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EBINTU BYONNNA N’AMAWULIRE GW’EBINTU EBIweereddwa KU MUTINDO GUNO BIKOZESEBWA KU KUSASANYA AMAWULIRE N’EBIKOLWA BY’OKUSOMESA.
Ebintu ebiweereddwa ku mukutu guno bigendereddwamu kunoonyereza mu kisenge (in vitro research) byokka. Okunoonyereza mu vitro (Olulattini: *mu ndabirwamu*, ekitegeeza mu bikozesebwa mu ndabirwamu) kukolebwa ebweru w’omubiri gw’omuntu. Ebintu bino si bya ddagala, tebikkiriziddwa kitongole kya Amerika ekivunaanyizibwa ku by’emmere n’eddagala (FDA), era tebirina kukozesebwa kuziyiza, kujjanjaba oba kuwonya mbeera yonna ya bujjanjabi, bulwadde oba bulwadde. Kikugirwa nnyo mu mateeka okuyingiza ebintu bino mu mubiri gw’omuntu oba ebisolo mu ngeri yonna.
1.Okulambika okutwaliza awamu
Mu kisaawe kya ssaayansi w’obulamu, okukaddiwa n’okulya omubiri (autophagy) bye bintu bikulu eby’okunoonyereza ebisikiriza ennyo okufaayo. Telomeres, nga ensengekera ez’enjawulo ku nkomerero za chromosomes, zikola kinene mu nkola zombi. Okunoonyereza bwe kugenda mu maaso, enkolagana enzibu wakati wa telomeres, okukaddiwa, ne autophagy yeeyongera okweyoleka.
Ekifaananyi 1 Okusasika kwa telomere, obuwanvu bwa telomere, ne telomerase.
2.Okulaba Ensengeka n’Emirimu gya Telomere
2.1 Ensengekera ya Telomere
Telomeres ze nsengekera za nyukiliyotayidi eziddiŋŋana ezikuumibwa ennyo ezisangibwa ku nkomerero za chromosomes za layini mu biramu ebiyitibwa eukaryotic. Zirimu ensengekera ennyangu eziddiŋŋana ezirimu guanine (G), ng’ensengekera y’okuddiŋŋana za telomere z’omuntu ye TTAGGG. Ensengekera eno ekuuma enkomerero za chromosomes obutavunda ne nucleases, eziyiza chromosomes okuyungibwa, era ekuuma chromosomes nga zitebenkedde. Ensengekera ya telomeres okusinga erimu DNA ya telomeric ne puloteyina ezigisiba. Puloteeni zino zikwatagana ne DNA ya telomeric okukola ensengekera ezenjawulo ez’omutendera ogw’oku ntikko, okwongera okutumbula okutebenkera kwa telomere.
2.2 Emirimu gya Telomeres
Omu ku mirimu emikulu egya telomeres kwe kukola ku 'ekizibu ky'okukoppa enkomerero.' Olw'engeri y'okukoppa kwa DNA, DNA polymerases eza bulijjo teziyinza kukoppa mu bujjuvu enkomerero za linear chromosomes, ekivaako telomere okukendeera mpolampola buli lwe yagabanyaamu obutoffaali. Okubeerawo kwa telomeres kuziyiza okufunza kuno okw’enkomerero, okukakasa obulungi n’obutebenkevu bwa chromosomes. Telomeres era zikola kinene nnyo mu kulungamya enzirukanya y’obutoffaali. Telomeres bwe zikendeera okutuuka ku ddaala eritali limu, zikola ebifo eby’okukebera enzirukanya y’obutoffaali, ne kireetera obutoffaali okuyingira mu kukaddiwa oba okufa, bwe kityo ne kikoma ku busobozi bwabwo obw’okukula okutaliiko kkomo. Enkola eno ya maanyi mu kuziyiza ebizimba okutondebwa era ekwatagana nnyo n’enkola y’okukaddiwa kw’ebiramu.
