Synergistic Anti-Ageing Los ntawm Senescent Cells Specific Reprogramming
Jul 12, 2022
Thov hu rauoscar.xiao@wecistanche.comyog xav paub ntxiv
Abstract:Hauv qhov kev tshuaj xyuas no, peb nrhiav lub tswv yim tshiab los tsim kom muaj kev txhawb nqa microenvironment los ntawm cov hlwb senescent 'cov reprogramming tshwj xeeb. Peb xav hais tias ib nrab reprogramming tuaj yeem tsim ib qho secretory phenotype uas pab txhawb cellular rejuvenation. Lub tswv yim no yog xav tau rau qee qhov kev rov ua dua tshiab raws li kev tswj hwm kom tsis txhob muaj kev pheej hmoo ntawm qog nqaij hlav thiab lub cev tsis ua haujlwm vim poob ntawm cellular tus kheej. Nws kuj alleviates tus mob inflammatory xeev txuam nrog kev laus thiab theem nrab senescence nyob rau hauv cov hlwb uas nyob ib sab los ntawm kev txhim kho cov senescence-koom nrog secretory phenotype. Cov ntawv sau no tseem cia siab tias yuav tshawb xyuas seb puas cuam tshuam hauv cellular senescence tuaj yeem txhim kho kev laus thiab txhawb kev kho kev puas tsuaj, feem ntau, ua rau tib neeg noj qab nyob zoo thiab txo qis. Kev ua tau zoo thiab muaj kev nyab xeeb hauv chaw kho mob txhais lus raws tu qauv yog qhov tseem ceeb hauv kev rov ua kom rov zoo los ntawm kev tswj hwm kev rov ua dua tshiab. Qhov kev tshuaj xyuas no tham txog cov kev txwv thiab kev tsis sib haum xeeb ntawm cov kev nce qib no 'daim ntawv thov (thaum teeb tsa cov ntawv sau raws li qhov muaj peev xwm kho mob txhais cov tswv yim) los tshawb txog cov lus qhia thiab cov kev xav uas muaj txiaj ntsig kev txhais lus rau kev tshawb fawb tom ntej.
Ntsiab lus:kev laus; kev laus; senolytics/senostatics;p16/nk4a;p19Arf; p21Wafl/Cip1; SASP
1. Taw qhia
Kev laus tuaj yeem txhais tau tias yog lub sijhawm poob ntawm kev ua haujlwm ntawm lub cev. Nyob rau theem cellular, nws cov ntsiab lus tuaj yeem pom raws li kev ua haujlwm tsis tu ncua ntawm tes ua haujlwm nrog los ntawm kev laus phenotypes [1,2]]. Kev ntxhov siab xws li telomere tsis ua haujlwm, DNA puas, kev ua haujlwm ntawm oncogene, thiab kev ua haujlwm ntawm lub cev ua kom lub cev tsis muaj zog ua kom muaj kev loj hlob ntawm cov cellular theem, kis tau los ntawm cov cellular microenvironment thiab ua kom lub cev tsis ua haujlwm thoob plaws hauv cov ntaub so ntswg, ua rau poob ntawm tag nrho cov haujlwm tseem ceeb ntawm lub cev. (lub cev tsis ua haujlwm).
Thov nias ntawm no kom paub ntxiv
Interestingly, muaj kev sib npaug ntawm tus kheej ntawm kev kho tom qab raug mob thiab rov ua dua tshiab tom qab kev laus hauv lub cev nws tus kheej.cistanche noov lojCov kev ntsuas ntsuas no suav nrog kev hloov pauv ntawm cov qia hlwb mus rau cov hlwb progenitor hauv ntau cov ntaub so ntswg hauv dynamic homeostasis. Lwm txoj hauv kev los tiv thaiv kev ua haujlwm tsis zoo ua rau lub cev ua haujlwm tsis zoo (piv txwv li, lwm txoj hauv kev mitochondrial glycolytic thiab glutamine metabolic txoj hauv kev, ua kom muaj kev kho lub cev los ntawm kev puas tsuaj nuclear) [3-5]. Nyob rau theem ntawm cov ntaub so ntswg, cov senescence-associated secretory phenotype (SASP) muaj qee qhov kev tiv thaiv kev laus ntxiv rau qhov ua rau muaj kev txhawb nqa senescence (xws li, interleukin-6(IL-6) tuaj yeem txhim kho cov ntaub so ntswg. los ntawm kev txhawb nqa reprogramming[6,7];interleukin-1 (IL-1) tuaj yeem txhawb kev tshem tawm ntawm cov hlwb los ntawm immunopurified NK hlwb [8-10]). Nws yog ib qho tseem ceeb kom nco ntsoov tias tsis muaj pov thawj tias kev tiv thaiv kev laus tuaj yeem ua tiav los ntawm kev siv cov txiaj ntsig zoo ntawm kev laus nws tus kheej. Qhov kev tshuaj xyuas no yog tsom los qhia tias kev cuam tshuam txog kev cuam tshuam ntawm cov hlwb senescent muaj peev xwm khaws cov khoom tseem ceeb no piv nrog kev tshem tawm ntawm senescent cell. Kuj tseem muaj qhov ua tau tias reprogramming tuaj yeem hloov kho tus kheej los ntawm cov txiaj ntsig saum toj no, nyob rau hauv uas senescence txhawb reprogramming: tib theem ntawm reprogramming yam yuav ua tau zoo dua nyob rau hauv ib puag ncig senescent. Nyob rau hauv sib piv, qhov ua tau zoo ntawm reprogramming yog txo thaum lub senescent ib puag ncig yog mitigated los yog thim rov qab, yog li zam qhov teeb meem tshwm sim los ntawm over-induction.
