, howr, donot mak clar which islt-associatd compartmnt isaging: is it th -clls thmsls, a ptati pancraticstm cll or anothr tiss that inflncs-cll prolifr-ation in a cll non-atonomos mannr? In fact, cllnon-atonomos factors ha n shown to ha amajor rol in th rglation of stm-cll aging in othrsystms. Rando and collags ha shown that thaging of a rgnrati cll of mscl, th satllit cll,is inflncd y th agd micronironmnt50. Satllitclls from agd mic wr rjnatd y xposr toa yong lood spply, sggsting that th agd mili,hormonal or othrwis, inflncs th rplicati fnc-tion of satllit clls. Likwis, whil som aspcts of thfnctional dclin that charactrizs aging of HSCs has

n shown to cll-atonomos, th HSC nich isalso xpctd to inflnc HSC aging to som dgr.For xampl, in mic with shortnd tlomrs, anag-dpndnt dcras was notd in th aility ofrcipint animals to spport lymphopoisis of trans-plantd HSCs from yong mic with normal tlomrs,and nhancd myloid prolifration occrrd whnHSCs wr transplantd into a micronironmnt thatharord dysfnctional tlomrs51.

Althogh this distinction twn cll-intrinsic andcll-xtrinsic aging is important, aging is, ltimatly, thsmmati proprty of th organism in toto. For xam-pl, th finding that srm from yong mic nhancs

satllit-cll prolifration sggsts that cll-intrinsicaging of som othr tiss occrs sch that it lao-rats (or fails to laorat) th rlant srm factor thatmodlats th prolifrati capacity of satllit clls. Thaility to targt gns conditionally in a tiss-spcificand tmporal mannr will prmit in vivo analyss todtrmin which compartmnts ag intrinsically, rssthos that ag y proxy.

Wha au o ag?

Althogh a fw mchanisms ha n sggstd toxplain clllar aging, indpndnt lins of idncsggst that forms of DNA damag lad to th actiationof tmor-spprssor mchanisms, sch as snscnc,to limit stm-cll fnction with incrasing ag.

DNA damage results in stem-cell attrition. Th acc-mlation of damag to clllar macromolcls (forxampl, protins and DNA) has n postlatd to a cas of clllar attrition with aging52. DNA issjctd to spontanos and xtrinsic mtational

nts on a daily asis, and dspit a formidal cap-acity for rpair, som damagd DNA appars to adrpair and accmlats or tim. eidnc in spportof th notion that DNA damag attnats stm-cllfnction with ag has n proidd y th stdy ofHSCs from mic that haror altrations in th DNA-damag rspons. Significant fnctional dfcts ar snin HSCs from mic that ar dficint in DNA-rpairprotins sch as FANCD1(ReF. 53), MSH2 (ReF. 54) oreRCC1 (ReF. 55). A mos strain with a ial, hypo-morphic alll of th DNA-rpair protin DNA ligas Ivthat was rcntly idntifid throgh a mtagnsisscrn xhiits a markd, ag-indcd dclin in HSCnmr and fnction56. Additionally, Morals et al. hashown that mic with a mtant alll of RAD50, a mm-r of th MRe11 DNA-rpair complx, dmonstratprofond on marrow hypoplasia57. This ffct can rscd in th stting of ataxia-tlangictasia mtatd(ATM) kinas dficincy, sggsting that th Rad50alll is hyprmorphic and that xcss DNA-damagsignalling rdcs HSC nmr and/or fnction.Ths data sggst that sral forms of DNA rpairar ndd to maintain HSC gnomic intgrity, and thatactiation of a rspons to DNA damag compromissHSC fnction.

A dmonstration of DNA damag in a tiss-spcific stm-cll compartmnt with aging coms from

a rcnt rport y Rossi and collags58. using micwith grmlin dficincis in DNA rpair or tlomrmtaolism (K80-, XPD- and mTeRC-knockot mic),th athors dmonstratd a markd prmatr dclinin th rgnrati fnction pr HSC in sral assays.This stdy frthr notd th incrasd xprssion ofmarkrs of th DNA-damag rspons (for xampl,histon H2AX foci) in highly prifid HSCs with normalphysiological aging n in wild-typ mic. Th athorsnotd an incras in apoptosis of progny from old HSCs,t not a dclin in th aility of old HSCs to prolifratin in vitro assays. Ths osrations corrspond wllwith a diminishd capacity of th hamatopoitic systm

Figure 2 | Pfn f-s wh . A sharpdecline in pancreatic-cell proliferation with ageingnormally occurs in wild-type mice (blue). This decline is

modulated by expression of the p16INK4a tumour

suppressor: increased expression (in a transgenic line;

green) correlates with reduced proliferation, whereas

decreased activity (in the p16INK4a knockout line; orange)

affords a resistance to -cell ageing.

