Immune Memory in Aging: A Wide Perspective Covering Microbiota, Brain, Metabolism, Thiab Epigenetics Part 2

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Kev sib txuam ntawm Metabolism thiab Kev Tiv Thaiv Kev Tiv Thaiv

Metabolism thiab metabolic o yog cov txheej txheem tseem ceeb uas cuam tshuam thiab cuam tshuam los ntawm kev laus. Cov kab mob metabolic xws li hom 2 mob ntshav qab zib mellitus, kab mob plawv, thiab rog rog kuj suav tias yog kab mob ntsig txog hnub nyoog. Cov mob no yog nrog los ntawm kev mob ntev, hu ua metaflammation, uas yog tsav los ntawm cov khoom noj ntau dhau. Txawm hais tias qhov tshwm sim tuaj yeem sib txawv, cov txheej txheem hauv qab metaflammation thiab o tuaj yeem zoo sib xws.

Mitochondrial dysfunction, tsub zuj zuj ntawm senescent hlwb thiab cellular khib nyiab, thiab hyperactivation ntawm lub cev tiv thaiv kab mob, xws li inflammasome, pab txhawb rau ob qho tib si txheej txheem [120]. Yog li ntawd, nws yog ib qho tseem ceeb kom nkag siab txog kev sib cuam tshuam ntawm cellular aging, metabolism, thiab o nyob rau hauv chronological aging thiab hnub nyoog-txog cov kab mob metabolic kom rov qab rau lawv.

T Cell Metabolism

Quiescent T hlwb tsuas yog siv cov txheej txheem catabolic, thaum lub hlwb ua kom muaj kev vam khom rau cov txheej txheem anabolic los txhawb kev tsim cov protein ntau thiab kev loj hlob. Cov hlwb yuav tsum tau ua kom muaj qhov tseem ceeb ntawm serine / threonine kinase, lub hom phiaj ntawm cov tsiaj txhu ntawm rapamycin (mTOR), kom ua rau txoj hauv kev anabolic [121]. Thaum tsav tsheb loj hlob thiab kev loj hlob, mTOR kuj txhawb nqa cov piam thaj thauj thiab glycolysis.cistanche tubulosa noj redditGlycolysis yog ib txoj hauv kev tseem ceeb rau kev tsim lub zog. Txawm hais tias nws tsis muaj zog - tsuas yog 2 adenosine triphosphate (ATP) cov molecules tuaj yeem tsim los ntawm ib cov piam thaj molecule - nws tsim lub zog sai heev, uas yog siv rau kev nquag thiab proliferating T hlwb [122].Kev ua cov piam thaj yield ATP, NADH, thiab pyruvate. Pyruvate ces hloov mus rau lactate thiab xa tawm raws li lactic acid nyob rau hauv cov ntaub ntawv ntawm glycolysis los yog lwm yam thauj mus rau mitochondria rau oxidative phosphorylation (OXPHOS).

Thov nias ntawm no kom paub ntxiv

OXPHOS yog txoj hauv kev ua kom muaj zog bioenergetic ntau dua, tsim 36 ATP molecules los ntawm txhua cov piam thaj molecule [123]. Hauv qhov no, pyruvate hloov mus rau acetyl-CoA thiab nkag mus rau lub voj voog tricarboxylic acid (TCA lub voj voog), uas yog txuas rau cov saw hlau thauj hluav taws xob (TCA) los ntawm electron pub NADH thiab FADH2. TCA lub voj voog tuaj yeem rov ntxiv los ntawm cov amino acids thiab oxidation ntawm fatty acids. Fatty acid oxidation (FAO) feem ntau yog siv los ntawm cov hlwb uas tsis muaj zog xav tau thiab ua lub luag haujlwm tseem ceeb hauv CD8 nco thiab CD4 ntxiv rau Treg txoj kev loj hlob [124]. Activated T hlwb upregulate lawv glutamine uptake thiab ua glutaminolysis kom tawm los -ketoglutarate, uas nkag mus rau lub voj voog TCA.

Tsis tas li ntawd, TCA lub voj voog metabolites tuaj yeem tswj hwm kev tiv thaiv kab mob hauv txoj hauv kev uas tsis yog kev tsim hluav taws xob. Piv txwv li, acetyl-CoA ua raws li cov cofactor tseem ceeb rau histone acetylation [125].Hauv T cells, acetyl-CoA yuav tsum tau rau IFNy ntau lawm los ntawm histone acetylation [126]. Acetyl-CoA kuj tseem pab txhawb rau acetylation ntawm mitochondrial proteins [127], uas muaj cov txiaj ntsig zoo rau ob qho tib si hauv lub cev thiab lub cev tiv thaiv kab mob [128].

Quiescent naive T hlwb ua tau raws li lawv lub zog xav tau nrog OXPHOS [129].cistanche แอมเวIL-7 thiab TCR signaling yog qhov tseem ceeb rau lawv cov kev cai metabolic thiab ciaj sia [130, 131]. Thaum T cells tau qhib, qhov kev xav tau tam sim rau lub zog tshwm sim rau cov haujlwm ua haujlwm thiab kev tsim biomass. Cov hlwb txhawb nqa kev thauj mus los zoo li cov piam thaj transporter 1 (GLUT1) thiab koom nrog aerobic glycolysis, txhawb kev tsim cov cytokine los ntawm txoj hauv kev, xws li phosphoinositide 3-kinase (PI3K)-AKT-mTOR axis thiab mitogen-activated protein kinase (MAPK) teeb liab [132]. Lub glycolytic hloov yog yuav tsum tau rau cov nyhuv effector, piv txwv li, IFNy ntau lawm tab sis tsis tseem ceeb rau prolif-eration[133].OXPHOS kuj tseem siv tau rau kev loj hlob thiab ciaj sia taus lub hom phiaj. Txawm hais tias activated T hlwb ua hauj lwm cia siab rau glycolysis, OXPHOS yeej tsis dispensable: thaum OXPHOS inhibited nrog oligomycin, T cell activation thiab proliferation raug thaiv [133].

