Los ntawm Cocer Peptides 
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Tag nrho cov kab lus thiab cov ntaub ntawv ntawm cov khoom lag luam muab rau ntawm lub vev xaib no tsuas yog rau cov ntaub ntawv tshaj tawm kev tshaj tawm thiab cov hom phiaj kev kawm.
Cov khoom muab rau hauv lub vev xaib no yog npaj tshwj xeeb rau kev tshawb fawb hauv vitro. Kev tshawb fawb hauv vitro (Latin: * hauv iav *, lub ntsiab lus hauv iav) yog ua los ntawm tib neeg lub cev. Cov khoom no tsis yog tshuaj, tsis tau txais kev pom zoo los ntawm US Food and Drug Administration (FDA), thiab yuav tsum tsis txhob siv los tiv thaiv, kho, lossis kho txhua yam mob, kab mob, lossis mob. Nws raug txwv nruj raws li txoj cai los qhia cov khoom no rau hauv tib neeg lossis tsiaj lub cev hauv txhua daim ntawv.
1.Txheej txheem cej luam
Hauv kev tshawb fawb txog lub neej, kev laus thiab autophagy yog qhov tseem ceeb ntawm kev tshawb fawb uas tau nyiam ntau yam. Telomeres, raws li cov qauv tshwj xeeb ntawm qhov kawg ntawm chromosomes, ua lub luag haujlwm tseem ceeb hauv ob txoj haujlwm. Raws li kev tshawb fawb txuas ntxiv mus, txoj kev sib raug zoo ntawm telomeres, kev laus, thiab autophagy tau dhau los ua qhov tseeb.
Daim duab 1 Telomere attrition, telomere ntev, thiab telomerase.
2.Txheej txheem cej luam ntawm Telomere Structure thiab Function
2.1 Telomere Structure
Telomeres yog ib qho kev txuag ntau heev repetitive nucleotide sequences nyob rau hauv qhov kawg ntawm linear chromosomes nyob rau hauv eukaryotic kab mob. Lawv suav nrog cov lus rov qab yooj yim uas nplua nuj hauv guanine (G), nrog rau tib neeg telomere rov ua ntu zus yog TTAGGG. Cov qauv no tiv thaiv qhov kawg ntawm chromosomes los ntawm kev degradation los ntawm nucleases, tiv thaiv chromosome fusion, thiab tswj cov chromosomal stability. Cov qauv ntawm telomeres feem ntau muaj telomeric DNA thiab cov proteins uas khi rau nws. Cov proteins no cuam tshuam nrog telomeric DNA los tsim cov qauv kev txiav txim siab dua, ntxiv txhim kho telomere stability.
2.2 Kev ua haujlwm ntawm Telomeres
Ib qho ntawm lub luag haujlwm tseem ceeb ntawm telomeres yog los daws qhov teeb meem 'kawg replication.' Vim yog cov yam ntxwv ntawm DNA replication, cov qauv DNA polymerases tsis tuaj yeem ua tiav qhov kawg ntawm cov kab chromosomes, ua rau telomere luv luv nrog txhua qhov kev faib tawm ntawm tes. Lub xub ntiag ntawm telomeres buffers qhov kawg luv luv, kom ntseeg tau tias kev ncaj ncees thiab ruaj khov ntawm chromosomes. Telomeres tseem ua lub luag haujlwm tseem ceeb hauv kev tswj lub voj voog ntawm tes. Thaum telomeres luv luv rau qee qhov, lawv ua rau lub voj voog ntawm tes, ua rau cov hlwb nkag mus rau hauv senescence lossis apoptosis, yog li txwv lawv lub peev xwm rau kev loj hlob tsis muaj kev txwv. Cov txheej txheem no tseem ceeb hauv kev tiv thaiv qog tsim thiab muaj feem cuam tshuam nrog kev laus ntawm cov kab mob.