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Cancer

Regenerative failure,SA-SP

Tissue dysfunctionand failure

Tissue dysfunctionand failure(for example, MDS)

Transformation

Senescence

Apoptosis

Dysfunction

RAS mutation,p53 loss

Telomeredysfunction

Unrepaired DSBs

Y-chromosomeor 5q loss

Stem cell

Telomerase

A ribonucloprotin complx

that xtnd th nd of

tlomr aftr rplication by

uing tlomra rvr

trancripta (TeRT) and an

RNA tmplat (TeRC) that i

part of th nzym complx.

in tlomr-dysfnctional mic to rcor followingchmothraptic challng, as wll as with a progrs-si nrodgnrati condition that is associatd withdcrasd NSC rsrs and fnction in th tlomra-knockot modl41,59. Togthr, ths rslts ar consist-nt with th iw that DNA damag accmlats withaging in th HSC compartmnt, as idncd y thaccmlation of H2AX foci, and that this damag can physiologically significant if nrpaird.

bt what cass DNA damag in stm-cll com-partmnts in adlt mic? Rcnt data from Rzankinaet al., who sd a conditional alll for th DNA-dam-ag rspons gn Atr(ataxia tlangictasia and Rad3-rlatd), ar worth considring in this rgard60. LossofAtris toxic to prolifrating clls61 and whn Atrwassomatically xcisd in adlt mic in a widsprad man-

nr y conditional inactiation, th ast majority of pro-lifrating clls rapidly disappard, prodcing markdintstinal atrophy and on marrow hypoplasia 2 wksaftr conditional actiation. Howr, th animals sr-id this transint priod of cll loss cas rar stmclls that had not rcomind th Atralll rplacdth lost clls. by 1 month aftr conditional actiation, thmic appard largly normal, with rapidly prolifr-ating tisss that had n flly rconstittd y spor-adic Atr-comptnt clls. Srprisingly thogh, thsrconstittd mic thn dlopd a markd progroidphnotyp a fw months latr, with ostopania, gryingand loss of lymphoid and hamatopoitic prognitors.

Thrfor, th xcss rgnration that was forcd tooccr to rconstitt prolifrati tisss aftr transintAtrinactiation in som prolifrating clls prodcda dral compromis of stm-cll fnction in Atr-comptnt clls (FIG. 1), althogh it is important tomphasiz that th possil adrs ffcts of ATRdltion on th stm-cll nich may also ha contri-td to th acclratd aging. This rslt is consistntwith th iw that sch forcd rgnration in rsponsto homostatic dmands, n in th asnc of xtrnalDNA-damaging agnts, can toxic to stm clls acrossmany organ systms.

In th DNA-damag accral modl of aging,nrpaird (or improprly rpaird) gnomic damagaccmlats with aging in stm-cll compartmnts.At som point, accmlatd damag prtrs normalstm-cll iology, driing stm clls to a fw possilfats: transformation, snscnc, apoptosis or dysfnc-tion; for xampl, a loss of th aility to rostly pro-dc progny or an impaird potntial for mltilinagdiffrntiation (FIG. 3). As this procss procds with tim,

dpltd and/or dysfnctional stm-cll compartmntscannot match th rgnrati nds of a gin organand homostatic failr nss. Likwis, if oncognicDNA-damag-indcd lsions accmlat, slf-rnw-ing clons that contain sch lsions ndrgo positislction, lading to cancr. Thrfor, it is tmpting tospclat that cancr and aging ar rlatd ndpointsof accmlating DNA damag within slf-rnwingcompartmnts.

How telomere shortening could affect stem-cell ageing.Thr has n significant intrst in th possiility thattlomr dysfnction, a spcializd form of DNA dam-ag, contrits to th aging of hman stm clls. In thasnc of adqat tlomras actiity, tlomr short-ning inxoraly occrs with prolifration, ntallytriggring a chang in tlomr strctr that is snsdy th cll as a DNA dol-strand rak. In hmans,rost tlomras actiity is prdominantly rstrictdto grm-cll compartmnts, som somatic arly stm-cll or prognitor compartmnts and prolifratinglymphocyts.