3. Enkolagana Wakati Wa Telomeres n’Okukaddiwa
3.1 Okufunza Telomere ng’akabonero k’okukaddiwa
Emyaka bwe gyeyongera, obuwanvu bwa telomeres mu butoffaali bw’omubiri obusinga obungi obwa bulijjo bukendeera mpolampola, ekintu ekirabibwa mu bitundu by’omubiri n’ebitundu by’omubiri eby’enjawulo. Mu butoffaali bwa mononuclear omusaayi gw’omuntu ogw’okumpi, obuwanvu bwa telomere bukendeera nnyo n’emyaka. Okunoonyereza kulaga nti okufunza telomere kukwatagana nnyo n’enkyukakyuka ez’enjawulo mu mubiri ezikwatagana n’okukaddiwa, gamba ng’okukendeeza ku busobozi bw’obutoffaali okukula, obusobozi bw’okuzza obuggya ebitundu by’omubiri okunafuwa, n’okwongera ku bulabe bw’endwadde ez’enjawulo ezitawona. Ku mutendera gw’obutoffaali, telomeres bwe zikendeera okutuuka ku buwanvu obukulu, obutoffaali bufiirwa obusobozi bwabwo obw’okukula ne buyingira mu mbeera y’okukaddiwa, emanyiddwa olw’okukyusa enkula y’obutoffaali, okukendeeza ku mirimu gy’okukyusakyusa ebiriisa, n’okweyongera kw’okwolesebwa kwa β-galactosidase (SA-β-Gal) ekwatagana n’okukaddiwa.
3.2 Enkola okufunza telomere mwe kuleetera okukaddiwa
Enkola okufunza telomere mwe kuleetera okukaddiwa okusinga zirimu amakubo g’okuddamu okwonooneka kwa DNA. Telomeres bwe zikendeera okutuuka ku ddaala eritali limu, ensengekera yazo efuuka etali nnywevu, era omulimu gw’obukuumi ku nkomerero za telomere gubula, ekivaako okutegeera enkomerero za chromosome ng’ebifo ebyonoona DNA obutoffaali. Kino kikola amakubo agawerako agalaga obubonero bw’okuddamu okwonooneka kwa DNA, gamba ng’ekkubo lya ATM/ATR-p53-p21. Nga zikola, puloteyina za ATM (ataxia-telangiectasia mutated) oba ATR (ataxia-telangiectasia ne Rad3-related) zikola phosphorylate ku puloteyina za p53 eziri wansi, zongera okutebenkera kwazo n’okutumbula okuyingira kwazo mu nucleus y’obutoffaali. Nga ensonga enkulu ey’okuwandiika, etereeza okwolesebwa kw’omuddirirwa gw’obuzaale obukwatagana n’okukwatibwa kw’enzirukanya y’obutoffaali n’okukaddiwa, omuli p21. p21 eziyiza emirimu gya cyclin-dependent kinases (CDKs), bwe kityo ne kiremesa obutoffaali okugenda mu maaso okuva mu mutendera gwa G1 okudda mu mutendera gwa S, ekivaako okukwatibwa kw’enzirukanya y’obutoffaali era okukkakkana nga kivuddeko okukaddiwa kw’obutoffaali. Okufunza telomere nakyo kiyinza okutumbula okukaddiwa nga kikosa enkola ya mitochondria. Okwonooneka kwa telomere kuleeta okweyongera kw’okunyigirizibwa kw’okwokya kwa mitochondrial n’okukendeeza ku busobozi bw’oluwuzi lwa mitochondrial, bwe kityo ne kikosa enkyukakyuka y’amasoboza ga mitochondrial ne bbalansi ya redox mu butoffaali, okwanguya enkola y’okukaddiwa.
