Ionizing Radiation-Induced Brain Cell Aging And The Potential Underlying Molecular Mechanisms Part 3

Txoj kev autophagy tswj cov protein ntau suav nrog kev txhawb nqa misfolding thiab degradation ntawm aggregated proteins. Mitochondrial zoo tswj yuav tshem tawm cov puas mitochondria los ntawm autophagy.

Qhov tseem ceeb ntawm autophagy hauv kev tswj lub cev kev noj qab haus huv tau raug lees paub los ntawm cov voj voog kev kawm. Ntxiv nrog rau nws lub luag haujlwm hauv kev saib xyuas kev noj qab haus huv, nws tseem ua lub luag haujlwm tseem ceeb hauv kev tswj hwm kev nco.

Cov txheej txheem autophagy yog txheej txheem tseem ceeb rau tshem tawm cov khoom metabolic hauv cov hlwb. Nws ua rau lub cev noj qab haus huv los ntawm kev rhuav tshem cov hlwb tuag thiab tso cov khoom noj tshiab uas muaj txiaj ntsig zoo. Cov kev tshawb fawb tau pom tias autophagy tseem txhawb nqa kev muaj sia nyob ntawm neuronal thiab tshem tawm cov plaques protein uas tshwm sim los ntawm kev sib xyaw ua ke lom. Cov plaques no ua haujlwm zoo li lawv thaiv cov kev sib txuas lus ntawm cov neurons, ua rau muaj teeb meem xws li nco tsis tau.

Raws li peb muaj hnub nyoog, kev ua haujlwm ntawm autophagy machinery kuj poob qis. Qhov kev poob qis no tsis tsuas yog cuam tshuam rau lub cev tiv thaiv kab mob thiab cov metabolism, tab sis kuj cuam tshuam rau kev ua haujlwm neuronal thiab kev noj qab haus huv. Cov teeb meem no yuav ua rau kev txawj ntse poob qis thiab tshwm sim ntawm cov kab mob neurodegenerative hauv cov neeg laus. Yog li, yog tias autophagy tuaj yeem txhim kho, nws tuaj yeem ncua kev laus ntawm tib neeg lub cev thiab lub hlwb, txhawb kev noj qab haus huv ntawm tes, thiab txhim kho kev nco thiab kev txawj ntse.

Txhawm rau txhim kho kev ua haujlwm autophagy, peb tuaj yeem siv qee qhov kev hloov pauv hauv kev ua neej yooj yim, xws li hloov pauv kev noj zaub mov, ua kom muaj zog, thiab tswj kev pw tsaug zog txaus. Tsis tas li ntawd, qee cov tshuaj kuj tau raug pov thawj los txhawb kev ua haujlwm ntawm autophagy mechanism, xws li siv cov tshuaj vitamin D loj los txhawb autophagy thiab txhim kho lub hlwb ua haujlwm.

Hauv cov ntsiab lus, autophagy mechanism plays lub luag haujlwm tseem ceeb hauv kev saib xyuas lub cev kev noj qab haus huv thiab kev nco. Cov txheej txheem uas txhim kho autophagy tuaj yeem pab tib neeg ncua lub cev kev laus thiab txo qhov kev pheej hmoo ntawm cov kab mob neurodegenerative. Los ntawm kev txhawb nqa kev ua haujlwm ntawm autophagy mechanism los ntawm kev ua neej zoo thiab kev kho tshuaj, peb tuaj yeem tswj hwm lub cev kev noj qab haus huv thiab nco, thiab ua lub neej zoo dua. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub ntxiv los txhim kho kev nco

Autophagy cargo receptors lees paububiquitin-hloov mitochondria, ua kom yooj yim rau lawv cov sequestration hauv autophagosomesand lysosome-mediated breakdown. Cov qauv molecular ntsig txog kev puas tsuaj mitochondrial kuj yog ib qho laj thawj rau kev tsim cov inflammatory cytokines.

Tus txheej txheem ntawm autophagy los tswj senescence yog los txhawb lub disintegration thiab degradation ntawm lub nuclear lamina. Cov amino acids dawb tso tawm los ntawm lysosome thaum lub sij hawm muaj hnub nyoog txhawb kev ua haujlwm anabolic, suav nrog kev tsim cov cytokineshat ua rau SASP (Daim duab 2).

