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BiologyReviewpart3(bysomewikimaterial,EssentialCellBiology,andpersonaladds)

(Maytheforcebewithus)

Cellularsenescenceandmedicalimplication

Cellularsenescenceisthephenomenonbywhichnormal

diploidcellslosetheabilitytodivide,normallyafterabout

50celldivisionsinvitro.Somecellsbecomesenescentafter

fewerreplicationscyclesasaresultofDNAdoublestrandbreaks,toxins,etc.Thisphenomenonisalsoknownas

"replicativesenescence",the"Hayflickphenomenon",orthe

HayflicklimitinhonourofDr.LeonardHayflickwhowasthe

firsttopublishthisinformationin1965.InresponsetoDNA

damage(includingshortenedtelomeres),cellseitherageor

self-destruct(apoptosis,programmedcelldeath)ifthe

damagecannotbeeasilyrepaired.Inthis'cellularsuicide',

thedeathofonecell,ormore,maybenefittheorganismasawhole.Forexample,inplantsthedeathofthewater-

conductingxylemcells(tracheidsandvesselelements)

allowsthecellstofunctionmoreefficientlyandsodeliver

watertotheupperpartsofaplant.Theonesthatdonotself-

destructremainuntildestroyedbyoutsideforces.

Asnotedabove,senescenceisnotuniversal,andsenescence

isnotobservedinsingle-celledorganismsthatreproducethroughtheprocessofcellularmitosis.Moreover,cellular

senescenceisnotobservedinseveralorganisms,including

perennialplants,sponges,corals,andlobsters.Inthose

specieswherecellularsenescenceisobserved,cells

eventuallybecomepost-mitoticwhentheycannolonger

replicatethemselvesthroughtheprocessofcellularmitosis;

i.e.,cellsexperiencereplicativesenescence.Howandwhy

somecellsbecomepost-mitoticinsomespecieshasbeenthesubjectofmuchresearchandspeculation,but(asnoted

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above)itiswidelybelievedthatcellularsenescenceevolved

asawaytopreventtheonsetandspreadofcancer.Somatic

cellsthathavedividedmanytimeswillhaveaccumulated

DNAmutationsandwouldthereforebeindangerof

becomingcancerousifcelldivisioncontinued.

Lately,theroleoftelomeresincellularsenescencehas

arousedgeneralinterest,especiallywithaviewtothe

possiblegeneticallyadverseeffectsofcloning.The

successiveshorteningofthechromosomaltelomereswith

eachcellcycleisalsobelievedtolimitthenumberof

divisionsofthecell,thuscontributingtoaging.Therehave,

ontheotherhand,alsobeenreportsthatcloningcouldaltertheshorteningoftelomeres.Somecellsdonotageandare,

therefore,describedasbeing"biologicallyimmortal".Itis

theorizedbysomethatwhenitisdiscoveredexactlywhat

allowsthesecells,whetheritbetheresultoftelomere

lengtheningornot,todividewithoutlimitthatitwillbe

possibletogeneticallyalterothercellstohavethesame

capability.Itisfurthertheorizedthatitwilleventuallybe

possibletogeneticallyengineerallcellsinthehumanbodytohavethiscapabilitybyemployinggenetherapyand,

therefore,stoporreverseaging,effectivelymakingthe

entireorganismpotentiallyimmortal.

Thelengthofthetelomerestrandhassenescenceeffects,

telomereshorteningactivateextensivealterationsin

alternativeRNAsplicingthatproducesenescencetoxins

suchasprogerinthatdegradesthetissueandmakesitmore

susceptibletofailure.Cancercellsareusuallyimmortal.Inabout85%oftumors,

thisevasionofcellularsenescenceistheresultofup-

activationoftheirtelomerasegenes.Thissimpleobservation

suggeststhatreactivationoftelomeraseinhealthy

individualscouldgreatlyincreasetheircancerrisk.

Whethercellsenescenceplaysanyroleinorganismalaging

isatpresentunknown,andisanactiveareaofinvestigation.

Mousemutantslackingtelomerasedonotimmediatelyshowacceleratedaging.

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CellularDeath,NecrosisandApoptosis

Necrosisistheprematuredeathofcellsandlivingtissue.

Necrosisiscausedbyfactorsexternaltothecellortissue,

suchasinfection,toxins,ortrauma.Thisisincontrastto

apoptosis,whichisanaturallyoccurringcauseofcellular

death.Whileapoptosisoftenprovidesbeneficialeffectsto

theorganism,necrosisisalmostalwaysdetrimentalandcan

befatal.

Cellsthatdieduetonecrosisdonotusuallysendthesame

chemicalsignalstotheimmunesystemthatcellsundergoing

apoptosisdo.Thispreventsnearbyphagocytesfromlocatingandengulfingthedeadcells,leadingtoabuild-upofdead

tissueandcelldebrisatornearthesiteofthecelldeath.For

thisreason,itisoftennecessarytoremovenecrotictissue

surgically,aprocessknownasdebridement.

Causesofnecrosis:

Cellularnecrosiscanbeinducedbyanumberofexternalsources,includinginjury,infection,cancer,infarction,

poisons,ROS(ReactiveOxygenSpecies),andinflammation.