Txhawm rau tshawb nrhiav cov peev txheej tiv thaiv kev laus ntawm qhov sib npaug, qhov kev tshuaj xyuas no yuav tham txog qhov ua tau thiab qhov ua tau ntawm kev txo qis qis los ntawm kev sib cuam tshuam ntawm cov cell hauv qab no:
Txhawm rau tawm tswv yim los tiv thaiv kev laus kom paub meej lub tswv yim ntawm kev sib koom ua ke anti-a.]
Kev laus nrog ntau yam rejuvenating yam thiab ua hauj lwm rau cov kev tshawb fawb tom ntej ntawm txoj kev tseem ceeb tshiab uas tuaj yeem siv ua ke nrog txoj kev paub txog kev laus. b.
Lub tswv yim ntawm tus hluas secretory phenotype yog npaj siab kom generalize lub anti-aging yam (tshwj xeeb tshaj yog, NAD ntxiv, en amp, GSTM2, thiab lwm yam. yog koom nyob rau hauv tag nrho-lub cev tiv thaiv kev laus los ntawm regulating lub circulating NAD ntxiv / NADHbalance) pom nyob rau hauv lub secretome ntawm cov tub ntxhais hluas cov ntshav thiab cov hlwb hluas thiab ua haujlwm rau yav tom ntej kho mob txhais lus thiab kev sib koom ua ke.
Txhawm rau tshaj tawm qhov kev xav uas tswj tau reprogramming (txhais tias yog induction C.
ntawm Yamanaka yam qhia kom thim rov qab cov laus phenotype ntawm cov hlwb tab sis tsis muaj iPSCs-vim pluripotent qia cell tsim) tuaj yeem sib koom ua ke los tiv thaiv hnub nyoog los ntawm cov hluas secretory phenotype.
2. Cov yam ntxwv ntawm kev laus thiab lawv cov peev xwm rau kev txhais lus
2.1. "Asynchronous Effect" hauv Kev Laus
Raws li peb muaj hnub nyoog, kev laus ntawm cov kab mob sib txawv thiab cov ntaub so ntswg tsis synchronized, thiab cov parenchymal hlwb uas ua rau lub cev ua haujlwm ntawm lub cev / cov ntaub so ntswg nyob rau ntau theem ntawm senescence [1].
Nws tau pom nyob rau hauv cov nas uas cov ntshav plasma thiab cov tshuaj tiv thaiv kab mob uas lawv secrete infiltrate ntau yam kabmob, tshwm sim hauv lub raum, plawv, siab, nqaij, rog, ntsws, thiab thymus [2]. Qhov no txhais tau hais tias kev laus hauv ib lub cev tuaj yeem ua rau lossis ua kom cov laus muaj feem cuam tshuam nrog kev mob thiab ua haujlwm tsis zoo thoob plaws hauv lub cev los ntawm kev ua haujlwm. Tsis tas li ntawd, thaum nas mus txog nruab nrab hnub nyoog, lub cev tiv thaiv kab mob (T thiab B hlwb [2], M1 macrophages [11,12) tau ua kom muaj zog hauv cov ntaub so ntswg adipose [2]. Cov kev tshawb fawb no qhia tias kev laus thiab kev tiv thaiv kab mob tsis muaj kev sib txuas, thiab kev laus yog txheej txheem "asynchronous". Ntawm qhov tod tes, cov ntaub so ntswg adipose yog ib qho ntawm thawj qhov chaw ntawm lub cev los qhia pom kev muaj feem cuam tshuam txog pheno-types (inflammatory cell infiltration thiab cov tsos ntawm senescence ntsig txog secretory phenotypes)[1,2].