3.1. Oxidative Stress

Endogenous ROS ntau lawm yog ib tug byproduct ntawm li niaj zaus cell metabolism, tab sis exogenousROS ntau lawm kuj tshwm sim vim hluav taws xob thiab tshuaj compounds [107]. ROS tuaj yeem tsim los ntawm ntau qhov chaw tom qab irradiation [108]. Classical radiobiology qhia tau hais tias piv nrog rau feem ntau ntawm lwm yam kev ntxhov siab oxidative, tus nqi ntawm ROS uas tsim los ntawm theradiolysis ntawm dej yog me dua thiab lub sij hawm txij nkawm luv dua. Raug ionizingradiation yuav tsim ROS nyob rau hauv 2 nm ntau ntawm DNA thiab tsim complex DSBs, yog li ua rau siab cytotoxicity.

Lub mitochondrial membrane-bound nicotinamide adeninedinucleotide phosphate oxidases (NOX) lossis lwm yam oxidases yuav muaj kev sib txuas tsis ncaj nrog DDR txoj hauv kev.

Cov oxidases yog lub hauv paus tseem ceeb ntawm cellular ROS tshwm sim los ntawm oxidative kev nyuaj siab. [109–111]. Cov hluav taws xob kuj tuaj yeem ua rau ROS tiam los ntawm cov peev txheej no los ntawm kev ua rau mitochondria, thiab txhawb NOX lossis lwm yam oxidases [110,111], ua rau ATP tso tawm, ion channel ua kom [112], thiab purinergic signaling [113]. Ib qho piv txwv ntawm kev puas tsuaj-txuas nrog cov qauv molecular (DAMP) pom tom qab irradiation yog ib qho kev nthuav qhia ntawm cov pab pawg neeg siab zog lub thawv 1 (HMGB1) protein, ib qho chromatin-binding nuclear protein uas ua los ntawm tus xov tooj hu-zoo li receptor 4 (TLR4) signaling los txhawb ntxiv ROS. kev tsim kho [114].

Kev ua haujlwm siab ROS tuaj yeem cuam tshuam ncaj qha rau macromolecules xws li lipids, nucleic acids, thiab cov protein. DNA puas, feem ntau nyob rau hauv daim ntawv ntawm strand so thiab cross-links, ua rau genomic mutations. Tsis tas li ntawd, ROS ua rau muaj kev ntxhov siab oxidative siab hauv cov hlwb uas cuam tshuam. Hauv cov hlwb, kev puas tsuaj oxidative nyob ntawm ROS concentration thiab qhov sib npaug ntawm cov txheeb ze ntawm ROS thiab antioxidants.

Thaum cov oxidant-antioxidant tshuav nyiaj li cas, oxidative kev nyuaj siab tshwm sim, hloov thiab rhuav tshem ntau intracellular macromolecules, raws li tau hais yav dhau los [115].Lub free-radical txoj kev xav ntawm kev laus yog muab tso tawm los ntawm Harman nyob rau hauv 1956, thiab nws tom qab qhia tau hais tias mitochondrial thawj ua pa. oxidative kev nyuaj siab [116] Kev laus yog nrog los ntawm kev nce hauv ROS qib thiab txo qis hauv kev ua haujlwm thiab kev qhia ntawm cov enzymes antioxidant, suav nrog superoxide dismutase, catalase, thiab glutathione peroxidase [117,118].

Tsis tas li ntawd, kev puas tsuaj los ntawm hluav taws xob tshwm sim qhia tau hais tias ntau tus yam ntxwv feem ntau ntawm cov xov tooj ntawm tes-thiab-tua, xws li kev hloov pauv ntawm somatic, uas tuaj yeem ua rau muaj kev loj hlob ntawm cov kab mob laus [119]. ROS thiab reactive nitrogenspecies (RNS) tua macromolecules thiab ua rau oxidative kev nyuaj siab, thiab cov txheej txheem no tau cuam tshuam rau ntau yam kab mob. Nws kuj tau pom tias txawm tias qis qis ntawm ROS thiab RNScan ua rau lub hlwb laus [120] .Qhov rhiab heev ntawm cov hlwb rau hluav taws xob yog xav tias yog nyob ntawm cov khoom tsim tawmROS.