Txawm hais tias lawv cia siab rau OXPHOS thiab FAO nyob rau hauv lub xeev so, nco T hlwb yuav tsum tau teb sai thiab ua tau zoo thaum ntsib antigen. Yog li, lawv tuaj yeem hloov mus rau glycolysis sai dua li naive T hlwb [134]. Ntau dua mitochondrial loj thiab muaj zog mitochondrial seem ua pa muaj peev xwm tau txuas rau qhov txiaj ntsig bioenergetic [135, 136]. Tsis tas li ntawd, mitochondrial fusion yog qhov tseem ceeb rau kev txhim kho thiab kev ua haujlwm ntawm lub cim xeeb T hlwb [137].

Kev cuam tshuam ntawm Kev laus ntawm T Cell Metabolism

Nce p38 MAPK kev ua si yog ib qho ntawm cov yam ntxwv ntawm senescent T hlwb. inhibiting p38 txhim kho telomerase kev ua ub no, proliferation, autophagy, thiab mitochondrial qoj, nyob rau hauv ib txoj kev mTOR- ywj siab [17]. MAPK inhibition kuj tseem txhim kho T cell thiab cov tshuaj tiv thaiv kab mob hauv cov nas qub uas tau txhaj tshuaj tiv thaiv kab mob khaub thuas[138].

Cov neeg mob uas muaj kev hloov pauv ntawm kev ua haujlwm hauv PI3K tau depleted naive T hlwb tab sis ib qho tsub zuj zuj ntawm senes-cent effector hlwb, ib yam li cov neeg laus [139]. Inhibit-ing mTOR kev ua ub no nrog kev kho mob rapamycin ib nrab rov ua dua cov phenotype hauv cov neeg mob no. Yog li, overactive PI3K / AKT / mTOR signaling yog pom zoo raws li ib qho ntawm cov tsav tsheb ntawm T cell senescence.

Cov neeg laus uas tsis muaj hnub nyoog T hlwb muaj ntau dua mitochondrial, tab sis qhov nthuav, tsawg dua mitochondrial ua pa muaj peev xwm, tej zaum vim yog transcriptional downregulation ntawm respiratory chain genes [140]. Tsis tas li ntawd, enzymes ntawm ib-carbon metabolism yog tsis txaus nyob rau hauv cov laus naive T hlwb, thiab supplementation nrog formate thiab glycine, ib-carbon metabolism metabolites, txhim kho cell ciaj sia taus thiab ua kom [14].

Autophagy yog ib qho tseem ceeb rau tiam ntawm T cell nco, thiab induction ntawm autophagy los ntawm spermidine txhim kho CD8 ntxiv rau T cell teb tiv thaiv kev txhaj tshuaj tiv thaiv kab mob khaub thuas hauv cov nas muaj hnub nyoog [142]. CD4 ntxiv rau lub cim xeeb T hlwb ntawm cov neeg laus tso saib oxidative phosphorylation, reactive oxygen hom (ROS) ntau lawm, thiab fatty acid oxidation [143].bioflavonoidsLawv kuj muaj qhov qhia ntau dua ntawm Sirtuin 1 (SIRT1), NAD-dependent deacetylase, piv rau cov hlwb hluas. SIRT1 thiab AMPK, ob lub ntsiab lus tseem ceeb-sensing molecules thiab tsis zoo regulators ntawm mTOR, muaj kev cuam tshuam rau ib leeg [144].Thiab rau CD4 ntxiv rau cov hlwb, cov laus-txuas nrog qhov sib txawv ntawm lub cim xeeb CD8 ntxiv rau CD28-T hlwb muaj ib siab glycolytic muaj peev xwm, uas yog txuas nrog lawv downregulated SIRTI qhia [145].

CD8 ntxiv rau TEMRA hlwb muaj kev qhia ntau dua ntawm glycolysis thiab glutaminolysis-txog cov noob thiab lub pas dej ATP loj dua piv rau naive thiab EM hlwb [146]. Txawm hais tias kev tswj hwm glycolytic transcription hauv TEMRA hlwb, basal glycolysis qib zoo ib yam li cov hlwb tsis zoo thiab EM. Zoo li EM hlwb, TEMRA hlwb tuaj yeem nce glycolysis thiab OXPHOS sai sai thaum ua haujlwm [146].Raws li kev ua haujlwm, TEMRA hlwb muaj peev xwm ntawm cytotoxicity thiab cytokine ntau lawm, txawm tias lawv lub xeev senescent thiab impaired mitochondrial function [17, 36].

Cov kab mob CMV ntev ntev, paub txog kev tiv thaiv kev tiv thaiv kab mob, kuj tseem hloov pauv cov cellular metabolism ntawm T hlwb, ua kom cov piam thaj nce ntxiv, txhawb nqa glycolysis, rov tsim cov lipid rafts, thiab cuam tshuam cov roj cholesterol metabolism [147, 148]. Tsis tas li ntawd, mob o vim CMV mus ntev. Kev kis kab mob cuam tshuam rau pancreatic -cells thiab ua rau muaj kev pheej hmoo rau hom 2 mob ntshav qab zib hauv cov neeg laus [149].

B Cell Metabolism

Cov txheej txheem metabolic uas tswj T hlwb kuj tseem ceeb rau B cell ua haujlwm, txawm tias tsis tau tshawb fawb ntau txog B cell metabolism. Thaum B cell yog qhib raws li antigen paub los ntawm BCR thiab T cell pab, nws activates PI3K/AKT/mTOR signaling [150]. Ib yam li cov activated T hlwb, activated B hlwb xav tau lub zog sai sai kom biomass thiab proliferate. Yog li ntawd, cov piam thaj thiab glutamine uptake nce, nrog rau kev noj cov pa oxygen, OXPHOS, thiab mitochondrial remodeling [151]. OXPHOS thiab glutamine-fueling ntawm TCA lub voj voog tau raug pom tias yog txoj hauv kev tseem ceeb ntawm bioenergetic rau B cell loj hlob thiab kev ua haujlwm, thaum cov piam thaj yog dispensable [152].

Ib txoj kev tshawb fawb tau pom tias cov hlwb B tau txais muaj ntau dua mitochondria tab sis cov nqi zoo sib xws ntawm mitochondrial DNA, qhia tias fission ntawm naive B cell mitochondria nrog ntau nucleoids, es tsis yog mitochondrial replication, tshwm sim thaum ua kom [152]. Lwm txoj kev tshawb fawb qhia tias kev hloov kho mitochondrial thiab ROS theem txiav txim siab txoj hmoo ntawm cov kab mob B hlwb. Cells nrog nce mitochondrial loj thiab siab dua ROS theem thaum ua kom muaj destined rau chav kawm hloov recombination, whereas hlwb nrog txo mitochondrial loj undergo plasma cell txawv [153].