3.3 Telomeres n’endwadde ezeekuusa ku myaka
Endwadde nnyingi ezikwata ku myaka, gamba ng’endwadde z’emisuwa, endwadde z’obusimu, ne kookolo, zikwatagana nnyo n’okukendeera kw’obusimu obuyitibwa telomere. Mu ndwadde z’emisuwa, okukendeera kwa telomere kukwatagana nnyo n’obutakola bulungi mu butoffaali bw’omubiri (endothelial cell dysfunction) n’okukula kw’okuzimba emisuwa. Obuwanvu bwa telomere ya leukocyte mu musaayi ogw’okumpi mu balwadde b’omutima bumpi nnyo okusinga mu balamu abafuga, era obuwanvu bwa telomere bukwatagana bubi n’obuzibu bw’obulwadde. Mu ndwadde ezikendeeza ku busimu ng’obulwadde bwa Alzheimer ne Parkinson, obuwanvu bwa telomere mu busimu obuyitibwa neurons mu bwongo nabwo bukendeezebwa nnyo. Okukendeera kwa telomere kuyinza okuvaako okukuŋŋaanyizibwa kw’okwonooneka kwa DNA n’okwongera ku apoptosis mu busimu obuyitibwa neurons, bwe kityo ne kyanguyira okugenda mu maaso kw’enkola z’obusimu. Mu kookolo, wadde ng’obutoffaali bwa kookolo butera okuba n’enkola ezikuuma obuwanvu bwa telomere (nga telomerase activation), okufunza telomere mu mitendera egy’olubereberye egy’okutondebwa kw’ebizimba kuyinza okuleeta obutabeera mu ntebenkevu mu genomic, okwongera ku mikisa gy’enkyukakyuka mu buzaale n’okuwa omusingi gw’okukula kw’ekizimba.
4. Enkolagana Wakati Wa Telomeres ne Autophagy
4.1 Okulungamya enkola ya Autophagy nga ekolebwa Telomeres
Autophagy nkola nkulu ey’okwevunda n’okuddamu okukola mu butoffaali eggyawo ebitundu by’omubiri ebyonooneddwa, puloteyina ezibikkiddwa obubi, n’obuwuka obuleeta endwadde okuva mu katoffaali, okukuuma obutebenkevu bw’embeera y’omu butoffaali. Okunoonyereza okwakakolebwa kulaga nti waliwo enkolagana enzibu ey’okulungamya wakati wa telomeres ne autophagy. Okufunza telomere kuyinza okuleeta autophagy. Telomeres bwe zikendeera okutuuka ku ddaala eritali limu olw’okugabanya obutoffaali oba ensonga endala, zikola amakubo agalaga obubonero bw’okunyigirizibwa mu butoffaali, bwe kityo ne kivaako autophagy. Mu bikolwa by’obutoffaali ebimu ebibulamu telomerase, nga telomeres zigenda zikendeera, emitendera gy’okwolesebwa kwa puloteyina ezikwata ku autophagy gyeyongera nnyo, era omuwendo gwa autophagosomes nagwo gulinnya nnyo. Autophagy era esobola okukwata ku kunyweza telomere mu ngeri ey’okuddiŋŋana. Nga erongoosa ensonga z’okwonoona DNA n’okukuuma obutebenkevu bw’obutonde bw’obutoffaali, autophagy mu ngeri etali butereevu ekuuma telomeres okuva mu kwonooneka era ekendeeza ku nkola y’okufunza telomere.
Ekifaananyi 2 Obungi bw’ensengekera za telomeric ezitali nnungi mu PBMCs zeeyongera n’emyaka gy’omugabi.
4.2 Enkola za molekyu ez’okulungamya telomere mu autophagy
Enkola za molekyu telomeres mwe zifuga autophagy zirimu amakubo ag’obubonero agawera. Mu bino, ekkubo ly’obubonero erya mTOR (mechanistic target of rapamycin) likola ng’omutala omukulu ogugatta telomeres ne autophagy. mTOR ye serine/threonine protein kinase etegeera embeera y’ebiriisa mu butoffaali, emitendera gy’amasoboza, n’obubonero bw’ensonga y’okukula, bwe kityo n’etereeza enkola z’obutoffaali ng’okukula, okukula, n’okulya mu butoffaali. Okunoonyereza kulaga nti ekitundu ekiyitibwa catalytic subunit ekya telomerase, TERT (telomerase reverse transcriptase), kisobola okukwatagana ne mTOR ne kiziyiza emirimu gya kinase egya mTOR complex 1 (mTORC1). Mu mbeera eya bulijjo, mTORC1 eri mu mbeera ya activated, okuziyiza okubeerawo kwa autophagy. Naye, telomeres bwe zikendeeza oba TERT expression si ya bulijjo, ekikolwa ky’okuziyiza ekya TERT ku mTORC1 kyongerwako, ekivaako okukendeeza ku mirimu gya mTORC1, bwe kityo ne kisitula okuziyiza ku autophagy n’okutumbula okutandika kwayo.