Cov irradiation ntawm cov laus hlwb uas twb muaj ntau cov activeoxygen yuav undoubtedly overwhelm lub antioxidant system lub luag hauj lwm rau tshem tawm ntau npaum li cas ntawm oxygen metabolites [121]. Kev tiv thaiv antioxidant tiv thaiv kev kho mob thiab txo cov koob tshuaj IR hauv tib neeg cov ntshav txo qis thaum muaj hnub nyoog [122]. Cov kev tshawb fawb no qhia txog lub luag haujlwm ntawm oxidative stress regulation systems hauv kev txiav txim siab hluav taws xob rhiab heev ntawm senescent hlwb.

3.2. Mitochondrial Dysfunction

Mitochondria muaj nyob rau hauv neuronal dendrites thiab axons ntawm neurons, thiab lawv tsim cov adenosine triphosphate (ATP) uas yuav tsum tau rau electrochemical neurotransmissionand cell tu thiab kho [123].

Raws li cov hlwb thiab cov kab mob muaj hnub nyoog, qhov ua tau zoo ntawm theelectron thauj saw (ETC) zoo li poob qis, ua kom cov hluav taws xob xau thiab txo cov khoom ATP [124]. Feem ntau cov hlwb hauv hlwb qhia txog kev sib txuam ntawm cov dysfunctionalmitochondria, raws li pom nyob rau hauv kev sib piv cov kev tshawb fawb ntawm neurons thiab astrocytes nyob rau hauv nas ntawm ntau pawg hnub nyoog [125,126]. Nrog rau lub hnub nyoog nce, mitochondrial tsis ua haujlwm ua rau nce ROS ntau lawm, ua rau ntxiv mitochondrial degradation thiab tag nrho cov cell puas [127].

Lub luag haujlwm tseem ceeb ntawm cov pa oxygen nquag yog los qhib cov lus teb tsis tu ncua ntawm lub xeev.Yog tias ROS qib nce ntau dua li qhov pib, qhov tsis txaus ntseeg hauv ROS homeostasis tshwm sim, thaum kawg ua rau muaj hnub nyoog ntsig txog kev puas tsuaj [128]. Mitochondrial dysfunction kuj tuaj yeem ua rau kev laus ntawm ROS-txoj kev ywj pheej. Mitochondrial defects tuaj yeem cuam tshuam rau apoptosissignals los ntawm kev ua kom muaj kev cuam tshuam ntawm mitochondria rau cov lus teb rau kev ntxhov siab [129] thiab ua rau muaj kev mob tshwm sim los ntawm kev txhawb nqa ROS-mediated thiab / lossis permeability-relatedinflammasome activation [124].

Tsis tas li ntawd, kev ua haujlwm tsis zoo ntawm mitochondria tuaj yeem ua rau muaj kev cuam tshuam ncaj qha rau ntawm lub xov tooj ntawm tes thiab inter-organ crosstalk los ntawm kev cuam tshuam tsis zoo rau ntawm daim nyias nyias-endoplasmic reticulum interface [130].

Mitochondria cais tawm ntawm cov tsiaj lub hlwb qhia ntau yam kev hloov pauv hnub nyoog, suav nrog nce mitochondrial DNA oxidative puas tsuaj [131], mitochondrial o lossis fragmentation [132], nce tus naj npawb ntawm mitochondria nrog depolarizing daim nyias nyias [133], thiab impaired ETC function [134]. Kev hloov pauv thiab tshem tawm ntawm mitochondrialDNA (mtDNA) hauv cov neeg laus kuj tseem tuaj yeem ua rau kev laus [135].

Vim yog oxidativemicroenvironment nyob rau hauv mitochondria, mtDNA tsis muaj kev tiv thaiv histones. Qhov kev ua tau zoo ntawm mtDNA kho tshuab kuj tseem qis dua li ntawm nuclear DNA kho mechanisms.Li no, mtDNA tau xav tias yog lub hom phiaj tseem ceeb ntawm kev laus-txog kev hloov pauv ntawm somatic [136].

Thaum lub sij hawm kev loj hlob ntawm lub hlwb, qhov txawv txav mitochondrial tawg tuaj yeem ua rau mitochondrialdysfunction thiab ROS ntau dhau lawm, thaum kawg ua rau lub hlwb laus, kev paub tsis meej, thiab tus cwj pwm txawv txav [137].IR raug cuam tshuam tuaj yeem ua rau mitochondrial dysfunction, uas indirectly ua rau kev laus ntawm lub sij hawm. uas tshwm sim tom qab raug rau tsib Gy ntawm -irradiation yog raws li nram no.