Lub zog xav tau ntawm activated B hlwb hauv GCs nquag hloov [154].npaum li cas cistanche cojHauv thaj chaw hypoxic lub teeb, cov hlwb siv cov pa oxygen tsawg dua thiab ntau dua glycolytic.mTORC1 tsis tsim nyog rau kev tswj hwm ntawm glycolysis ntawm no, tab sis nws yog ib qho tseem ceeb, ua ke nrog c-Myc, rau kev xaiv zoo ntawm cov hlwb thiab tsiv mus rau qhov tsaus ntuj. rau proliferation thiab somatic hypermutation [155,156].

Cistanche tuaj yeem tiv thaiv kev laus

Thaum GC maturation, thaum lub xovtooj sib txawv rau hauv lub cim xeeb B hlwb, lub xeev metabolic ua ntau quiescent nrog OXPHOS tseem ceeb. Txawm li cas los xij, kev rov ua kom sai sai ntawm mTORC1 thiab glycolysis yog ua tau rau tom qab sib txawv rau hauv cov tshuaj tiv thaiv kab mob uas tsim cov plasmablasts [157]. Tsis tas li ntawd, nco B hlwb muaj siab basal autophagy, uas yog qhov tseem ceeb rau lawv txoj sia nyob mus txog thaum antigen ntsib [158,159].

GCs kuj tso tawm cov ntshav plasma ntev, uas tuaj yeem tsim ntau txhiab cov tshuaj tiv thaiv ib ob. Qhov no, ib txwm muaj, yog lub zog xav tau.mTORC1 yog qhov tseem ceeb rau kev tsim cov ntshav plasma thiab cov tshuaj tiv thaiv kab mob sib txuas [160]. Plasma cells muaj cov piam thaj ntau ntxiv, tab sis feem ntau ntawm cov piam thaj yog siv rau cov protein glycosylation [161]. Txawm li cas los xij, kev muaj sia nyob thiab tshuaj tiv thaiv kab mob ntawm cov plasma hlwb raug cuam tshuam thaum cov piam thaj transporter Glute raug tshem tawm [162]. Tsis tas li ntawd, mitochondrial ntshuam ntawm pyruvate, muab los ntawm glycolysis, yog qhov tseem ceeb rau kev saib xyuas cov ntshav plasma mus ntev [161].

Thaum kawg, cov ntaub so ntswg nyob hauv B1 B cov hlwb muaj zog ntau dua hauv glycolysis thiab OXPHOS dua li lwm cov B hlwb, cov classical anti-lub cev tsim, thiab nco B hlwb. Tsis tas li ntawd, autophagy yog qhov tseem ceeb rau kev ua haujlwm mitochondrial thiab rov ua nws tus kheej ntawm B1 hlwb [163].

Kev cuam tshuam ntawm Kev laus ntawm B Cell Metabolism

Muaj tsawg cov ntaub ntawv hais txog yuav ua li cas B cell metabolism raug tswj thiab cuam tshuam ua haujlwm raws li lub hnub nyoog. Ib txoj kev tshawb nrhiav pom tias cov tshuaj tiv thaiv kab mob zais B hlwb ntawm cov neeg muaj hnub nyoog qis dua SIRTI qhia, thiab qib SIRT1 siab dua tau cuam tshuam nrog cov tshuaj tiv thaiv zoo dua rau ntau hom kab mob khaub thuas [164]. Tsis tas li ntawd, cov hlwb tsis paub qab hau thiab qhib B hlwb ntawm cov neeg laus muaj lub peev xwm glycolytic me ntsis thiab txo qis hauv OXPHOS.Nyob rau hauv cov nas, cov laus B hlwb muaj glycolysis thiab OXPHOS tus nqi zoo li lawv cov tub ntxhais hluas tab sis tsis tuaj yeem txhim kho OXPHOS ntxiv rau kev txhawb nqa [165 ]. Txawm li cas los xij, cov hlwb muaj peev xwm txhawb nqa glycolysis kom tau raws li lawv lub zog xav tau.

Leptin, pro-inflammatory hormone secreted los ntawm adipocytes, yog siab dua nyob rau hauv cov neeg rog rog [166]. Ntawm cov neeg tsis rog, cov leptin concentrations tau nce siab dua hauv cov neeg laus [167]. Leptin abundance nyob rau hauv cov ntshav qab zib kuj zoo txuam nrog frailty [168]. Tom qab kis tau rau leptin, B hlwb los ntawm cov tub ntxhais hluas lean cov neeg pom qhov zoo ib yam li B hlwb ntawm cov laus lean thiab cov hluas rog rog txog transcriptional profile thiab antibody secretion [167]. Leptin kuj txo qis cov kab mob khaub thuas tshwj xeeb cov tshuaj tiv thaiv kab mob los ntawm B hlwb hauv vitro. Kev rog rog paub tias ua rau tsis zoo rau B cell teb rau kev txhaj tshuaj, thiab cov kev tshawb fawb qhia tias leptin tej zaum yuav muaj feem cuam tshuam rau qhov no [169].

Tsis tas li ntawd, post-transcriptional glycosylation ntawm cov tshuaj tiv thaiv kab mob hloov lawv txoj haujlwm, thiab hloov pauv glycosylation qauv tau txuas rau kev laus [170,171]. 4-Galactosyltransferase kev ua ub no nce nrog hnub nyoog [172], uas yuav muaj txiaj ntsig zoo, txawm tias tseem tsis tau tshawb nrhiav.