Okugatta ku ekyo, ekkubo ly’obubonero bwa p53 era likola kinene nnyo mu kulungamya telomere mu autophagy. Okufunza telomere kukola ekkubo ly’obubonero bwa p53, era p53 esobola okulung’amya autophagy nga ekyusa butereevu okwolesebwa kw’obuzaale obukwatagana ne autophagy oba okukwata mu ngeri etali butereevu ekkubo ly’obubonero bwa mTOR. Okusingira ddala, p53 esobola okulinnyisa okwolesebwa kw’obuzaale obukwatagana ne autophagy nga LC3 ne Beclin1, okutumbula okutondebwa kwa autophagosomes era bwe kityo n’ereeta autophagy.
4.3 Enkola ya autophagy ku kutebenkera kwa telomere
Enkola ya autophagy ku telomere stability okusinga etuukibwako nga tukuuma homeostasis mu mbeera y’obutoffaali. Autophagy esobola okugogola ebika bya oxygen ebikuŋŋaanyiziddwa (ROS) mu butoffaali, okukendeeza ku kwonooneka kw’okunyigirizibwa okw’okwokya (oxidative stress damage) ku DNA ya telomere. ROS molekyu ezikola ennyo ezikolebwa mu kiseera ky’okukyusakyusa obutoffaali, era ROS ezisukkiridde zisobola okuleeta okwonooneka kwa DNA okw’okwokya, omuli okwonooneka kwa DNA ya telomere. Autophagy era esobola okusaanyawo mitochondria eyonoonese munda mu butoffaali, okuziyiza okukola ROS okuyitiridde okuva ku mitochondria obutakola bulungi. Okugatta ku ekyo, autophagy esobola okugogola ebika ebikubiddwa obubi oba ebikuŋŋaanyiziddwa ebya puloteyina eziddaabiriza okwonooneka kwa DNA ne puloteyina endala ezikwatagana n’okulabirira telomere, okukakasa nti zikola bulungi era bwe kityo ne zikuuma telomere stability. Okunoonyereza kulaga nti obutoffaali obulina obuzibu mu autophagy bulaga okweyongera okwonooneka kwa DNA ya telomere n’okufunza telomere okwangu, ate nga okuleeta autophagy kiyinza okulongoosa ebintu bino.
Enkozesa y’endowooza ya Telomere mu kunoonyereza ku kulwanyisa okukaddiwa
5.1 Enkola z’okukola Telomerase
Okuva okufunza kwa telomere bwe kukwatagana ennyo n’okukaddiwa, okukuuma obuwanvu bwa telomere nga tukola telomerase kifuuse obulagirizi obukulu mu kunoonyereza ku kulwanyisa okukaddiwa. Telomerase ye ribonucleoprotein complex ekoleddwa mu RNA ne proteins ezisobola okukozesa RNA yaayo nga template okukola telomere DNA ne bagigatta ku nkomerero za chromosomes, bwe kityo ne kigaziya obuwanvu bwa telomere. Okunoonyereza okumu kukozesezza ebirungo ebirina molekyu entono okukola telomerase. TA-65 kirungo kya molekyu entono ekiggibwa mu Astragalus, nga kigambibwa nti kirina ebikolwa ebikola telomerase. Mu kugezesa ebisolo, oluvannyuma lw’okuweebwa TA-65, obuwanvu bwa telomere bw’ebibe bwagaziwa okutuuka ku ddaala eritali limu, era ebimu ku bifaananyi ebikwatagana n’emyaka ng’okugonza olususu n’okugonza enviiri nabyo byalongoosebwa.