Ua ntej, cellular ROS qib nce ntau hauv thawj ob peb feeb tab sis txo qis hauv 30 min. Tom qab ntawd, mitochondrial dysfunction tau kuaj pom 12 h tom qab irradiation, raws li pom los ntawm kev txo qis hauv kev ua haujlwm ntawm nicotinamide adenine dinucleotide (NADH) dehydrogenase, thawj regulator ntawm ROS tso tawm los ntawm ETC [138] .Limoli li al. soj ntsuam cov mitochondrial membrane muaj peev xwm nyob rau hauv unstable GM10115cells tom qab hluav taws xob raug.

 Lawv pom tias tus naj npawb ntawm cov mitochondria tsis ua haujlwm tau nce, thiab cov peev txheej mitochondrial tau txo qis [139]. IRionizes dej molecules (H2O), feem ntau ua rau zus tau tej cov •OH, lub ROS nrog lub siab tshaj plaws kev puas tsuaj-ua muaj peev xwm [140]. •OH tuaj yeem oxidize lom molecules, xws li cov protein thiab lipids [121,141].

Lub puab mitochondrial membrane muaj phospholipids, xws li phosphatidylcholine, phosphatidylcholine, thiab cardiolipin, uas yuav tsum tau rau optimization thiab pab lub zog ntawm ntau yam enzymes ntawm mitochondrialETC [142,143].

Ib qho kev hloov pauv hauv lipid profile ntawm daim nyias nyias, xws li qhov txo qis hauv cov ntsiab lus lipid thiab peroxidation, tuaj yeem ua rau lossis txhim kho kev tsim cov O2- ntawm electronleakage los ntawm ETC enzymes. Yog li ntawd, lub •OH tsim tawm vim irradiation induces mitochondrial oxidation ntawm phospholipid peroxidation, yog li txhawb O2- ntau lawm.

3.3. Telomere Attrition

Telomeres yog tshwj xeeb nuclear protein complexes uas tiv thaiv qhov kawg ntawm linear chromosomes nyob rau hauv eukaryotic hlwb. Telomeres raug khi los ntawm tus yam ntxwv polyprotein complextermed shelterin [144] uas tiv thaiv kev nkag mus ntawm DNA kho rau hauv telomeres uas tsis yog yuav "kho" vim muaj qhov pom tseeb DNA tawg, ua rau lub peev xwm qis rau kho DNA puas hauv cheeb tsam no.

Yog li, kev puas tsuaj telomere feem ntau ua rau cov cellular senescence thiab / lossis apoptosis [145,146]. Qhov poob-ntawm-kev ua haujlwm ntawm cov chaw nyob ua rau ua rau lub cev tsis muaj zog ntawm cov ntaub so ntswg sai thiab ua rau kev laus, txawm tias thaum telomeres yog qhov ntev [147].IR tuaj yeem ua rau cov cell proliferation, apoptosis, thiab senescence, tag nrho cov uas cuam tshuam nrog telomeres, los ntawm oxidative puas thiab DNA cuam tshuam.

Ib txoj kev tshawb fawb ntawm peripheralblood tau los ntawm 83 Chornobyl cov tshuaj ntxuav tau pom tias piv nrog cov neeg mob ntshav qab zib, qhov txheeb ze ntev ntawm telomeres hauv cov tshuaj ntxuav Chornobyl yog luv luv. Txoj kev tshawb no qhia tias cov tshuaj irradiation qis ua rau telomere luv, thiab cov kev hloov pauv tau txhawb nqa txawm tias 20 xyoo tom qab irradiation [148].

Microglial senescence kuj tseem cuam tshuam rau qhov luv ntawm telomeres. Qhov txo qis hauv telomere ntev inmicroglia tuaj yeem ua rau lub peev xwm ntawm cov hlwb no los teb kom tsim nyog rau CNS kev puas tsuaj, ua rau apoptosis [149].

Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias nyob rau hauv lub hlwb ntawm cov neeg mob Alzheimer's tus kab mob, malnutrition ntawm microglia qhia tau hais tias muaj zog koom haum nrog degeneration ntawm tau-zoo neurons, piv txwv li, tau pathology yog txuam nrog microglialmalnutrition.