3. Kev sib raug zoo ntawm Telomeres thiab Kev laus
3.1 Telomere Shortening ua tus cim ntawm Kev Laus
Raws li lub hnub nyoog nce, qhov ntev ntawm telomeres nyob rau hauv feem ntau ib txwm somatic hlwb maj mam shortens, ib tug tshwm sim pom nyob rau hauv ntau yam ntaub so ntswg thiab kabmob. Nyob rau hauv tib neeg peripheral ntshav mononuclear hlwb, telomere ntev ho txo qis nrog hnub nyoog. Kev tshawb fawb qhia tau hais tias telomere shortening yog ze ze nrog ntau yam kev hloov ntawm lub cev muaj feem xyuam rau kev laus, xws li txo cov cell proliferation muaj peev xwm, tsis muaj zog cov ntaub so ntswg regenerative muaj peev xwm, thiab muaj kev pheej hmoo ntawm ntau yam kab mob. Nyob rau theem cellular, thaum telomeres luv luv mus rau qhov tseem ceeb, cov hlwb poob lawv lub peev xwm loj hlob thiab nkag mus rau hauv lub xeev senescent, tus cwj pwm los ntawm kev hloov pauv ntawm cov cell morphology, txo cov metabolism hauv, thiab nce kev qhia ntawm senescence-associated β-galactosidase (SA-β-Gal).
3.2 Mechanisms uas telomere shortening ua rau kev laus
Cov txheej txheem los ntawm qhov uas telomere shortening ua rau kev laus feem ntau koom nrog DNA kev puas tsuaj teb txoj hauv kev. Thaum telomeres luv luv rau qee qhov, lawv cov qauv ua tsis ruaj khov, thiab kev tiv thaiv kev ua haujlwm ntawm telomere kawg ploj, ua rau kev lees paub ntawm chromosome xaus raws li DNA puas qhov chaw los ntawm cov hlwb. Qhov no ua rau muaj kev puas tsuaj DNA cov lus teb qhia txoj hauv kev, xws li ATM / ATR-p53-p21 txoj hauv kev. Thaum ua haujlwm, ATM (ataxia-telangiectasia mutated) lossis ATR (ataxia-telangiectasia thiab Rad3-txog) cov proteins phosphorylate downstream p53 proteins, ua rau lawv ruaj khov thiab txhawb lawv nkag mus rau hauv lub cell nucleus. Raws li qhov tseem ceeb ntawm kev sau ntawv, tswj cov kev qhia ntawm cov noob caj noob ces cuam tshuam nrog kev kaw lub voj voog ntawm tes thiab kev laus, suav nrog p21. p21 inhibits cov kev ua ntawm cyclin-dependent kinases (CDKs), yog li tiv thaiv cov hlwb los ntawm kev nce qib ntawm G1 theem mus rau theem S, ua rau lub voj voog ntawm tes thiab thaum kawg ua rau cellular senescence. Telomere shortening kuj tseem txhawb kev laus los ntawm kev cuam tshuam mitochondrial kev ua haujlwm. Telomere kev puas tsuaj ua rau muaj zog mitochondrial oxidative kev nyuaj siab thiab txo cov mitochondrial membrane muaj peev xwm, yog li cuam tshuam mitochondrial zog metabolism thiab intracellular redox tshuav nyiaj li cas, accelerating cov txheej txheem aging.
3.3 Telomeres thiab Kab Mob Hnub nyoog
Ntau yam kab mob uas muaj hnub nyoog, xws li cov kab mob plawv, kab mob neurodegenerative, thiab mob qog noj ntshav, muaj feem cuam tshuam nrog telomere shortening. Hauv cov kab mob plawv, telomere luv luv yog cuam tshuam nrog endothelial cell dysfunction thiab kev loj hlob ntawm atherosclerosis. Peripheral ntshav leukocyte telomere ntev nyob rau hauv cov neeg mob cov kab mob plawv yog luv luv dua li hauv kev noj qab haus huv ntawm cov tswj, thiab telomere ntev yog qhov tsis zoo cuam tshuam nrog kev mob hnyav. Hauv cov kab mob neurodegenerative xws li Alzheimer's kab mob thiab Parkinson's kab mob, telomere ntev hauv cov neurons hauv lub hlwb kuj tseem luv luv. Telomere shortening yuav ua rau tsub zuj zuj ntawm DNA puas thiab nce apoptosis nyob rau hauv neurons, yog li ua kom cov txheej txheem neurodegenerative. Hauv kev mob qog noj ntshav, txawm hais tias cov qog nqaij hlav cancer feem ntau muaj cov txheej txheem los tswj telomere ntev (xws li telomerase activation), telomere shortening nyob rau theem pib ntawm cov qog nqaij hlav tuaj yeem ua rau genomic instability, nce qhov tshwm sim ntawm cov noob hloov pauv thiab muab lub hauv paus rau kev loj hlob qog.