Qhov tseeb, kev tshem tawm ntawm cov hlwb senescent tuaj yeem txo qhov tsis zoo ntawm cov khoom ua ntej senescent (piv txwv li, senescent cell ablation-senolytics) [13]. Raws li cellular senescence tsis synchronized, lub senescence microenvironments originated los ntawm pre-senescent hlwb tuaj yeem ua rau lub voj voog tsis zoo (lub senescence ntawm ib lub cev txhawb kev poob thoob plaws hauv lub cev) ntawm cov ntaub so ntswg qib [1,2]. Cov "cov xwm txheej qub" uas txhawb kev laus yuav raug diluted los yog suppressed los ntawm lwm qhov "rejuvenating factor (muaj nyob rau hauv cov ntshav hluas thiab yog secreted los ntawm ib tug heterogeneous subgroup ntawm aging hlwb), yog li ua raws li ib tug rejuvenating neeg sawv cev [14,15].cistanche hmoovLos ntawm transplanting pre-senescent adipocytes, nws tau pom tias lub senescence ntawm ib tug me me ntawm adipose precursor hlwb yog txaus rau induce lub cev senescence nyob rau hauv cov me nyuam nas. Kev tshem tawm ntawm cov noob qes hloov pauv los ntawm cov nas me thiab cov hlwb tsis zoo los ntawm cov nas uas tsis muaj zog los ntawm cov tshuaj ntsuam xyuas qhov ncauj tsis tu ncua txhim kho kev laus (kev ua haujlwm hauv nruab nrog cev, kev ciaj sia tau nce los ntawm 36 feem pua, thiab kev pheej hmoo ntawm kev tuag raug txo los ntawm 65 feem pua) [13].
Lub heterogeneity ntawm kev laus yog xav txog ntawm ib sab tes nyob rau hauv qhov tseeb hais tias mob mob sib txawv nyob rau hauv cov ntaub so ntswg sib txawv, tshwj xeeb tshaj yog nyob rau hauv lub fact tias SASP muaj ntau theem nyob rau hauv cov ntaub so ntswg sib txawv [2]. Ntawm qhov tod tes, nws tau xav txog qhov sib txawv ntawm cov tsos ntawm cov hlwb senescent thiab qhov sib txawv ntawm qhov sib txuam [1].
Cistanche tuaj yeem tiv thaiv kev laus
Piv txwv li, nyob rau hauv lub raum, qhov twg senescent hlwb nce zuj zus raws li lub hnub nyoog, Cu / Zn-superoxide dismutase (Sod1) knockout nas ua rau cov qib siab ntawm oxidative cellular senescence[16]. Senescence-related secretory phenotypes (tshwj xeeb yog IL-6 thiab IL-1 ) kuj tau nce ntxiv [16]. Cov qib siab ntawm cov cytokines circulating qhia tau hais tias qhov ceev senescence phenotype tuaj yeem yog vim muaj kev mob ntxiv los ntawm kev sib xyaw ua kom nrawm ntawm cov hlwb senescent [17]. Lub tsub zuj zuj ntawm senescent hlwb, nyob rau hauv lem, ua rau ib tug nce nyob rau hauv mob o [16].
Remarkably, asynchrony ntawm senescence persists txawm nyob rau hauv tib lub laus laus (fibroblasts nyob rau hauv cov laus nas) [14]. Txawv subpopulations nrog txawv secretory phenotypes cuam tshuam tus nqi ntawm qhov txhab kho hauv vivo los ntawm kev cuam tshuam kev ua haujlwm ntawm reprogramming [14].
Ua ke, nws muaj peev xwm cuam tshuam rau hauv cov ntaub so ntswg pre-senescent rau tag nrho cov txiaj ntsig los ntawm kev ua kom zoo dua ntawm asynchrony hauv kev laus [18]. Nws kuj tseem paub tias microenvironment muaj qhov cuam tshuam tseem ceeb ntawm lub xeev ntawm kev laus ntawm tes (cov cell raug rau cov secretome ntawm cov hlwb senescent yuav muaj hnub nyoog sai dua)|13]. Es tsis txhob, kev txhim kho cov cellular micro-ib puag ncig (ua kom cov secretory phenotype ntawm cov tub ntxhais hluas hlwb) los tiv thaiv kev laus yog ib qho kev cog lus [19]. Tshwj xeeb, cov ntaub so ntswg adipose yog ib qho ntawm thawj qhov cuam tshuam los ntawm kev laus (tseem muaj qhov cuam tshuam tseem ceeb ntawm lub xeev inflammatory txuam nrog kev laus)[1,2].