Whras tlomr dysfnction in th stting of anintact DNA-damag rspons can sr as a potnttmor-spprssor mchanism, th rol of tlomr-mdiatd chckpoints in stm-cll aging rmains anara of acti instigation. Mic ha long tlomrs

rlati to hmans and, ths, tlomr dysfnctionappars not to a major cas of stm-cll xhastionin many strains ofMus musculus. Accordingly, in thtlomras-knockot mos62, th lack of tlomrasactiityper se prodcs a modst phnotypic ffct inadlt mic59,63. Mrin tlomr lngth can madmor limiting and rdcd to a hmanizd lngth ysrial intrcrossing of mic that ar dficint in tlo-mras actiity. In this xprimntal stting, tlomrlngth coms shortr with ach sccssi gnrationntil tlomr dysfnction nss with dramatic phno-typic ffcts, ths proiding a modl systm to addrssth stm-cll iss.

Figure 3 | Fs f s s. A limited number of outcomes appear to be

possible for stem cells with heritable DNA damage. Although it is likely that many

mutational events do not lead to any alteration of stem-cell function, significant

damage is expected to induce apoptosis, senescence, transformation or dysfunction.

Importantly, these outcomes are not necessarily mutually exclusive; for instance, manygenetic events associated with stem-cell dysfunction (for example, the oncogenic

translocation that fuses BCRandABL (forming the Tyr kinase BCR/ABL) in

haematopoietic stem cells (HSCs)) are also associated with subsequent transformation.

Examples of DNA lesions associated with each outcome are indicated. Mutations in RAS

and the tumour-suppressor p53 are associated with transformation, whereas loss of the

long arm of chromosome 5 (5q) or the Y-chromosome are associated with dysfunction

of HSCs, manifesting as myelodysplasia (MDS). Unrepaired double-strand DNA breaks

(DSBs) and telomere dysfunction induce apoptosis and senescence, respectively.

SA-SP, senescence-associated secretory phenotype.

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Chromosome 9p21

Exon 1

p15INK4b p16INK4a ARF

2 1 1 2 3

CDK4/6 MDM2

p53

CHK1 and/or CHK2

ATM and/or ATR

DNA damage (for example,telomere dysfunction, ROS,stalled replication forks)

p21CIPpRB family

Senescence Apoptosis

Region of linkage disequilibrium

Human 9p21 22,000k 22,100k

ANRIL

ARF

p15INK4b

p16INK4a

a

b

** * * *** ** *

Animals with dysfnctional tlomrs dlop fa-trs of prmatr aging casd y th actiation ofsnscnc and apoptosis mchanisms in crtain slf-rnwing compartmnts sch as HSCs, th intstinal

crypt and th tsts59,6366. Dficincy of p53 rscs manyof th stm-cll dfcts in mic that haror dfctitlomrs, t dos not xtnd th lifspan of ths miccas of incrasd tmorignsis67,68. by contrast, lossof p21CIP, a p53 transcriptional targt that potntly inhi-its th cll cycl (FIG. 4a), partially xtnds th longityof mic with tlomr dysfnction withot incrasdtmorignsis, and attnats som of th prolifratidfcts that ar sn in arios stm-cll compartmntsof tlomr-dficint mic66. Thrfor, DNA dam-ag indcd y tlomr shortning is partly snsdand managd throgh p53, and p53 xrts importantanti-prolifrati ffcts in stm clls throgh p21CIP.

Senescence contributes to ageing. DNA damag andtlomr dysfnction appar to actiat th classicaltmor-spprssor mchanisms of snscnc andapoptosis. Snscnc rqirs actiation of th rtino-lastoma (Rb) and/or p53 protins and xprssion ofthir rglators, most prominntly p16INK4a and ARF(ReFs 6971)(FIG. 4a). Th notion that snscnc pr-nts cancr is wll-spportd and is not controrsial(riwd in ReFs72,73). Th xprssion of markrs ofsnscnc sch as snscnc-associatd-galactosidasand p16INK4a markdly incrass with aging in manytisss from disparat mammalian spcis (riwd inReF. 73; s also th Riw y Campisi and DAdda diFagagna in this iss). Caloric rstriction (CR) potntlyslows aging in rodnts, and CR and its rlatd ditarychangs rtard or n aolish th ag-indcd incrasin th xprssion of snscnc markrs, inclding thxprssion of p16INK4a(ReFs 7476). Proocatily, CR,similar to p16INK4a dficincy77, nhancs stm-cll fnc-tion with aging78, which sggsts th possiility that CRmay slow aging in mammals y dcrasing th actiation