Metabolism hauv Kev Tiv Thaiv Kev Tiv Thaiv

Metabolic reprogramming yog ib qho ntawm cov txheej txheem tseem ceeb hauv kev kawm kev tiv thaiv kab mob (tseem hu ua innate immune nco), nrog rau kev kho chromatin. Qhov tseeb, kev hloov pauv hauv metabolic tuaj yeem ua rau muaj kev hloov pauv ntawm epigenetic txij li qee cov metabolites, xws li acetyl-CoA, tuaj yeem tswj hwm cov enzymes epigenetic [173]. Fumarate yog ib qho piv txwv ntawm TCA metabolites tsav cov kev hloov pauv hloov pauv. Nws tuaj yeem ua rau muaj kev tiv thaiv kev tiv thaiv ntawm nws tus kheej, thiab nws cov tsub zuj zuj ntawm cov txheej txheem no induces trimethylation ntawm histone 3 lysine 4 ntawm cov neeg txhawb nqa ntawm IL-6 thiab TNF [104]. Qhov no yog vim fumarate inhibiting kev ua ntawm lysine-specific histone demethylase KDM5.

Txoj kev AKT/mTOR/HIFl yog txoj hauv kev tseem ceeb tshaj plaws rau kev txhawb nqa aerobic glycolysis hauv -glucan-kawm monocytes [174]. Contrary to -glucan-induced kawm tiv thaiv, BCG upregulates tsis yog glycolysis tab sis kuj OXPHOS [175]. Glutaminolysis thiab cholesterol synthesis yog lwm txoj hauv kev tseem ceeb hauv metabolic rau -glucan-induced kawm tiv thaiv kab mob [104]. Kev cuam tshuam cov txheej txheem no thaiv cov txheej txheem hauv vitro thiab hauv vivo.BCG kuj ua rau glutaminolysis, thiab muaj glutamine tseem ceeb rau cov lus teb [175].

Lub synthesis ntawm cov roj cholesterol nws tus kheej tsis yog qhov tseem ceeb rau kev cob qhia kev tiv thaiv kab mob tab sis theej qhov sib xyaw ntawm cov nruab nrab mevalonate. Blocking mevalonate tiam inhibits kev tiv thaiv kev tiv thaiv, thaum mevalonate ib leeg tuaj yeem ua rau muaj kev tiv thaiv kab mob hauv monocytes los ntawm kev ua kom cov insulin zoo li kev loj hlob 1 (IGF1) receptor thiab mTOR [176].dab tsi yog cistancheTsis tas li ntawd, kev hloov pauv hauv glycolysis thiab mevalonate txoj hauv kev tau pom tsis yog hauv monocytes nkaus xwb tab sis kuj hauv HSPCs [108].

oxLDL, uas tsis yog-microbial inducer ntawm lub cev tiv thaiv kab mob hauv lub cev, txhawb nqa ob qho tib si glycolysis thiab oxygen noj, thiab muaj cov piam thaj ntau ntxiv ntxiv txhim kho cov lus teb kev tiv thaiv kab mob [103]. Ib yam li ntawd, catecholamine-induced kawm tiv thaiv kab mob yog nrog los ntawm kev nce glycolysis thiab oxygen noj. Nco ntsoov, qhov tshwj xeeb metabolic rewiring tej zaum yuav txawv rau txawv inducers ntawm lub cev tiv thaiv kab mob nco. Piv txwv li, stimulation nrog aldosterone tsis cuam tshuam nrog nce glycolysis lossis OXPHOS tab sis yog nyob ntawm fatty acid synthesis [177].

Txog tam sim no, cov lus teb tau txais kev tiv thaiv kab mob thiab cov kab mob metabolic cuam tshuam tsis tau pom nyob rau hauv cov ntsiab lus ntawm kev laus. Txawm li cas los xij, ntau qhov kev tshawb fawb loj txuas ntxiv ntawm kev txhaj tshuaj BCG hauv cov neeg laus yuav sai sai rau qhov cuam tshuam ntawm BCG-induced cob qhia kev tiv thaiv kab mob ntawm cov metabolism hauv cov laus tiv thaiv kab mob (NCT04537663, NCT04417335).

Lub luag hauj lwm ntawm Epigenetic Alterations hauv Immune Memory

Epigenetic hloov pauv suav nrog kev hloov kho histone thiab DNA methylation uas tswj txoj kev ua haujlwm ntawm noob. Cov kev hloov kho no muaj zog thiab cuam tshuam rau txhua lub hlwb thiab cov ntaub so ntswg thoob plaws lub neej. Ib puag ncig thiab kev ua neej, nrog rau kev laus, tuaj yeem ua rau muaj kev hloov pauv ntawm epigenetic. Rau lub hom phiaj ntawm qhov kev tshuaj xyuas no, peb yuav tsom mus rau yuav ua li cas lub hnub nyoog ntawm kev hloov pauv epigenetic hloov pauv hauv lub cev thiab hloov lub cev tiv thaiv kab mob.

DNA Methylation hauv Adaptive Immunity

DNA methylation yog qhov kev hloov pauv ntau tshaj plaws epigenetic uas tshwm sim los ntawm kev hloov ib pawg methyl mus rau 5th carbon ntawm cytosine [178]. DNA methylation tsis yog ib txwm qhia txog cov noob caj ces qis; Txawm li cas los xij, methylation hauv cov noob txhawb nqa feem ntau cuam tshuam nrog kev tsis zoo TF khi thiab txo cov ntawv sau tseg [179]. Kev sib deev lom neeg, keeb kwm ntawm caj ces, ib puag ncig, thiab hnub nyoog cuam tshuam rau DNA methylation profile [180]. Ntawm cov xwm txheej no, hnub nyoog-dependent methylation yog qhov zoo heev. Zoo kawg li, cov qauv lej sib txawv tau tsim los kwv yees lub hnub nyoog lom neeg raws li qib methylation ntawm qee qhov chaw CpG los ntawm ntau cov ntaub so ntswg lossis hlwb [180-182].