2.2 "Synergistic Effect" hauv Anti-Ageing
Nws tau pom tias kev kho ntshav muaj ntau yam sib txawv los tiv thaiv kev laus (GDF11 [20], GPLD1 [21], clusterin [22], Klotho [23], thiab lwm yam). Ntawm ib sab, nws ua rau muaj kev sib cav [19, tab sis ntawm qhov tod tes, nws kuj qhia tias cov txiaj ntsig zoo dua tuaj yeem ua tiav los ntawm synchronizing ntau yam los tiv thaiv kev laus. Synergistic anti-aging yog ib qho tshwm sim nyob rau hauv uas kev sib koom ua ke ntawm ntau yam kev tiv thaiv kev laus ua rau muaj txiaj ntsig ntau dua li cov txiaj ntsig ntawm kev hloov pauv ib qho ntawm lawv tus kheej. Yog li ntawd, cov kev tshawb fawb ntawm cov qauv kev laus yog cov lus qhia thaum nrhiav pom txoj hauv kev tseem ceeb ntawm kev tiv thaiv kev laus nrog kev sib koom ua ke (piv txwv li, hauv eukaryotes yooj yim).
Qee cov kab mob poov xab qhia txog kev hloov pauv nuclear tseem ceeb thaum lub sij hawm cell aging thiab nthuav tawm ribosomal senescence, thaum lwm tus tsim mitochondrial dysfunction. Nyob rau hauv cov poov xab nrog ib tug ribosomal senescence qauv, overexpression ntawm Sir2 (ib tug lysine deacetylase uas muaj txhawb rau ribosomal DNA silencing) yuav ncua qhov nruab nrab lifespan ntawm cov poov xab [24,25].cistanche salsa extractOverexpression ntawm Sir2 thiab Hap4 prolongs lifespan los ntawm kev tsim synergistic es tsis ntxiv cov teebmeem [26]. Ib qho kev sib koom ua ke zoo sib xws tau pom thaum lub sijhawm fob1A lub neej ntev mutant txhim kho rDNA kev ruaj ntseg ua ke nrog Hap4 overexpression [25]. Cov qauv no kuj piav qhia txog kev tiv thaiv kev laus ntawm kev txwv caloric, txhawb heme activator protein (HAP), thiab Sir2 [26]. Ob qhov zoo li kev ywj pheej ntawm lub neej no tuaj yeem nkag siab tias yog ob qho tseem ceeb los tiv thaiv kev laus thiab lub hom phiaj nrog kev sib koom ua ke los tiv thaiv kev laus. Ob leeg tuaj yeem suav hais tias yog qhov tseem ceeb los tiv thaiv kev laus cov nodes uas yuav tsum tau tswj hwm ib txhij.
Hauv lwm txoj kev tshawb fawb siv Caenorhabditis elegans (C.elegans) ua qauv, ib qho tseem ceeb regulator gene hu ua CYC-2.1(ib tug nematode cytochrome C ortholog), ib tug cytochrome muaj zog txuam nrog mitochondrial laus raug txheeb xyuas. Txo CYC-2.1 qhia tau qhib lub "unfolded protein teb" nyob rau hauv mitochondria, txhawb lawv faib thiab yog li no ho txuas nematode lifespan [27]. Cov kev pheej hmoo-1(C.elegans ribosomal S6Kortholog) kev hloov pauv tau nce qhov nruab nrab ntawm lub neej los ntawm 20 feem pua, tus daf-2(ib qho nematode insulin loj hlob yam 1 receptor ortholog) kev hloov pauv tau nce qhov nruab nrab ntawm lub neej los ntawm 169 feem pua, thiab cov daf-2 thiab kev pheej hmoo-1 ob npaug kev hloov pauv tau nce qhov nruab nrab lifespan los ntawm 454 feem pua ntawm cov tsiaj qus; yog li ntawd, qhov ua kom lub neej ntev dua ntawm daf-2 thiab kev pheej hmoo -1 ob chav mutants tsis yog ib qho ntxiv tab sis muaj kev sib koom ua ke ntawm kev ua neej ntev [28]. Ntawm qhov tod tes, TOR (lub hom phiaj ntawm rapamycin) tswj cov qib mRNA txhais lus ntawm ribosomal S6 kinase (S6K) [29]; Yog li ntawd, nws qhia tau hais tias muaj kev sib koom ua ke tseem ceeb los tiv thaiv mitochondrial aging nyhuv ntawm IIS (insulin /insulin-zoo li signaling) thiab TOR [27]. Txoj kev tshawb no tseem qhia tau hais tias kev sib koom ua ke ntawm ribosomal protein genes thiab mitochondrial muaj nuj nqi tuaj yeem ua rau muaj kev sib koom ua ke ntawm cov tseem ceeb tiv thaiv kev laus kom ntau dua. Nws kuj txhais tau hais tias kev tswj hwm kev ua haujlwm mitochondrial tuaj yeem ua tiav los ntawm metabolic reprogramming induced los ntawm tej thaj chaw deb intercellular regulation thiab yuav elicit ib tug dav teb lo lus teb los ntawm ntau yam kev tiv thaiv kab mob-metabolic hlwb thiab lub cev los ntawm ib tug anti-aging secretory phenotype.