of snscnc in slf-rnwing compartmnts.A rol for ROS in snscnc ars particlar rl-

anc. ROS indcs snscnc in crtain cll-cltrsystms79,80 t may also ha an important rol in ffct-ing th snscnt phnotyp81. In ATM-dficint mosHSCs, incrasd ROS lls appar to compromis HSCfnction in part throgh a p38MAPK-dpndnt actiationofInk4a/Arfxprssion34,35, which can attnatd yantioxidants. Likwis, HSCs that lack th FOXO trans-cription factors show diminishd slf-rnwal and pr-matr xhastion ndr conditions of incrasd ROSprodction82. Thrfor, FOXO transcription factorsmaintain HSC qiscnc and srial, primarily iath rglation of physiological lls of ROS. WhilFOXO-dficint HSCs show ROS-dpndnt nhancdcll-cycl ntry and incrasd apoptosis, incrasd ROSmay also rslt in th accmlation of DNA damagand nschdld actiation of snscnc mchanismsin this stm-cll compartmnt in th long trm.

Althogh th xprssion of snscnc markrsis associatd with aging, this osration dos notstalish a casal rlationship twn snscnc andaging. Rcnt stdis of slf-rnwal in HSCs, NSCsand pancratic islt clls from p16INK4a-dficint andp16INK4a-orxprssing mic ha gn to addrss thisiss43,49,77,83. Ths rslts showd that incrasing llsof p16INK4a ar not only associatd with aging, t partly

contrit to th ag-indcd rplicati failr of thstisss. In all thr compartmnts, p16INK4a dficincyattnatd th ag-indcd dclin in prolifrationand fnction. Likwis, orxprssion of p16 INK4aattnatd HSC fnction and islt prolifration in anag-dpndnt mannr (FIG. 2). Th ffcts of p16INK4aloss wr consistnt across ths disparat slf-rnwingtisss, sggsting that p16INK4a can promot agingin tisss that ar dlopmntally distinct. Howr,th loss of p16INK4a did not compltly arogat thffcts of aging in any of th organs stdid, indicat-ing that p16INK4a-indpndnt aging occrs in ach ofths compartmnts.

Figure 4 | SNPs n - phnps h INK4a/ARF/INK4b s n

hn hs 9p21. | Proteins encoded by the INK4/ARFlocus on

chromosome 9p21 regulate the p53 and retinoblastoma protein (pRB) tumour-

suppressor pathways to promote senescence (p53 and pRB-family activation) or

apoptosis (p53 activation). Activation of p53 in response to several types of DNA damage

also can occur via an ataxia-telangiectasia mutated (ATM)/ataxia telangiectasia andRad3-related (ATR)-mediated pathway independent of ARF function. | Single

nucleotide polymorphisms that are significantly associated with the indicated

phenotypes are shown (frailty, green; vascular heart disease, red; type 2 diabetes

mellitus, orange). The open reading frames for p16INK4a, ARF and p15INK4b are indicated,

as is the ANRIL transcript. The large (>100 kb) region of linkage disequilibrium is also

indicated. CDK4/6, cyclin-dependent kinases-4/-6; CHK1/2, checkpoint kinases-1/-2;

MDM2, murine double minute-2, p53-binding protein; ROS, reactive oxygen species.

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Single nucleotide

polymorphism

A common, ingl-ba

diffrnc in a gn among

individual within a pci.

Frailty

A clinically validatd, functional

maur ud in clinical

griatric. It i cord a a

continuou variabl uing a

ri of routin, aily

maurd tt uch a gait

pd. Frail individual ar l

abl to liv indpndntly, ar

mor likly to harbour co-morbid illn, and xhibit

incrad mortality.

Linkage disequilibrium

(LD). A maur of gntic

aociation btwn alll at

diffrnt loci, which indicat

whthr alllic or markr

aociation on th am

chromoom ar mor

common than xpctd. Loci

ar gnrally conidrd to b

in trong LD if thir corrlation

i highr than a pr-dfind

cut-off (for xampl, 0.8).