Yog li, es tsis txhob mob hlwb, qhov tsis muaj microglial txhawb nqa yog qhov tseem ceeb ua rau neurodegeneration. Lub hnub nyoog ntawm microglia tuaj yeem cuam tshuam txog totelomere luv. Telomeres yog qhov kawg ntawm eukaryotic chromosomes thiab luv luv withage, ua rau muaj kev nkag siab ntawm "replication" hauv microglia nrog lub peev xwm rov ua dua nws tus kheej [150].

Kev tshawb fawb ntawm 20 cov neeg mob laus uas mob qog noj ntshav taub hau thiab caj dab los ntawm Unryn li al. qhia tau hais tias kev kho hluav taws xob tau ua rau luv luv ntawm telomere ntev hauv txhua tus neeg mob [151].

Zhang et al. tshuaj xyuas cov teebmeem ntawm telomere dysfunction los ntawm telomeric repeatbinding factor 2 (TRF2)-mediated inhibition ntawm neurons thiab mitotic paj hlwb (astrocytes thiab neuroblastoma hlwb). Lawv tau pom tias telomere tsis ua haujlwm ua rau DDRsand ua rau kev ua kom muaj p53 thiab p21 thiab kev laus [152]. Cov lus teb ntawm tes rau IR suav nrog cov xov tooj ntawm tes kuaj xyuas qhov chaw ntes thiab programmed cell tuag. Txij li thaum hluav taws xob tshwm sim ob zaug-strand tawg hauv DNA ua rau txo qis hauv telomere ntev, cov hluav taws xob teb tau tshwm sim los ntawm qhov tsis tsim nyog induced cellular senescence [153].

Cov txheej txheem hauv qab nrawm nrawm vim IR yog tib yam li qhov hauv qab ROS-mediated aging. Kev puas tsuaj hluav taws xob rau telomeres kuj zoo ib yam li oxidativedamage pom nyob rau hauv cov cheeb tsam no thiab ua rau kom luv luv ntawm telomeres thiab ua rau cov cell aging. Ib koob tshuaj loj ntawm IR tuaj yeem ua rau tuag taus ntawm tes, ua rau tsis muaj kev faib tawm ntawm tes. Accelerated proliferation ua rau telomere shortening, yog li ua kom aging nyob rau hauv tag nrho cov kab mob, raws li pom nyob rau hauv cov tib neeg raug rau IR [154].Yog li ntawd, telomere shortening yuav suav hais tias yog ib tug ntawm cov mechanisms underlyingradiation-induced aging [155].

3.4. DNA puas

IR induces DNA puas los ntawm ob qho tib si ncaj qha thiab tsis ncaj txoj kev. Txoj kev ncaj qha hais txog DNA ionization ntawm lub zog hluav taws xob, thiab txoj hauv kev tsis ncaj qha hais txog lub cim ntawm ntau tus ROS tom qab radiolysis ntawm dej molecules. Txoj kev tom kawg tuaj yeem ua rau muaj kev puas tsuaj DNA los ntawm ntau yam txheej txheem, suav nrog kev puas tsuaj hauv paus thiab tso tawm, depolymerization, kev sib txuas, thiab kev sib tsoo [156].

Xws liDNA kev puas tsuaj, tshwj xeeb tshaj yog DSBs, ua rau txoj hauv kev nyuaj thiab tswj hwm DDR thiab kho txoj hauv kev. DNA ionization ncaj qha ua rau kev puas tsuaj rau noob caj noob ces macromolecules, whereas cytosol ionization ua rau cov tiam ntawm active tshuaj xws li •OH.Hydrated electrons thiab hydrogen atoms, uas diffuse mus rau hauv nanoscale cheeb tsam ib ncig ntawm cov xwm txheej, inevitably hnov ​​​​mob nrog DNA Cheebtsam thiab indirectly ua rau lawv. Qee qhov kev puas tsuaj no tshwm sim ntawm cov kab mob caj dab molecular, ua rau cov cim ntawm DNA puas lossis ntau qhov chaw puas tsuaj.

Raws li qhov xwm txheej endogenous ntawm qhov kev puas tsuaj, nws muaj feem yuav raug kho yuam kev ntau dua li kev puas tsuaj loj dua, ua rau kev puas tsuaj ntawm tes [157].Thaum qib molecular, irradiated microglia qhia txog kev txhim kho ntawm cov noob cuam tshuam nrog DDRs, cellular stress, cell. Lub voj voog raug ntes, thiab oxidative kev nyuaj siab [158,159]. Cellshave ib qho kev txuag thiab complex DNA puas paub thiab kho network (DDR) uas lawv siv los teb rau ntau hom DNA puas [160]. Cov kev tshawb fawb siv cov kab kev lag luam thiab cov kab lis kev cai tseem ceeb tau pom tias DNA puas tuaj yeem ua rau lub cev raug ntes mus tas li [161], ua rau lub xeev tsis muaj zog uas cov hlwb puas tuaj yeem muaj sia nyob tab sis tsis tuaj yeem loj hlob, hu ua cellular senescence [162].