Lub hnub nyoog nce qib yog txuam nrog kev poob qis ntawm cov cim methylation ntawm DNA [183], txawm hais tias cov qauv hypermethylation txawv txav kuj tau pom nyob rau hauv qee cov gene txhawb nqa [184]. Kev hloov pauv hauv thaj chaw methylation yog Kev poob ntawm CD28 co-stimulatory protein nyob rau hauv CD4 ntxiv rau T hlwb yog ib qho ntawm cov cim kev laus zoo, ua rau muaj kev cuam tshuam T cell ua kom tsis zoo thiab sib txawv. Ib qho kev sib piv ntawm methylation profiles ntawm CD28 ntxiv thiab CD28"l T hlwb tau nthuav tawm 296 qhov sib txawv ntawm cov methylated genes cuam tshuam nrog cov tsis zoo TCR signaling thiab cytotoxic teb [194]. Tsis tas li ntawd, kev qhia ntawm cov noob koom nrog inflammasome activation yog siab dua hauv CD28nul T hlwb, tawm tswv yim. Lwm txoj kev tshawb fawb tau tshaj tawm tias cov tshuaj methylation ntawm BACH2 qhov chaw ntawm CD4 ntxiv rau T hlwb hauv cov hnub nyoog nruab nrab thiab cov laus ua rau qis dua BACH2 qhia [195].BACH2 muaj lub luag haujlwm tswj kev tiv thaiv kab mob. Cov lus teb, modulating CD4 ntxiv rau T cell sib txawv thiab tswj kev mob [196]. Zuag qhia tag nrho, kev hloov pauv hauv DNA methylation qauv ua rau CD4 ntxiv rau T hlwb ua mob rau cov neeg laus.

Ob peb txoj kev tshawb fawb pom qhov pom ntawm DNA methylation profile ntawm B hlwb thaum ua kom muaj kab mob thiab kab mob [197-200]; Txawm li cas los xij, seb B hlwb puas cuam tshuam los ntawm cov hnub nyoog-raws li kev hloov pauv methylation tseem tsis tau paub.

Histone Hloov Kho hauv Adaptive Immunity

N-terminal histone tails yog lub hom phiaj rau kev hloov kho tom qab kev txhais lus enzymatic suav nrog acetylation, methylation, phosphorylation, ubiquitylation, thiab sumoylation [201]; Txawm li cas los xij, qhov kev tshuaj xyuas no yuav tsom mus rau methylation thiab acetylation, uas yog cov kev hloov pauv zoo tshaj plaws uas tswj hwm cov qauv histone. Methyl pawg tau ntxiv rau histone los ntawm histone methyltransferases thiab tshem tawm los ntawm histone demethylase [202]. Lub trimethylation ntawm histone 3 lysines 4 (H3K4me3), histone 3 lysine 36 (H3K36), thiab histone 3 lysine 79 (H3K79) yog txuas rau qhib thiab nquag sau cov cheeb tsam [203]. Ntawm qhov tod tes, mono-methylation ntawm histone 3 lysine 9 (H3K9me), histone 3 lysine 27 (H3K27me), thiab histone 4lysine 20 (H4K20me) yog txuam nrog cov cheeb tsam kaw thiab tsis muaj zog chromatin. Tsis tas li ntawd, histone acetylation yog txuam nrog loosened chromatin qauv thiab nce gene transcription [204]. Histone acetyltransferases catalyze lysine acetylation, whereas histone deacetylases (HDACs) thim rov qab qhov kev hloov kho [205]. Kev hloov pauv tom qab kev hloov pauv ntawm histones tsis tsuas yog cuam tshuam rau kev nkag mus tau thiab kev hloov pauv ntawm cov noob tab sis kuj hloov pauv lwm txoj kev splicing, DNA replication, thiab kho [206]. Histones thiab epigenetic cim ntawm histones tau hloov pauv nrog kev laus. HSCs los ntawm cov nas qub muaj ntau dua H3K4me3 thiab H3K27me3 peaks piv rau cov tub ntxhais hluas HSCs [186]. Tsis tas li ntawd, kev qhia ntawm FLT3, ib qho ntawm cov tswj hwm ntawm CLPs, tau txo qis vim H3K27me3 hauv cov laus HSCs, qhia txog kev sib txuas ntawm cov qog ntshav qog ntshav tsis zoo. ntawm HSCs hauv cov neeg laus. Ib txoj kev tshawb fawb dav tau ua rau cov menyuam yaus thiab laus cov menyuam ntxaib monozygotic tau pom tias kev hloov kho chromatin thaum laus tsis yog cuab yeej cuab tam [207]. Ntxiv mus, histone hloov kho profiles yog, rau qee qhov, homogenous ntawm cov neeg hluas thiab ntau yam ntawm cov neeg laus. Heterogeneity nyob rau hauv cov kev hloov kho histone tau pom ntawm cov tib neeg thiab cov hom cell hauv cov neeg laus.

Epigenetic kev hloov pauv yog ib qho ntawm cov hauv paus ntsiab lus ntawm qhov tsis xws luag pom hauv CD8 ntxiv rau T hlwb ntawm cov neeg laus. Cov cheeb tsam kaw ntau chromatin tau pom nyob rau hauv thaj chaw txhim kho thiab txhawb nqa ntawm cov noob ntsig txog T cell signaling hauv cov neeg laus piv rau cov hluas [208]. Tsis tas li ntawd, -7R, hauv lub cim xeeb CD8 ntxiv rau T hlwb, yog ib qho ntawm cov noob saum toj kawg nkaus uas muaj feem xyuam rau ntau qhov kaw chromatin peaks hauv cov neeg laus. Raws li IL-7 ua kom homeostasis thiab kev saib xyuas ntawm T thiab B hlwb, tsis zoo IL-7 kev taw qhia rau cov neeg laus tej zaum yuav yog ib qho laj thawj rau kev tiv thaiv kab mob tsis zoo [209]. Tsis tas li ntawd, naive CD8 ntxiv rau cov hlwb hauv cov neeg laus muaj qis dua chromatin nkag mus rau ntawm cov noob caj noob ces cuam tshuam nrog kev ua pa tsis zoo ntawm lub cev tsis zoo 1 (NRF1) khi [140]. Xav txog lub luag haujlwm ntawm NRF1 hauv oxidative phosphorylation, kev ua haujlwm ntawm chromatin txo qis tuaj yeem piav qhia qee yam ntawm CD8 T cell metabolism hauv cov neeg laus [210]. Lwm qhov kev tshawb pom tseem ceeb ntawm txoj kev tshawb no yog qhov qhib chromatin thaj tsam cuam tshuam nrog lub cim xeeb ntawm tes, thiab kev nkag mus tau ntawm cov neeg txhawb nqa tau ploj zuj zus rau cov neeg laus.