Forexample,aninfarction(blockageofbloodflowto

musculartissue)causesnecrosisofmuscletissueduetolack

ofoxygentotheaffectedcell,suchasoccursinamyocardial

infarction--aheartattack.Certainspider(brownrecluse)

andsnake(rattlesnake,Bothrops)venomscancause

necrosisofthetissuenearthebitewound,ascanaGroupAstreptococcusinfection(oneofthe"flesh-eating"bacteria).

Necrotictissuedoesnotundergothesamechemical

reactionsthatnormallydyingapoptotictissuedoes.The

suddenfailureofonepartofthecelltriggersacascadeof

events.Inadditiontothelackofchemicalsignalstothe

immunesystem,cellsundergoingnecrosiscanrelease

harmfulchemicalsintothesurroundingtissue.Inparticular,

cellscontainsmallorganellescalledlysosomes,whicharecapableofdigestingcellularmaterial.Damagetothe

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lysosomemembranecantriggerreleaseofthecontained

enzymes,destroyingotherpartsofthecell.Worse,when

theseenzymesarereleasedfromthenon-deadcell,theycan

triggerachainreactionoffurthercelldeath.Ifasufficient

amountofcontiguoustissuenecrotizes,itistermed

gangrene.Propercareandtreatmentofwoundsoranimal

bitesplaysakeyroleinpreventingthistypeofwidespread

necrosis.Duringasurgicalbiopsy,thisnecrosischain-

reactionishaltedbyfixationorfreezing.[citationneeded]

Necrosistypicallybeginswithcellswelling,chromatin

digestion,anddisruptionoftheplasmamembraneand

organellemembranes.LatenecrosisischaracterizedbyextensiveDNAhydrolysis,vacuolationoftheendoplasmic

reticulum,organellebreakdown,andcelllysis.Therelease

ofintracellularcontentafterplasmamembraneruptureis

thecauseofinflammationinnecrosis.

Apoptosis(keyfeatures)

Isaformofcellulardeathtriggeredbyactivationofdeathreceptors,withdrawalofsurvivalfactors,orasa

resultofDNAdamage

Apoptosisinvolvestheorderlydismantling(makinginpieces)ofadyingcellscontents

Proteasescalledcaspasesarekeymediatorsofapoptosis.Initiatorcaspasescanbeactivatedinseveral

ways,includingthroughthereleaseofcytochromec

frommitochondria.Initiatorcaspasesactivateexecutionercaspases,whichinturnactivateother

apoptosisproteins.

Stepbystepinductionofapoptosis:

1.Celldeathsignals,suchasligandsonthesurfaceofacytotoxicTlymphocyte,canleadtoapoptosis.

2.Ligandbindstoadeathreceptoronthesurfaceofatargetcell.Bindingcausesclusteringofreceptorsand

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recruitmentodadaptorproteinsinthetargetcell,

resultinginclusteringofinitiatorprocaspase-8protein

3.Initiatorcaspasesthenbecomeactivated4.Theinitiatorcaspasesinturnactivatetheexecutioner

caspase-3,akeyinitiatorofapoptosis

5.Whensurvivalfactorsarenolongerpresent6.Death-promotingproteinsaccumulate,

counterbalancinganti-apoptoticproteinsatthe

mitochondrialoutermembranecausingthereleaseof

cytochromec

7.Thislastformsacomplexwithotherproteins,resultinginactivationofaninitiatorcaspase-98.Theinitiatorcaspaseinturnactivatestheexecutionerscaspase-3,triggeringapoptosis

9.DNAdamagecanalsoleadtoapoptosisthroughtheactivityoftheproteinp53

Medicalimplication(thxwiki)

DefectiveapoptoticpathwaysThemanydifferenttypesofapoptoticpathwayscontaina

multitudeofdifferentbiochemicalcomponents,manyof

themnotyetunderstood.[34]Asapathwayismoreorless

sequentialinnature,itisavictimofcausality;removingor

modifyingonecomponentleadstoaneffectinanother.Ina

livingorganismthiscanhavedisastrouseffects,ofteninthe

formofdiseaseordisorder.Adiscussionofeverydisease

causedbymodificationofthevariousapoptoticpathwayswouldbeimpractical,buttheconceptoverlyingeachoneis

thesame:thenormalfunctioningofthepathwayhasbeen

disruptedinsuchawayastoimpairtheabilityofthecellto

undergonormalapoptosis.Thisresultsinacellthatlives

pastits"use-by-date"andisabletoreplicateandpasson

anyfaultymachinerytoitsprogeny,increasingthe

likelihoodofthecellbecomingcancerousordiseased.

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InhibitionofApoptosis

Inhibitionofapoptosiscanresultinanumberofcancers,

autoimmunediseases,inflammatorydiseases,andviral

infections.Itwasoriginallybelievedthattheassociated

accumulationofcellswasduetoanincreaseincellular

proliferation,butitisnowknownthatitisalsoduetoa

decreaseincelldeath.Themostcommonofthesediseasesis

cancer,thediseaseofexcessivecellularproliferation,which

isoftentimescharacterizedbyanoverexpressionofIAP

familymembers.Asaresult,themalignantcellsexperience

anabnormalresponsetoapoptosisinduction:cycle

regulatinggenes(suchasp53,rasorc-myc)aremutatedorinactivatedindiseasedcells,andfurthergenes(suchasbcl-

2)alsomodifytheirexpressionintumors.