Rlatd osrations ha likwis sggstd a pro-aging rol for p53 and its ffctors in mic66,84,85 andhmans86. Th cas for p53, howr, appars to morcomplicatd cas p53 and its downstram ffctorssch as p21CIP also ha important rols in rglating thDNA-damag rspons. In fact, an intriging rcnt stdyy Srrano and collags, who sd carflly dsigndtransgnic strains, has shown that incrasd ARF andp53 actiity can incras th mrin lifspan y prnt-ing cancr withot an attndant incras in organismalaging87. Additionally, HSCs from p21CIP-dficint micdmonstrat prmatr xhastion88, consistnt withth notion that a p53- and p21CIP-dpndnt cll-cyclpas in rspons to DNA damag may importantfor stm-cll longityin vivo. Ths rslts sggstthat p53 actiation can oth pro-aging and anti-aging dpnding on th natr and dration of th strsshind its actiation.

Aging and h INK4/ARFou

Th dscrid links twn stm-cll fnction and

aging prdict that indiidals who diffrntially rg-lat snscnc-promoting mchanisms might xhiitdiffrnt prdispositions to cancr rss aging.Accordingly, hypomorphic allls that affct p16 INK4a orp53 fnction and that ar associatd with incrasd typsof cancr ar wll dscrid (riwd in ReF. 73). Rcntdata also sggst that non-coding polymorphisms narth opn rading frams (ORFs) of p16 INK4a, ARF andp15INK4 modify th onst of ag-associatd phnotypsin hmans. In a rmarkal sris of rcnt stdis,ingl nuclotid polymorphim (SNPs) that ar ry clos(1 M fromth rlatd ORFs ar wll stalishd99 and, thrfor, thINK4/ARFlocs appars wll within th rang of schrglatory lmnts. Althogh thr has n a rcntdscription of an apparntly non-protin-coding tran-script in this rgion (ANRIL100; FIG. 4b), thr dos notappar to anothr protin-coding transcript narths SNPs. Thrfor, in light of th mrin gnticstdis that link Ink4a/Arfand stm-cll fnction, pro-

tins ncodd y th locs ar th strongst candidatsto mdiat th ffcts of ths polymorphisms on thincidnc of ths common hman disass that arassociatd with aging.

Ouanding quion

W li that th data drid from disparat rodntand hman xprimntal systms spport th iw thata dclin in th rgnrati fnction of stm clls withag contrits to mammalian aging and ag-associatddisas. Gin this modl, a fw crcial qstions facingth fild rmain.

Does telomere dysfunction affect human ageing?Animportant iss is whthr sfficint tlomr attritionoccrs in hman slf-rnwing compartmnts dringphysiological aging to actiat a DNA-damag rsponsand th ssqnt compromis of rplicati fnc-tion. W fl that th crrnt data do not yt proida clar answr. Hmans who haror short tlomrscas of congnital dficincis of componnts of thtlomras complx (th RNA componnt TeRC, tlom-ras rrs transcriptas (TeRT) or dyskrin) dlopan ag-rlatd failr of on marrow or lng101105.Moror, tlomr shortning in th lir prcds thonst of lir failr (cirrhosis) in patints with chronichpatitis106109, an association that has n alidatd in

th tlomras-dficint mos110. A fw stdis hadmonstratd a corrlation twn tlomr lngthin priphral lood lymphocyts (PbLs) and th onstof crtain disass that ar associatd with aging. Schstdis in non-noplastic disass ha shown that PbLtlomr lngths can proid a iomarkr that forcaststh dlopmnt of athrosclrosis111,112, cancr risk113,114and mortality115. Ths rslts spport a connctiontwn tlomr dysfnction and hman aging.

by contrast, argmnts can mad against tlo-mr-asd aging in hmans. Mrin aging appars toha many similaritis to hman aging, yt w lithat it occrs largly indpndntly of tlomr lngth.

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Additionally, althogh tlomr lngth shortns withhman aging in many tisss, orall tlomr lngthdos not linarly corrlat with ag, with th most rapidshortning occrring y yong adlthood102,105,116. It ispossil, howr, that man tlomr lngth is a poorindicator of tlomr stats cas th shortst tlomrappars to capal of actiating th DNA-damagrspons117.