Raws li tau hais hauv ntu DNA methylation, qhov muaj hnub nyoog cuam tshuam nrog BACH2 qhia tau pom hauv CD4 ntxiv rau T hlwb. Lwm txoj hauv kev ua rau qis dua BACH2 cov noob hloov pauv yog vim Menin tsis muaj peev xwm pom nyob hauv lub cev tsis muaj zog [211]. Menin induces BACH2 qhia los ntawm kev khi rau nws qhov chaw thiab tswj histone acetylation. Txo kev khi ntawm Menin rau BACH2 locus thiab tom qab ntawd txo BACH2 qhia ua rau muaj kev tiv thaiv kab mob hauv CD4 ntxiv rau T hlwb. Ib txoj kev tshawb nrhiav cov kev hloov pauv hauv cov kab mob hauv B cell precursors hauv cov laus thiab cov nas me uas cuam tshuam cov kev hloov pauv no nrog cov kab mob gene [212]. Nws tau nthuav tawm tias cov hnub nyoog ua ntej B hlwb pom qhov poob ntawm H3K4me3 ntawm qhov chaw txhawb nqa ntawm insulin receptor substrate 1 (IRSI), uas cuam tshuam nrog qis dua. Raws li insulin signaling yog tsim nyog rau kev loj hlob ntawm B hlwb nyob rau hauv cov pob txha pob txha [213], txo qis insulin loj hlob yam tseem ceeb (IGF) signaling yuav ua rau muaj teeb meem ntawm B cell txoj kev loj hlob.

Epigenetic Reprogramming raws li ib tug Hallmark ntawm kev cob qhia kev tiv thaiv

Ib qho tshwj xeeb epigenetic profile tswj kev cob qhia kev tiv thaiv cov lus teb tom qab thawj qhov kev thuam. Raws li qhov tshwm sim ntawm qee yam kab mob los yog kev txhawb nqa, cov hlwb primed tau txais kev ua haujlwm ntawm epigenetic reprogramming uas tso cai rau lawv los teb cov lus muaj zog ntawm cov kab mob heterologous los ntawm kev pab txhawb kev hloov pauv ntawm cov noob ntsig txog kev mob thiab cov metabolism [106].

H3K4me3 yog thawj tus cim epigenetic cim nyob rau hauv monocytes tom qab -glucan kho [91]. Kev soj ntsuam ntxiv tau nthuav tawm tias H3K4me3 peaks tau ua kom muaj txiaj ntsig zoo ntawm cov chaw txhawb nqa ntawm TNF, IL6, IL18, DESTINY, thiab MYD88 cov noob, qhia tias cov noob qoob loo muaj ntau dua hauv cov cheeb tsam no. Tsis tas li ntawd, nce H3K27ac yog qhov cim zoo ntawm histone cim hauv cov hlwb uas tau kawm, txhawb nqa glycolysis thiab PI3K / AKT txoj kev ua kom [174, 214]. Dhau li ntawm kev txhawb nqa hauv H3K4me3 thiab H3K27ac, txo H3K9me3 tau pom nyob rau hauv cov neeg txhawb nqa ntawm cov noob muaj feem xyuam rau cytokine ntau lawm thiab glycolysis[175]. Txij li H3K9me3 yog ib qho kev tsim txom, txo qis trimethylation qhia tias muaj qhov qhib chromatin cheeb tsam. Cov kev tshawb fawb no qhia tau hais tias cov lus teb tau txais kev tiv thaiv kab mob yog hloov kho los ntawm kev hloov pauv ntawm epigenetic uas pab txhawb kev txhim kho cytokine cov lus teb thiab cov kev hloov metabolic tshwj xeeb. Kev cob qhia cov hlwb sib koom ua ke ntawm cov kab mob epigenetic; Txawm li cas los xij, sib txawv stimuli tuaj yeem ua rau me me tshwj xeeb hloov pauv ntawm epigenetic.

Cov kab mob thiab qee qhov kev txhawb nqa tawm cov cim ntawm DNA methylation profile, nrog rau histones, ntawm lub cev tiv thaiv kab mob [215]. Cov kev tshawb fawb qhia txog lub luag haujlwm ntawm DNA methylation hauv cov lus teb los tiv thaiv mycobacterium tom qab txhaj tshuaj tiv thaiv BCG, kev ntxub ntxaug los ntawm cov neeg tsis teb [216,217]. Cov lus teb rau kev txhaj tshuaj BCG tau tshwm sim los ntawm kev txo qis DNA methylation ntawm cov neeg txhawb nqa ntawm cov noob caj ces [216]. Txawm li cas los xij, seb DNA (de)methylation ua lub luag haujlwm ncaj qha hauv kev txhim kho cov lus teb tsis muaj kev tiv thaiv tshwj xeeb tseem raug tshawb xyuas.

Raws li nyob rau hauv cov neeg laus, kev kawm tiv thaiv kab mob yog modulated los ntawm histone modifications nyob rau hauv cov neeg laus. Giamarellos-Bourboulis thiab cov npoj yaig tsis ntev los no tau qhia tias kev tsim cov cytokine ntau ntxiv thaum txhaj tshuaj tiv thaiv BCG hauv cov neeg laus tau nrog acetylation ntawm H3K27 ntawm thaj chaw txhawb nqa ntawm TNF thiab IL6 noob [113]. Txawm li cas los xij, cov kev tshawb fawb ntxiv tau lees paub los sib piv qhov sib txawv ntawm epigenetic tom qab kev txhim kho hauv lub cev tiv thaiv kab mob ntawm cov neeg laus thiab cov neeg laus thiab tshawb xyuas qhov kev laus cuam tshuam cov cim epigenetic hauv cov ntsiab lus ntawm kev tiv thaiv kab mob.

Gut Microbiota Modulating Immune Memory

Kev laus ua rau muaj kev hloov pauv thoob plaws lub cev ntawm tib neeg, thiab trillions ntawm microbes nyob tsis muaj kev zam. Cov muaj pes tsawg leeg thiab ntau haiv neeg ntawm plab microbiota dynamically hloov nyob rau hauv cov me nyuam mos, nyob twj ywm nyob rau hauv tus neeg laus, thiab pib poob nrog cov laus [218].