Reactive oxygen species (ROS)-induced DNA damage response (DDR) activates mTORC1 through direct phosphorylation of protein kinase B(PKB/Akt) by ATM and activated Akt phosphorylates the TSC1/TSC2 complex, in this way activating mTORC1.
Ua kom mTORCl txhawb nqa ROS-dependent DDR, thiab, los ntawm mitochondrial biogenesis transcriptional co-activator peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1), txhawb kev laus phenotypes (xws li, ASAP) , thaum kawg ua rau ROS-mediated DDR activation (upregulation ntawm DR protein yH2A.X) thiab cell voj voog ntes (nrog txo kev qhia ntawm p21Maf1/Cipl thiab p16INK4a)[4]. Lub voj voog vicious no, yog tias tsis tawg, ua rau muaj kev nce siab ntxiv. Yog li, kev txhim kho hauv mitochondrial muaj nuj nqi thiab hloov pauv redox xwm txheej yog qhov tseem ceeb hauv kev rhuav tshem qhov kev tsis txaus siab no.
Mitochondrial dysfunction-associated senescence (MiDAS) ua rau txo qis ntawm NAD * / NADH piv, uas ua rau kev ua kom AMPK thiab p53, uas ua rau ob qho tib si loj hlob ntawm cov hlwb senescent (ua los ntawm p53 ua kom, nrog pyruvate tiv thaiv MiDAS kev loj hlob raug ntes. tab sis rov qab ua haujlwm NF-kB) thiab AMPK-mediated p53 activation txo IL-1 secretion [3]. Qhov no txhais tau hais tias muaj ntau yam thiab sib txawv ntawm ASAP xws li cov tswv yim reprogramming nyob ntawm IL-6 boosting efficiency tuaj yeem rhuav tshem mitochondrial dysfunction (MiD)-ROS-dependent DR vicious voj voog los ntawm kev hloov pauv NAD ntxiv / NADH piv (tejzaum nws nyob rau hauv parallel nrog cov lus teb pyruvate) thaum teb rau kev txhawb nqa ntawm senescence microenvironment. Nws txhais tau hais tias qhov tshwm sim thiab tsis tu ncua ntawm rejuvenation microenvironments nyob rau hauv cov ntshav [30] (xws li, endocrine rejuvenation microenvironment), nrog rau kev tiv thaiv kab mob rejuvenation microenvironments, yog qhov tseem ceeb vim lawv qhov systemic ( cuam tshuam yuav luag txhua lub hlwb) thiab qhov dav ntawm lawv cov teebmeem. ( koom nrog yuav luag txhua txoj hauv kev muaj feem cuam tshuam txog kev rov zoo dua).
Lub sij hawm luv luv rau Oct4, Sox2, Klf4, thiab c-Myc (OSKM) (tseem hu ua "Yamanaka yam") thim rov qab cov laus phenotype ntawm cov hlwb [31], qhia tias kev laus yog rov qab los [32]. Qhov no txhais tau hais tias rejuvenating senescent hlwb yog lub tswv yim tshiab rau cuam tshuam lub voj voog ntawm kev laus los ntawm kev tsim kom muaj zog rejuvenation homeostasis hauv ntau txoj hauv kev ua ke. Txawm li cas los xij, nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias kev txiav tawm ntxov ntawm reprogramming tuaj yeem ua rau tsis ua tiav hauv kev rov ua dua tshiab ntawm MSCs [3]. Yog li, ib nrab reprogramming (txhais tau tias yog inducing Yamanaka yam qhia kom thim rov qab cov laus phenotype ntawm cov hlwb tab sis tsis muaj iPSCs-induced pluripotent stemcells tsim) yog qhov muaj peev xwm tiv thaiv kev laus [31](Daim duab 1).