4. Kev sib raug zoo ntawm Telomeres thiab Autophagy
4.1 Kev tswj ntawm Autophagy los ntawm Telomeres
Autophagy yog ib qho tseem ceeb intracellular self-degradation thiab recycling mechanism uas tshem tawm cov organelles puas, misfolded proteins, thiab pathogens los ntawm lub cell, tswj lub stability ntawm lub intracellular ib puag ncig. Cov kev tshawb fawb tsis ntev los no tau pom tias muaj kev tswj hwm kev sib raug zoo ntawm telomeres thiab autophagy. Telomere shortening tuaj yeem ua rau autophagy. Thaum telomeres luv luv rau qee qhov vim yog kev faib tawm ntawm tes lossis lwm yam, lawv qhib cov kev ntxhov siab hauv lub cev, yog li ua rau autophagy. Hauv qee cov qauv ntawm telomerase-tsis muaj cell, raws li telomeres nce zuj zus, cov qib qhia ntawm autophagy-txog cov proteins tau nce, thiab cov autophagosomes kuj tseem ceeb nce. Autophagy tuaj yeem cuam tshuam rau telomere stability. Los ntawm kev tshem tawm DNA puas yam tseem ceeb thiab tswj cov cellular ib puag ncig kev ruaj ntseg, autophagy tiv thaiv telomeres los ntawm kev puas tsuaj thiab ua rau cov txheej txheem telomere shortening.
Daim duab 2 Qhov ntau ntawm cov qauv telomeric tsis zoo hauv PBMCs nce nrog cov hnub nyoog pub dawb.
4.2 Molecular mechanisms ntawm telomere kev tswj ntawm autophagy
Cov txheej txheem molecular uas telomeres tswj autophagy koom nrog ntau txoj hauv kev taw qhia. Ntawm cov no, mTOR (mechanistic lub hom phiaj ntawm rapamycin) kev taw qhia txoj kev ua haujlwm ua tus choj tseem ceeb txuas telomeres thiab autophagy. mTOR yog ib qho serine / threonine protein kinase uas hnov qab cov khoom noj hauv lub cev, qib zog, thiab cov cim kev loj hlob, yog li tswj cov txheej txheem ntawm tes xws li kev loj hlob, kev loj hlob, thiab autophagy. Kev tshawb fawb tau pom tias cov catalytic subunit ntawm telomerase, TERT (telomerase thim rov qab transcriptase), tuaj yeem cuam tshuam nrog mTOR thiab inhibit qhov kev ua kinase ntawm mTOR complex 1 (mTORC1). Raws li ib txwm muaj, mTORC1 yog nyob rau hauv lub xeev qhib, inhibiting qhov tshwm sim ntawm autophagy. Txawm li cas los xij, thaum telomeres luv luv lossis TERT qhia txawv txav, cov nyhuv inhibitory ntawm TERT ntawm mTORC1 yog txhim kho, ua rau txo qis mTORC1 kev ua, yog li tshem tawm qhov inhibition ntawm autophagy thiab txhawb nws txoj kev pib.
Tsis tas li ntawd, p53 txoj kev taw qhia tseem ua lub luag haujlwm tseem ceeb hauv telomere kev tswj hwm ntawm autophagy. Telomere shortening activates p53 signaling pathway, thiab p53 tuaj yeem tswj autophagy los ntawm kev hloov pauv ncaj qha rau kev qhia ntawm cov noob caj noob ces lossis cuam tshuam tsis ncaj qha rau mTOR teeb liab txoj hauv kev. Tshwj xeeb, p53 tuaj yeem txhim kho qhov kev qhia ntawm autophagy-txog cov noob xws li LC3 thiab Beclin1, txhawb kev tsim cov autophagosomes thiab yog li inducing autophagy.