Kev sib cuam tshuam ntawm Microbiota thiab AdaptiveImmune System

Lub plab microbiota muaj lub luag haujlwm tseem ceeb hauv kev qhia txog kev hloov kho lub cev tiv thaiv kab mob los ntawm kev ua kom muaj qee theem ntawm kev tiv thaiv kab mob thiab kho qhov mob zoo. Piv txwv li, Bacteroides fragilis, ib qho commensal hauv plab, txhim kho thiab tswj CD4 ntxiv rau T cell sib txawv rau T pab 1 (Th1) thiab Th2 [219].Thaum muaj kab mob plab thiab TGF, naive CD4 ntxiv rau T hlwb ua Tregs, tsim IL-10 los tswj kev tiv thaiv homeostasis. Ntawm qhov tod tes, Tregs thiab Th17 hlwb nyob rau hauv cov qog ntshav hauv cov plab hnyuv induce B cell class switching, ua rau IgA secretion [220,221]. Microbiota-associated IgA, IgM, thiab IgG secretion los ntawm B hlwb kuj tshwm sim ntawm TLR signaling activation yam tsis muaj T cell pab [22].

Lub cev tiv thaiv kab mob yoog tau tuaj yeem txwv cov kab mob inflammatory tiv thaiv kab mob plab microbes kho los ntawm lub cev tiv thaiv kab mob. IgA tsim los ntawm B hlwb tau piav qhia raws li ib feem ntawm kev sib raug zoo ntawm tus tswv-microbe kev sib cuam tshuam, tswj cov lus teb inflammatory tawm tsam cov kab mob muaj txiaj ntsig [223]. Tsis tas li ntawd, cov plab hnyuv Treg qhia TCRs rau plab hnyuv antigens, xws li cov khoom siv metabolic thiab commensals, thaum lwm cov Tregs hauv lub cev qhia TCRs rau tus kheej-antigens [224].Yuav ua li no, plab hnyuv Tregs suppress lub cev tiv thaiv kab mob tawm tsam plab hnyuv antigens thiab ua si ib qho kev tiv thaiv kab mob. luag hauj lwm nyob rau hauv lub siab.

Yuav ua li cas microbiota strikingly shapes lub adaptive tiv thaiv kab mob kev loj hlob kuj tau pom nyob rau hauv cov nas tsis muaj kab mob: qhov tsis muaj cov kab mob microbial nyob rau hauv lub plab yog tus cwj pwm los ntawm kev tsis xws luag nyob rau hauv lub thib ob lymphoid cov ntaub so ntswg kev loj hlob [225], thiab qis IgA ntau lawm [226], thiab txo Th17. Cell thiab Tregs [227]. Nws yuav tsum tau muab sau tseg tias luv-chain fatty acids (SCFAs) tsim los ntawm microbial hom nyob rau hauv lub plab zoo heev pab rau lub cev kev loj hlob thiab cov lus teb [228].

Lub plab hnyuv microbiota muaj pes tsawg leeg yog qhov tseem ceeb hauv kev tiv thaiv tib neeg los ntawm cov kab mob. Ua piv txwv, IL-10 zais IgA ntxiv rau cov ntshav plasma thiab cov ntshav plasmablasts los ntawm lub plab confer tiv thaiv rau kev sim autoimmune encephalomyelitis induced hauv nas [229]. Lwm txoj kev tshawb fawb tau tshaj tawm tias lub plab microbiota tiv thaiv kab mob ua pa tshwm sim los ntawm S.pneumoniae thiab K. pneumoniae los ntawm inducing GM-CSF thiab IL-17A secretion [230].

Lub luag haujlwm ntawm Dysbiosis hauv Kev Laus

Qhov tshwm sim ntawm plab dysbiosis, qhov tsis txaus ntawm cov kab mob microbial, nce nrog hnub nyoog thiab cuam tshuam nrog ntau yam teeb meem kev noj qab haus huv [231]. Txawm li cas los xij, nws tsis paub meej tias kev hloov pauv ntawm cov cellular thiab molecular hloov pauv ntawm lub cev tiv thaiv kab mob thaum lub sijhawm laus cuam tshuam rau kev muaj pes tsawg leeg thiab kev ua haujlwm ntawm lub plab microbiota, lossis yog tias muaj hnub nyoog ntsig txog dysbiosis ua rau lub cev tsis muaj zog. Nws yog qhov zoo li ob qho tib si muaj tseeb, tab sis kev nkag siab zoo ntawm lub plab microbiota-tiv thaiv kab mob sib cuam tshuam yog qhov tsim nyog los daws cov lus nug no.

Raws li cov tib neeg muaj hnub nyoog, qhov poob ntawm qee yam kab mob uas muaj txiaj ntsig, xws li Bifidobacterium, yog hloov los ntawm kev loj hlob ntawm cov kab mob pathogenic, xws li Enterobacteriaceae [232]. Kev txo qis hauv Firmicutes thiab nce hauv Proteobacteria kuj tau tshaj tawm hauv cov neeg laus [233]. Tsis tas li ntawd, plab dysbiosis yog txuam nrog ntau yam kab mob uas muaj hnub nyoog, suav nrog kev rog [234], hom 2 mob ntshav qab zib mellitus [235], Alzheimer's disease [236], thiab nce kev kis kab mob [237-239]. Qhov kev pheej hmoo ntawm kev tsim mob qog noj ntshav kuj tseem siab dua rau cov neeg laus vim yog dysbiosis-koom nrog mob o, debilitated phagocytosis ntawm senescent thiab dormant qog hlwb, thiab impaired activation ntawm qog-specific CD8 ntxiv rau T hlwb [240].