3. Cov tswv yim rau Reversing Senescence thiab cov peev txheej hauv qab txheej txheem
3.1.Reprogramming-Based Therapies rau Reverse Senescence
Ib nrab reprogramming ib txhij lengthens telomeres, inhibits p53, thiab restores mitochondrial muaj nuj nqi [31]. Interestingly, telomerase thim rov qab transcriptase overexpression nyob rau hauv cov nas transgenic (Sp53 / Sp16 / SArf / Tg Tert nas) tau pom cov qog ua haujlwm zoo dua qub thiab tau pom los tiv thaiv kev laus ntawm kev degeneration (feem ntau atrophy) thiab cov txheej txheem inflammatory, qib ntshav siab dua ntawm IGF1, thiab a txo y-H2AX foci. Kev ua kom cov piam thaj ntau dua thiab kev sib koom ua ke ntawm neuromuscular ua rau lub neej ntev dua [40].cistanche qiatelomere-p53-PGC txoj hauv kev thiab nws cov noob caj noob ces hauv qab tswj hwm lub xeev ua haujlwm ntawm ntau lub cev thiab kev laus: nce qib ntawm p53 (Trp53) ua rau inhibition ntawm peroxisome proliferator-activated receptor-gamma coactivator-l alpha (PGC -1o) Lub germline tshem tawm ntawm p53 tag nrho rov qab PGC network qhia; PGC-1 ib qho kev qhia rov ua pa mitochondrial, lub plawv ua haujlwm, thiab qabzib allosteric [41]. Tsis tas li ntawd, txo cov peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1b) attenuates cellular senescence-related phenotypes [4]. Qhov no txhais tau hais tias lub sij hawm luv luv cyclic qhia ntawm OSKM tuaj yeem rov ua kom cov hlwb senescent ' epigenome hauv vivo, txo p16lnk4a thiab SASP, thiab cuam tshuam rau ntau yam kev coj noj coj ua (xws li mitochondria dysfunction, DNA puas, tsis muaj protein ntau folding, telomere shortening, thiab o. [31]), yog li exerting ib synergistic anti-aging nyhuv.
Daim duab 1. Kev nce qib tseem ceeb hauv rejuvenation los ntawm ib nrab reprogramming. Manukyan et al: Cuaj hnub ntawm OSKML kev qhia tau kho cov qib heterochromatin protein 1 (HP1) hauv cov neeg laus fibroblasts [32]. Ocampo et al: Lub sij hawm luv luv OSKM qhia alleviated aging phenotypes thiab nce lifespan ntawm cov nas progeria (LAKI4F nas)[31].Oliva li al.: Ib nrab reprogram-ming (OSKM) induced ruaj khov rejuvenation ntawm cov neeg laus fibroblasts ua ntej iPSCs tsim [ 34] ib. Horvath et al: Steve Horvath tau tsim ib qho "epigenetic moos" raws li DNA methylation los kwv yees lub hnub nyoog (lub Horvath moos) [35]. Sarkar et al.: Lub sij hawm luv luv OSKMNL qhia rov qab lub hnub nyoog epigenetic (Horvath moos) ntawm cov laus tib neeg fibroblasts thiab endothelial hlwb los ntawm mRNA transfection [36]. Lu Y et al.: OSK kev kho mob rov pib lub hnub nyoog epigenetic (Horvath moos) thiab kho cov nas lub qhov muag los ntawm tus kab mob adeno-associated (AAV) vector[37]. Gill et al: Transient reprogramming (OSKM) rejuvenated mature human cells [38]. Alle et al: OSKM kev kho mob tau nce lub neej thiab txhim kho phenotypes ntxov ntxov hauv cov nas progeria [39].
Vim yog "asynchronous" tus cwj pwm ntawm kev laus, senescent cell reprogramming nyiam cuam tshuam rau cov ntaub so ntswg uas thawj zaug cuam tshuam los ntawm kev laus (xws li, cov ntaub so ntswg adipose, lub cev tsis muaj zog, thiab fibroblasts [1,2]). Yog li ntawd, peb pib sib tham nrog cov ntaub so ntswg adipose (Daim duab 2). Kev laus feem ntau nrog rau kev poob qis hauv subcutaneous adipocytes cim los ntawm kev txo qis ntawm adipose precursor hlwb [42], uas ua rau muaj kev hloov pauv ntawm cov ntaub so ntswg rog - piv txwv li, visceral dawb rog ntau dua thiab cov rog tsawg dua [43,44] ib yam nkaus. raws li ectopic fat deposits [45]cistanche tubulosa cov txiaj ntsig thiab kev phivQhov kev hloov pauv no ua rau lub voj voog tsis zoo ntawm kev tsim cov kev laus microenvironment los ntawm qhov tsis txaus ntseeg hauv lub xeev inflammatory thiab cellular metabolic lub xeev cuam tshuam nrog kev laus thiab, yog li, cuam tshuam ntawm cellular homeostasis (proteostasis) [46].
Senescence ntawm adipose precursor hlwb (ua los ntawm sirtuin 1 txo) ua rau tsub zuj zuj ntawm senescent adipocytes [43], uas secrete pro-inflammatory yam uas ua rau thawj feem ntawm senescent microenvironment thiab ua rau mob inflammatory infiltration ntawm adipose ntaub so ntswg [47]. Raws li kev laus redistributes rog (visceral rog nce), senescent adipose ntaub so ntswg nqa cov mob inflammatory xeev txuam nrog senescence (Mcp-1 thiab l-6) thoob plaws hauv lub cev thiab maj accumulates.