Althogh th osrations of on marrow failrand plmonary firosis in patints with dfcti tlo-mras componnts stalishs that tlomr dysfnc-tion can cas hman disas, som indiidals fromsch kindrds who haror th dfcti alll do notdmonstrat any ort phnotyp. In fact, htrozygosTeRT and TeRC grmlin mtations in hmans showstrong anticipation102,104,105, which mans that thphnotypic ffcts of th mtation ar mor srin ssqnt gnrations; this is analogos to find-ings in tlomras-dficint mic. Thrfor, TeRT orTeRC dficincy is most phnotypically prononcd inpatints that also inhrit for-shortnd tlomrs from

thir parnts, sggsting that tlomras dficincyper semay not sfficint to indc ort ag-associatdpathology. Importantly, howr, stdis of th naf-fctd carrirs of ths kindrds ha so far not nsfficint to xcld stl, ag-associatd phnotyps,and phnotypic consqncs of tlomras dficincymay notd in sch indiidals with mor carflosration. Considrd in aggrgat, w li that thdata ar consistnt with oth tlomr-indpndnt andtlomr-dpndnt aging of hman stm clls.

How do senescence factors contribute to ageing?Thsimplst xplanation for how p16INK4a limits rplica-ti fnction with ag wold that th indction ofp16INK4a, in rspons to snscnc-promoting cs,intrinsically limits rplication y indcing snscncor at last dcrasing cll-cycl ntry. For xampl,pancratic -cll rplication is known to rqir cyclin-dpndnt kinas-4 (CDK4) actiity118,119, th iochmi-cal targt of p16INK4. bcas p16INK4a accmlats withphysiological aging in hman and rodnt islts49,120,and th loss of p16INK4a agmnts islt prolifration inan ag-dpndnt way49, p16INK4a might dirctly limitth rplication of slf-rnwing clls with aging. Thiscll-atonomos modl is frthr spportd y th factthat th nhancd fnction of p16INK4a-dficint HSCs issn n whn sch clls ar transplantd into p16INK4a-

comptnt rcipint mic77,83. Importantly, howr,p16INK4a xprssion incrass significantly with agingin linag-ngati on marrow clls (of which 1 M) rglation of anothr protin-codingor microRNA transcript. Stdis in hmans and mic

to ndrstand whthr this corrlation rflcts an ffctofINK4/ARF-asd tmor-spprssor mchanisms onhman aging ar moing at a rapid pac. Sch ffortsar hamprd, howr, y a larg rgion of linkagdisqilirim that compriss th INK4a/ARFlocs aswll as almost all of th disas-corrlatd SNPs (FIG. 4b),which implis that th rlant gntic rglatory ntscold hiding anywhr within a larg rgion arondp15INK4b. Rgardlss of th mchanistic asis, howr, asth minor alll frqncis of th rlant SNPs in achof ths rports ar larg (>10%), ths polymorphismsappar to ha a major rol in dtrmining th onst ofths highly common, ag-indcd phnotyps.

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conuion

In smmary, w li th data sggst that w growold partly cas or stm clls grow old as a rslt ofmchanisms that spprss th dlopmnt of cancror a liftim. In this rgard, or slf-rnwing stmclls appar to grow old cas of hrital intrinsicnts, sch as DNA damag, t also d to cll-xtrinsic nts sch as altrations in thir spportingnichs. Anti-cancr mchanisms sch as snscnc and

apoptosis, which rly on tlomr shortning and/orp53 and p16INK4a actiation, appar to promot agingjst as thir failr is associatd with cancr. W lithat a frthr, mor prcis mchanistic ndrstandingof this procss will rqird for this knowldgcan translatd into hman anti-aging thrapis. Forth tim ing, th most prdnt, clinically alidatdadic appars still to : dont smok, at rasonalyand tak xrcis.

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setting of BMI1 deficiency.

AcknowledgementsWe thank E. Sahin, J.-H. Paik, T. Letai and K. Mohlke for criti-

cal reading and advice on the manuscript. R.A.D. is a director,

co-founder and scientific advisor of AVEO Pharmaceuticals,

Inc. in Cambridge, Massachusetts, USA, and is an American

Cancer Society Research Professor and an Ellison Medical

Foundation Senior Scholar. This work was supported by grants

from the Sidney Kimmel Foundation for Cancer Research

(N.E.S.), the Ellison Medical Foundation (N.E.S. and R.A.D.),

the American Federation of Aging Research (N.E.S.), the

Burroughs Wellcome Fund (N.E.S.) and the US National

Institutes of Health (R.A.D.). R.A.D. is supported by the LeBow

Fund to Cure Myeloma and the Robert A. and Renee E. Belfer

Foundation Institute for Innovative Cancer Science.

Competing interests statement

The authors declare no competing financial interests.

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How stem cells age and why

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