HyperactiveApoptosis

Ontheotherhand,lossofcontrolofcelldeath(resultingin

excessapoptosis)canleadtoneurodegenerativediseases,

hematologicdiseases,andtissuedamage.Theprogressionof

HIVisdirectlylinkedtoexcess,unregulatedapoptosis.Inahealthyindividual,thenumberofCD4+lymphocytesisin

balancewiththecellsgeneratedbythebonemarrow;

however,inHIV-positivepatients,thisbalanceislostdueto

aninabilityofthebonemarrowtoregenerateCD4+cells.In

thecaseofHIV,CD4+lymphocytesdieatanacceleratedrate

throughuncontrolledapoptosis,

TheprogressionofthehumanimmunodeficiencyvirusinfectionintoAIDSisprimarilyduetothedepletionofCD4+

T-helperlymphocytesinamannerthatistoorapidforthe

body'sbonemarrowtoreplenishthecells,leadingtoa

compromisedimmunesystem.

Virusescantriggerapoptosisofinfectedcellsviaarangeof

mechanismsincluding:

Receptorbinding ActivationofproteinkinaseR(PKR)

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Interactionwithp53 ExpressionofviralproteinscoupledtoMHCproteins

onthesurfaceoftheinfectedcell,allowingrecognition

bycellsoftheimmunesystem(suchasNaturalKillerandcytotoxicTcells)thattheninducetheinfectedcell

toundergoapoptosis

KeypointsofthebiologyofCancer

Cancercellsproliferateinanuncontrolledwayandare

capableofspreadingbyinvasionandmetastasis Thebalancebetweencelldivisionanddifferentiationis

disruptedincancers,leadingtoaprogressiveincrease

inthenumberofdividingcells

Cancercellsareanchorage-independent,exhibitadecreasedsusceptibilitytodensity-dependent

inhibitionofgrowth,andarecapabletoreplenishtheir

telomeres

Sustainedtumorsgrowthrequiresanetworkofbloodvesselswhosegrowthistriggeredbyanincreased

productionofangiogenesisactivatorsandadecreased

productionofangiogenesisinhibitors

Cancercellsinvadesurroundingtissues,enterthecirculatorysystem,andmetastasizetodistantsites.

Invasionisfacilitatedbydecreasedcell-celladhesion,

increasedmotility,andsecretionofproteasesthat

degradetheextracellularmatrixandbasallamina.Onlyatinyfractionofthecancercellsthatenter

bloodstreamestablishsuccessfulmetastases

Sitesofmetastasesaredeterminedbythelocationofthefirstcapillarybedaswellasbyorgan-specific

conditionsthatinfluencecancercellgrowth

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Maincausesofcancer:

Somecancersarecausedbycertainkindsofchemicals,includingthosefoundintobaccosmoke.Chemicals

causecancerthroughamultistepprocessinvolving

initiation,promotion,andtumorprogression.Initiation

isbasedonDNAmutation,whereaspromotion

involvesaprolongedperiodofcellproliferation

accompaniedbyselectionofcellsexhibitingenhaced

growthproperties.Duringtumorprogression,

additionalmutationsaswellasepigeneticchangesin

geneexpressionproducecellswithincreasinglyaberranttraits

Cancercanalsobecausedbyionizingradiationandbysunlight,bothwhichtriggerDNAmutations,aswellas

bycertainviruses,bacteriaandparasites

Somecancer-causingvirusesactbydirectlytriggeringcellproliferation,eitherthroughtheactionofviral

genesorbyalteringthebehaviorofcellulargenes.

Othervirusesandinfectiousagentscreatetissuedestructionthatindirectlystimulatescellproliferation

underconditionsinwhichDNAdamageislikely

Oncogenesandtumorsuppressorgenes:

Oncogenesaregeneswhosepresencecancausecancer.Althoughoncogenesaresometimesbroughtintocells

byviruses,moreoftentheyarisefromnormalcellulargenes(proto-oncogenes)bypointmutation.Gene

amplification.Chromosomaltranslocation,localDNA

rearrangements,orinsertionalmutagenesis

Manyoftheproteinsproducedbyoncogenesaresignalingpathwaycomponents,suchasgrowthfactors,

receptors,plasmamembraneGTP-bindingproteins,

non-receptorsproteinkinases,transcriptionfactors,

andcellcycleorcelldeathregulators.Oncogenescode

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forabnormalformsorexcessivequantitiesofsuch

proteins,therebyleadingtoexcessivecellproliferation

Tumorsuppressorgenesaregeneswhoselossorinactivationcanleadtocancer.Susceptibilitytocancer

isincreasedinpeoplewhoinheritdefectivetumor

suppressorgenes

Thegeneticinstabilityofcancercellsfacilitatestheacquisitionofmultiplemutations