Hauv cov neurons paub tab, homologousrecombination thiab non-homologous terminal junctions tsis txaus los kho DSBs, zoo li vim tias cov hlwb tsis sib faib. Yog li ntawd, nws feem ntau ntseeg tias cov neurons nce qhov tsis zoo DNA puas thaum lub sijhawm, uas tuaj yeem ua rau cov kab mob neurodegenerative [163]. Nyob rau theem mob tom qab raug hluav taws xob, hluav taws xob ua rau sab saum toj 53- kho kom nrawm nrawm thawj apoptosis thiab tardy secondary apoptosis (txuas nrog kev hloov pauv), yog li tshem tawm cov hlwb puas.

Cells nyob rau hauv lub hlwb feem ntau teb rau p53 activation los ntawm mus tas li cell voj voog ntes es tsis txhob ntawm apoptosis [164].Nrog rau kev laus, DNA puas accumulates, inducing poob ntawm cellular muaj nuj nqi thiab lub degeneration ntawm hlwb thiab cov ntaub so ntswg. Txawm li cas los xij, kev kho tsis raug tuaj yeem ua rau muaj kev hloov pauv thiab chromosomal aberrations. Unrepaired DNA puas feem ntau ua rau cell dysfunctionor senescence, ua rau ntau yam pathologies thiab cell tuag thaum laus [165,166].Qhov stimulation ntawm DDR los ntawm IR ua rau innate thiab adaptive tiv thaiv kab mob. Kev ua haujlwm txuas ntxiv ntawm DDR txhawb kev tsim cov cytokines inflammatory, nrog rau IL-6thiab IL-8 [167], pib cov lus teb inflammatory uas yuav ua rau cov ntaub so ntswg puas.

Qhov tseem ceeb, DNA kev puas tsuaj tuaj yeem tshwm sim tsis tau tsuas yog nyob rau hauv lub nucleus xwb tab sis kuj nyob rau hauv mitochondria, thiab mtDNA yog qhov yooj yim rau kev puas tsuaj ntau dua li cov DNA nuclear. ROS yog thawj qhov chaw ntawm mtDNA kev hloov pauv, uas tuaj yeem sib sau nrog hnub nyoog thiab kab mob kev loj hlob [168,169].Tsis tas li ntawd, DDR ua rau cell senescence, thiab txuas ntxiv senescence induces theSASP, uas inflammatory cytokines raug tso tawm.

Cov neeg nruab nrab no cuam tshuam cov hlwb nyob sib ze thiab ua rau muaj ntau yam pathologies [170].Unrepaired DDR induces cell senescence ntawm p53 txoj kev, activates lub SASP, ua rau lub secretion ntawm pro-inflammatory cytokines, thiab ntxiv activates lub innate immuneresponse, ua rau cov nqaij mos senescence thiab hnub nyoog- Cov kab mob ntsig txog [171–173].Senescent hlwb yog tus cwj pwm los ntawm kev ua kom muaj zog ntawm cov kab mob ntau tshaj plaws, SA- -gal, thiab qhov nthuav dav ntawm p21WAF1/Cip1. Thaum p21 tuaj yeem txhawb nqa cellular senescence nyob rau hauv raug rau IR, nws tseem tuaj yeem txhawb nqa G1 cell voj voog raug ntes.

Txawm li cas los xij, qhov no tsis yog ib txwm cuam tshuam nrog kev ua haujlwm p53. Ob qho p53 thiab p21 ua rau hauv senescentcells yog ib ntus txij li thaum p53 thiab p21 qhia tau txo qis thaum kawg thiab p16Ink4Atains kev loj hlob raug ntes hauv cov hlwb senescent [174]. Hauv kev sib piv ncaj qha rau kev rov ua dua tshiab, kev ntxhov siab ua ntej ntxov ntxov (SIPS) tshwm sim los ntawm DNA kev puas tsuaj yog ywj pheej ntawm telomere ntev lossis ua haujlwm [175,176].

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