Cov ntaub so ntswg dawb adipose ua rau txo qis hauv glutamine qib hauv cov ntaub so ntswg adipose, ua rau muaj zog macrophage glycolysis hauv cov ntaub so ntswg adipose, nce pro-inflammatory transcription, thiab tso tawm ntau ntawm SASP rau hauv peripheral microcirculation, tsim ib feem thib ob ntawm senescent microenvironment [ 48] ib.
M1 macrophages nyob rau hauv senescent dawb adipose cov ntaub so ntswg noj ntau ntau ntawm NAD ntxiv [11,12], thiab adipocytes secrete tsawg en amp vim senescence [49,50], ua rau ib tug systemic NAD ntxiv / NADH ratio imbalance (qis), uas accelerates mitochondrial dysfunction-related senescence nyob rau hauv cov hlwb thoob plaws hauv lub cev [3], ua rau muaj kev tsis txaus siab ntawm lub zog metabolic xwm txheej (glycolysis nce) thiab tsim qhov thib peb ntawm senescent microenvironment.
Mitochondrial metabolic disorders ua rau txhim kho glycolytic txoj hauv kev thiab cellular redox disorders, ua rau cov kab mob redox mob [3,4]. Cov kab mob fibroblasts nyob rau hauv kev cuam tshuam ntawm thawj peb feem ntawm senescence thiab lawv tus kheej senescence, txo GST secretion, exacerbating systemic peroxidation thiab tsim plaub feem ntawm senescence microenvironment [51].
Qhov teeb meem redox cuam tshuam rau genomic stability [5], tsim ntau cov misconfigured proteins, uas tsim aggregates uas raug ntiab tawm ntawm lub hlwb thiab adipocytes, uas kuj tso tawm hnub nyoog mitochondria, tsim lub thib tsib ntawm lub senescent microenvironment [52-54].
txoj kev los ntawm overexpression ntawm Sirt1 [43,55]) los ntawm doxycycline-induced overexpression ntawm OSKM. Kev thim rov qab ntawm senescence los ntawm reprogramming tuaj yeem txhim kho qhov ntsuas qhov tsis muaj zog (txo qis hauv p16, p21, senescence-sociated -galactosidase, thiab lwm yam) thiab tuaj yeem, tib lub sijhawm, ameliorate senescence-sociated secretory phenotypes (tsawg Mcp {{9}) Il-6, MMP13) thiab txawm txhim kho histone methylation raws li txoj cai (qis hauv H3K9me3, H4K20me3)[31]. Nrog rau rejuvenation ntawm cov ntaub so ntswg adipose (telomere lengthening, phenotypic rejuvenation remodeling, thiab txhawb kev kho cov noob kev puas tsuaj), lub upregulation ntawm adipocyte glutaminase 1 [56] yog thim rov qab thiab cov ntaub so ntswg yog li cawm los ntawm glutamine depleted lub xeev los ntawm kev laus. Kev nce qib ntawm glutamine yuav txhim kho cov mob ntev uas cuam tshuam nrog kev laus ntawm cov txheej txheem los ntawm kev txo cov kev hloov pauv ntawm cov noob caj noob ces hauv macrophages hauv cov ntaub so ntswg adipose [48]. Qhov no txhais tau hais tias kev tsim cov senescence-uas cuam tshuam nrog secretory phenotypes raug txo, yog li txhawb kev saib xyuas ntawm cov hluas hauv lub xeev nyob ib puag ncig fibroblasts, adipocytes, thiab lawv tus kheej. Lub reprogramming kuj txhawb kev tsim cov secretory en amp nyob rau hauv extracellular vesicles. Los ntawm kev hloov NAD ntxiv rau cov ntsiab lus ntawm cov hlwb los tswj lawv cov mitochondrial metabolic lub xeev thiab redox homeostasis, en amp txhawb lub rejuvenation ntawm ntau lub hlwb thoob plaws hauv lub cev (txhim kho pancreatic thiab hypothalamic secretion phenotypes, yog li amplifying anti-aging los ntawm cov tshuaj hormones) [49,57 ]. Macrophage rejuvenation tsis tsuas yog txhim kho lub rejuvenation ntawm lub systemic secretory phenotype tab sis kuj attenuates NADf degradation los ntawm txo CD38expression [11]. Qhov no tej zaum yuav muaj ib tug synergistic anti-senescence nyhuv nrog en amp. NAD ntxiv thiab rejuvenated secretory phenotype (tejzaum nws los ntawm metabolic reprogramming lossis cell rejuvenation ntawm ERK-AMPK kev cai ntawm P16 thiab P53) txhim kho GST secretory muaj peev xwm ntawm fibroblasts. Kev xa tawm ntawm GSTI rau cov kabmob thoob plaws hauv lub cev ntawm cov hlwv extracellular txhim kho cellular redox homeostasis, uas ua rau muaj kev cuam tshuam los tiv thaiv kev laus (txhim kho daim siab redox thiab lub raum laus) [51]. Noj ua ke, hauv zos reprogramming los ntawm kev sib txuas lus cellular (en amp, YSAP, GST, thiab lwm yam) tsim synergistic anti-aging teebmeem (kev txhim kho hauv redox thiab metabolic imbalances los ntawm mitochondrial senescence thiab protein instability los ntawm ribosomal senescence). Txawm li cas los xij, nws tsim nyog sau cia tias yuav tsum muaj kev tshawb fawb ntxiv los txiav txim siab seb reprogramming puas tuaj yeem tsim cov kev hloov pauv txaus hauv secretory phenotype thiab seb kev sib txuas lus intercellular puas tuaj yeem hloov pauv cov secretory phenotype ntawm cov hlwb uas nyob ib sab. (blub xub: ncaj qha stimulatory, puag ncig xub: voj voog, dotted xub: tentative stimulatory, down faded xub: txo, nce faded xub: nce; cov grey dotted kab qhia txog macro-theem kev txhim kho nyob rau sab laug thiab micro-theem kev txhim kho ntawm sab xis , ob leeg sib cais los ntawm cov kab ntsuab dotted).