4.3 Cov nyhuv ntawm autophagy ntawm telomere stability
Cov nyhuv ntawm autophagy ntawm telomere stability yog ua tiav los ntawm kev tswj hwm homeostasis hauv ib puag ncig intracellular. Autophagy tuaj yeem tshem tawm cov kab mob sib xyaw ua pa (ROS) hauv cov hlwb, txo cov kev ntxhov siab oxidative puas rau telomere DNA. ROS yog cov reactive molecules uas tsim thaum lub sij hawm cellular metabolism, thiab ntau dhau ROS tuaj yeem ua rau DNA oxidative puas tsuaj, nrog rau kev puas tsuaj rau telomere DNA. Autophagy tseem tuaj yeem ua kom puas mitochondria hauv cov hlwb, tiv thaiv ROS ntau dhau los ntawm mitochondrial dysfunction. Tsis tas li ntawd, autophagy tuaj yeem tshem tawm cov ntaub ntawv tsis raug lossis sib sau ua ke ntawm DNA puas kho cov proteins thiab lwm cov proteins uas cuam tshuam nrog kev saib xyuas telomere, ua kom lawv cov haujlwm ib txwm muaj thiab yog li tswj xyuas telomere stability. Cov kev tshawb fawb tau pom tias cov hlwb uas muaj cov kab mob autophagy tuaj yeem ua rau muaj kev puas tsuaj telomere DNA thiab ua kom telomere shortening, thaum inducing autophagy tuaj yeem txhim kho cov xwm txheej no.
Daim ntawv thov ntawm Telomere Theory hauv Kev Tshawb Fawb Txog Kev Laus
5.1 Telomerase Activation Strategies
Txij li thaum telomere shortening yog ze ze rau kev laus, tswj telomere ntev los ntawm activating telomerase tau dhau los ua ib qho tseem ceeb hauv kev tshawb fawb los tiv thaiv kev laus. Telomerase yog ib qho ribonucleoprotein complex uas muaj RNA thiab cov proteins uas tuaj yeem siv nws tus kheej RNA ua tus qauv los ua ke telomere DNA thiab ntxiv rau qhov kawg ntawm chromosomes, yog li txuas ntxiv telomere ntev. Qee qhov kev tshawb fawb tau siv cov tshuaj me me los ua kom telomerase. TA-65 yog ib qho me me-molecule compound rho tawm los ntawm Astragalus, tshaj tawm tias muaj cov teebmeem telomerase-activates. Hauv kev sim tsiaj, tom qab kev tswj hwm ntawm TA-65, telomere ntev ntawm nas tau txuas ntxiv mus rau qee qhov, thiab qee qhov muaj hnub nyoog ntsig txog phenotypes xws li tawv nqaij thiab plaub hau thinning kuj tau txhim kho.
5.2 Autophagy Regulation Strategies
Muab lub luag haujlwm tseem ceeb ntawm autophagy hauv kev tswj hwm cellular homeostasis thiab tiv thaiv telomeres, tswj autophagy kuj tau dhau los ua lub tswv yim zoo rau kev tiv thaiv kev laus. Ntawm ib sab, autophagy tuaj yeem raug ntxias los ntawm kev siv tshuaj lossis kev noj zaub mov noj. Rapamycin yog ib qho classic mTOR inhibitor uas induces autophagy los ntawm inhibiting qhov kev ua ntawm mTORC1. Hauv kev sim tsiaj, kev kho rapamycin txuas ntxiv nas lub neej thiab txhim kho lub hnub nyoog ntsig txog kev ua haujlwm ntawm lub cev. Qee cov khoom lag luam ntuj, xws li resveratrol thiab curcumin, kuj tau tshaj tawm los ua rau autophagy. Cov khoom lag luam ntuj no tuaj yeem tswj hwm autophagy los ntawm kev ua kom muaj kev taw qhia xws li SIRT1 (cov ntaub ntawv ntsiag to regulator 1). Rau cov hlwb lossis cov tib neeg uas muaj qhov tsis zoo autophagy muaj nuj nqi, autophagy muaj nuj nqi tuaj yeem rov qab los ntawm kev kho noob. Autophagy-hais txog cov noob tuaj yeem nkag mus rau hauv cov hlwb ntawm cov noob vectors txhawm rau txhim kho cellular autophagy muaj peev xwm.