5.2 Enkola z’okulungamya autophagy
Kubanga omulimu omukulu ogwa autophagy mu kukuuma cellular homeostasis n’okukuuma telomeres, okulungamya autophagy nakyo kifuuse enkola eyinza okukolebwa okulwanyisa okukaddiwa. Ku ludda olumu, autophagy esobola okuleetebwa okuyita mu kuyingirira eddagala oba eby’endya. Rapamycin ye classic mTOR inhibitor ereeta autophagy nga eziyiza emirimu gya mTORC1. Mu kugezesa ebisolo, obujjanjabi bwa rapamycin bwayongera ku bulamu bw’ebibe era ne bulongoosa emirimu gy’omubiri egyekuusa ku myaka. Ebintu ebimu eby’obutonde, nga resveratrol ne curcumin, nabyo kigambibwa nti bireeta autophagy. Ebintu bino eby’obutonde biyinza okulungamya autophagy nga bikola amakubo agalaga obubonero nga SIRT1 (silent information regulator 1). Ku butoffaali oba abantu ssekinnoomu abalina obuzibu mu nkola ya autophagy, enkola ya autophagy esobola okuzzibwawo okuyita mu bujjanjabi bw’obuzaale. Ensengekera z’obuzaale ezikwatagana ne autophagy zisobola okuyingizibwa mu butoffaali nga ziyita mu gene vectors okutumbula obusobozi bw’obutoffaali obukola autophagy.
5.3 Enkola z’okuyingira mu nsonga ezigatta
Kubanga enkolagana enzibu wakati wa telomeres, okukaddiwa, ne autophagy, okuyingira mu nsonga okugatta okugenderera telomeres zombi ne autophagy kuyinza okukiikirira enkola ennungamu ey’okulwanyisa okukaddiwa. Telomerase activators ne autophagy inducers zisobola okukozesebwa mu kiseera kye kimu: telomerase activators byongera ku buwanvu bwa telomere, ate autophagy inducers zigogola ebitundu by’obutoffaali ebyonooneddwa, okukuuma cellular homeostasis era synergistically exerting anti-aging effects. Mu kugezesa ebisolo, okukozesa awamu telomerase activators ne autophagy inducers kwalaga ebikolwa eby’amaanyi ebiziyiza okukaddiwa okusinga ekirungo kyonna kyokka, gamba ng’okulongoosa obulungi emirimu gy’omubiri egyekuusa ku myaka n’okwongera ku bulamu bw’ebisolo.
Mu bufunzi
Telomeres zikola kinene nnyo mu nkola z’okukaddiwa n’okulya autophagy. Okufunza telomere, ng’akabonero akakulu ak’okukaddiwa, kuleeta okukaddiwa kw’obutoffaali n’endwadde ez’enjawulo ezeekuusa ku kukaddiwa okuyita mu nkola nga okukola amakubo g’okuddamu okwonooneka kwa DNA n’okukosa enkola ya mitochondria. Waliwo enkolagana enzibu ey’okulungamya wakati wa telomeres ne autophagy. Telomeres zisobola okulungamya autophagy okuyita mu makubo agalaga obubonero nga mTOR ne p53, ate autophagy ekuuma telomere stability nga ekuuma intracellular environmental homeostasis. Okunoonyereza ku kulwanyisa okukaddiwa okwesigamiziddwa ku ndowooza ya telomere, gamba ng’enkola z’okukola telomerase, enkola z’okulungamya autophagy, n’enkola z’okuyingira mu nsonga ezigatta, kuwa essuubi eddene ery’okulwawo okukaddiwa n’okujjanjaba endwadde ezeekuusa ku myaka.
Ensonda
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[3] Zhu Y, Liu X, Ding X, n’abalala. Telomere n’omulimu gwayo mu makubo g’okukaddiwa: okufunza telomere, okukaddiwa kw’obutoffaali n’obutakola bulungi bwa mitochondria[J]. Ebiramu, 2019, 20 (1): 1-16.DOI: 10.1007 / s10522-018-9769-1.
[4] Ali M, Devkota S, Roh J, n’abalala. Telomerase reverse transcriptase ereeta enjala ya basal ne amino acid ereetebwa autophagy okuyita mu mTORC1.[J]. Empuliziganya y’okunoonyereza ku biramu n’ebiramu, 2016,478 3:1198-1204.
[5] Vaiserman A, Krasnienkov D. Obuwanvu bwa Telomere ng’akabonero k’emyaka gy’ebiramu: Embeera ey’omulembe, Ensonga enzigule, n’endowooza z’omu maaso[J]. Ensalo mu by'obuzaale,Volume 11 - 2020.