Protein mismatches ncav cuag lub sab sauv txwv ntawm cellular tso tawm thiab mus txuas ntxiv mus, ua rau lub cell lub noob caj noob ces kho mechanism, uas nyob rau hauv lem disrupts tag nrho cov cellular functions mus rau hauv lub xeev ntawm irreversible tuag, tso pov tseg tom qab nws tuag thiab yog li tsim lub thib rau ib feem ntawm lub senescent microenvironment. . (Yog li ntawd, qhov yooj yim tshem tawm ntawm senescent hlwb yuav tsis zam lub senescence teeb liab tso tawm txheej txheem thaum lub sij hawm senescent cell tuag).
3.2.Cov txheej txheem tseem ceeb muaj feem xyuam rau kev kho dua tshiab raws li kev kho mob
3.2.1. Cyclin-Dependent Kinase Inhibitors (p16INK4A)
Ntau cov ntaub ntawv pov thawj qhia p16INK4A qhov kev koom tes dav hauv cov txheej txheem kev laus, uas tuaj yeem ua qhov chaw tswj hwm lwm txoj hauv kev tiv thaiv kev laus. Cov nas uas muaj qib qis ntawm lub voj voog ntawm lub voj voog kuaj xyuas kinase BubR1 qhia tau raug kev txom nyem los ntawm kev nrawm ntawm kev laus nrog rau qib siab ntawm p16NK4A hauv cov ntaub so ntswg nrog hnub nyoog ntsig txog histopathology [58]. Lub hom phiaj kev hloov pauv ntawm p16INK4A ua rau muaj kev laus qeeb hauv BubR1 nas. Qhov kev ncua no mus ua ke nrog txo qis ntawm cov hlwb senescent. Qhov no qhia txog kev sib txuas ntawm kev laus laus thiab cellular senescence [59]. Hauv INK-ATTAC nas, qhov twg senescent hlwb qhia p16NKA raug tua tshwj xeeb, qhov poob ntawm cov hlwb senescent nce lub neej ntev thiab kev noj qab haus huv [60]. Nws tau raug pom tias p16NK4Ablocks E2F muaj nuj nqi thiab yog li inhibits a-klotho txhawb nqa kev ua ub no kom nrawm senescence [61]. P16INK4l tiv thaiv qhov tsis ua haujlwm ntawm retinoblastoma (Rb) phosphorylation los ntawm inhibiting cyclin D-dependent kinases. Tom qab ntawd Rb represses E2F transcription yam qhia qhia los ntawm recruiting histone deacetylases rau nws cov neeg txhawb nqa. Txoj kev activated retinoblastoma (Rb) ib txhij txhawb kev tsim ntawm senescence-associated heterochromatic foci (SAHF), zoo ib yam li refining lub senescence-txhawb mechanism ntawm p16INK4a [62].
Nws yog qhov tsis txaus ntseeg seb puas muaj kev phiv ntawm p16INK4a-zoo hlwb ablation. Kev tshem tawm ntawm p16NK4a cov hlwb zoo tuaj yeem ua rau muaj kev cuam tshuam ntawm fibrosis hauv daim siab thiab cov ntaub so ntswg perivascular, uas nyob rau hauv lem yuav txo tau lub neej expectancy [63]. Ib nrab reprogramming ntawm senescent hlwb yog li ntawd ib qho kev daws teeb meem rau qhov teeb meem no.
Kab lus no yog muab rho tawm los ntawm Cells 2022, 11, 830. https://doi.org/10.3390/cells11050830 https://www.mdpi.com/journal/cells