5.3 Cov tswv yim sib koom ua ke
Muab qhov sib cuam tshuam ntawm telomeres, kev laus, thiab autophagy, kev cuam tshuam kev sib koom ua ke ntawm ob qho tib si telomeres thiab autophagy tuaj yeem sawv cev rau lub tswv yim zoo los tiv thaiv kev laus. Telomerase activators thiab autophagy inducers tuaj yeem siv tau ib txhij: telomerase activators txuas telomere ntev, thaum autophagy inducers tshem tawm cov cellular puas, tswj cellular homeostasis thiab synergistically exerting los tiv thaiv kev laus. Hauv kev sim tsiaj, kev siv ua ke ntawm telomerase activators thiab autophagy inducers tau pom tias muaj kev tiv thaiv kev laus ntau dua li tus neeg sawv cev ib leeg, xws li kev txhim kho lub hnub nyoog ntsig txog lub cev thiab kev ua neej ntev.
Xaus
Telomeres ua lub luag haujlwm tseem ceeb hauv cov txheej txheem ntawm kev laus thiab autophagy. Telomere shortening, raws li tus cim tseem ceeb ntawm kev laus, ua rau cov cellular aging thiab ntau yam kab mob uas muaj feem xyuam nrog kev laus los ntawm cov txheej txheem xws li ua kom DNA puas tsuaj rau txoj hauv kev thiab cuam tshuam rau kev ua haujlwm mitochondrial. Muaj kev sib tshuam kev sib raug zoo ntawm telomeres thiab autophagy. Telomeres tuaj yeem tswj hwm autophagy los ntawm kev taw qhia txoj hauv kev xws li mTOR thiab p53, thaum autophagy tiv thaiv telomere kev ruaj ntseg los ntawm kev tswj hwm intracellular ib puag ncig homeostasis. Kev tshawb fawb los tiv thaiv kev laus raws li txoj kev xav ntawm telomere, xws li telomerase activation strategies, autophagy regulation strategies, thiab cov tswv yim sib koom ua ke, muaj kev cia siab dav rau kev ncua kev laus thiab kho cov kab mob muaj hnub nyoog.
Qhov chaw
[1] Boccardi V, Cari L, Nocentini G, et al. Telomeres Txhim Kho Cov Qauv Aberrant hauv Cov Neeg Laus [J]. Phau ntawv Journals of Gerontology Series a-Biological Sciences thiab Medical Sciences, 2020,75(2):230-235.DOI:10.1093/gerona/gly257.
[2] Green PD, Sharma NK, Santos JH. Telomerase Impinges ntawm Cellular Teb rau Oxidative Stress Los Ntawm Mitochondrial ROS-Mediated Regulation of Autophagy[J]. International Journal of Molecular Sciences, 2019, 20.
[3] Zhu Y, Li X, Li X, et al. Telomere thiab nws lub luag haujlwm hauv txoj kev laus: telomere shortening, cell senescence thiab mitochondria dysfunction [J]. Biogerontology, 2019,20(1):1-16.DOI:10.1007/s10522-018-9769-1.
[4] Ali M, Devkota S, Roh J, et al. Telomerase thim rov qab transcriptase induces basal thiab amino acid starvation-induced autophagy los ntawm mTORC1.[J]. Biochemical thiab Biophysical Research Communications, 2016,478 3:1198-1204.
[5] Vaiserman A, Krasnienkov D. Telomere Length raws li ib tug cim ntawm lub hnub nyoog lom neeg: Lub xeev-of-the-Art, Qhib Teeb meem, thiab yav tom ntej Perspectives [J]. Frontiers in Genetics, Volume 11 - 2020.