Dysbiosis kuj tau hais tias yog ib qho laj thawj tseem ceeb rau ntau yam kev muaj hnub nyoog txuam nrog pathologies thiab tuag ntxov ntxov hauv cov neeg laus los ntawm kev ua rau mob ntau dhau thiab ntau yam teeb meem, nrog rau cov plab hnyuv thiab txo qis hauv plab hnyuv [228]. Raws li qhov no, ib qho tshwj xeeb muaj pes tsawg leeg thiab ntau hom kab mob microbial muaj feem cuam tshuam nrog kev noj qab haus huv, kev noj qab haus huv, thiab kev muaj sia nyob ntxiv rau cov neeg laus [241,242]. Ib txoj kev tshawb fawb tsis ntev los no tau qhia tias cov neeg laus noj qab haus huv muaj kev cuam tshuam tshwj xeeb hauv lawv cov microbiota muaj pes tsawg leeg, thaum qhov kev sib tw no ploj lawm hauv cov neeg laus laus [242]. Tsis tas li ntawd, muaj Bacteroides siab ntau thaum muaj hnub nyoog sib cuam tshuam nrog kev muaj sia nyob tsawg dua li ntawm 4- xyoo rov qab. Lwm qhov kev ua haujlwm tsis ntev los no nrog 15 xyoo ntawm kev soj ntsuam tau tshaj tawm tias Enterobacteriaceae abundance tau cuam tshuam nrog kev tuag cuam tshuam nrog kev mob plab hnyuv thiab ua pa rau cov neeg laus [243].

dysbiosis tuaj yeem ua rau muaj qhov tsis xws luag hauv plab hnyuv plab, uas ua rau hloov pauv ntawm cov kab mob mus rau cov ntaub so ntswg. Cov kab mob no tsim o los ntawm kev nrhiav cov neutrophils thiab txawv Th17 hlwb [244]. Piv txwv li, translocation ntawm gram-zoo pathobionts E.gallinarum uas tshwm sim los ntawm qhov tsis xws luag hauv plab barrier induces Th17 teb thiab autoantibody ntau lawm [245].

Akkermansia yog ib qho txiaj ntsig zoo uas tau pom los tiv thaiv lub plab barrier kev ncaj ncees [228] thiab txhim kho cov tshuaj tiv thaiv kab mob thiab T cell teb [246]. Kev poob ntawm Akkermansia yog txuam nrog insulin tsis kam nyob rau hauv cov laus uas tsis yog tib neeg primates thiab nas [247. Txo butyrate thiab Akkermansia abundance nce plab to, uas nyob rau hauv lem ua rau pro-inflammatory teb.

Ib txoj kev tshawb fawb tib neeg, ntawm qhov tod tes, qhia tias Akker-mania muaj ntau dua hauv cov neeg laus [248]. Tsis tas li ntawd, Akkermansia tau cuam tshuam nrog cov ntshav IgA thiab CD8 ntxiv rau T hlwb thiab cuam tshuam tsis zoo nrog CD4 ntxiv rau T hlwb hauv cov neeg laus. Bacteroidetes, uas tsis tshua muaj nyob rau hauv cov neeg laus, tau muaj kev sib raug zoo nrog cov ntshav ntshav IgG thiab CD4 ntxiv rau T cell abundance nyob rau hauv nruab nrab hnub nyoog pawg. Hauv kev xaus, txoj kev tshawb no qhia txog kev sib raug zoo ntawm lub cev tiv thaiv kab mob thiab lub plab microbiota muaj pes tsawg leeg, txawm hais tias qhov sib txuas ncaj qha ntawm lawv ploj lawm.

Microbiota tseem cuam tshuam rau cov kab mob thiab cov tshuaj tiv thaiv cov lus teb rau cov neeg laus. Txawm hais tias kev kho tshuaj tiv thaiv kab mob rau tib neeg kev tiv thaiv kab mob tiv thaiv kab mob (HIV) ua tiav thiab ua rau muaj kev cia siab ntawm cov neeg mob, cov neeg laus HIV ntxiv rau cov neeg raug kev txom nyem ntau dua los ntawm cov neeg laus dua li HV. HIV ntxiv rau cov neeg laus muaj tsawg dua CD4 ntxiv rau Tcells thiab ntau CD8 ntxiv rau Tcells dua li cov neeg laus dua 55[249].Ntxiv mus, qhov ntau ntawm Prevotella hauv plab yog ntau dua rau cov tib neeg uas tsis tshua muaj CD4 ntxiv rau Tcell suav. Prevotella yav dhau los cuam tshuam nrog cov kab mob plawv [250], tab sis yuav ua li cas nws cuam tshuam nrog lub cev tiv thaiv kab mob tseem tsis tau paub meej. Kev hloov pauv hnub nyoog nyob rau hauv plab microbiota yuav ua rau muaj kev tiv thaiv tsis zoo tom qab txhaj tshuaj [251]. Qee qhov kev tshawb fawb tau tshaj tawm tias cov tshuaj probiotics nce cov tshuaj tiv thaiv kab mob tom qab txhaj tshuaj tiv thaiv kab mob khaub thuas hauv cov neeg laus [252-255], thaum qee qhov kev tshawb fawb pom tau txwv lossis tsis muaj txiaj ntsig [87,256,257]. Kev hloov pauv hauv cov txiaj ntsig tuaj yeem yog vim muaj ntau yam, suav nrog tus qauv loj, hom probiotics, thiab kev xa khoom. Txawm li cas los xij, cov kev tshawb fawb tau pom zoo tias qhov tsis txaus ntawm microbiota ua rau lub cev tsis muaj zog tiv thaiv kab mob, thiab rov ua kom muaj kev noj qab haus huv muaj txiaj ntsig zoo rau cov tshuaj tiv thaiv zoo dua rau cov neeg laus.

Innate Immune Memory Induction los ntawm Gut Microbiota

Raws li cov tshuaj tiv thaiv kab mob hloov pauv, cov tswv cuab ntawm lub cev tsis muaj zog tiv thaiv kab mob cuam tshuam nrog lub plab microbiota. Ob peb txoj kev tshawb fawb qhia tias microbiota tuaj yeem tswj hwm kev tiv thaiv kab mob kev tiv thaiv kab mob los ntawm kev tiv thaiv kab mob los yog ua rau lub hlwb nrog microbial antigens thiab SCFAs. Piv txwv li, -glucan, fungal cell phab ntsa tivthaiv, thiab BCG ua los ntawm Dectin-1 thiab NOD2 signaling pathways, feem [91,100]. Txij li thaum Dectin -1 thiab Nod-zoo li receptors (NLRs) muaj nyob rau ntawm ntau hom cell hauv txoj hnyuv, nrog rau cov hlwb uas tsis muaj kev tiv thaiv kab mob, nws muaj peev xwm hais tau tias cov hlwb no txhim kho kev tiv thaiv kab mob vim lawv raug rau lub plab microbiome . Sup-porting qhov kev sib cav no, peptidoglycan fragments muab tau los ntawm plab microbiota tau pom tias yog thawj lub cev tiv thaiv kab mob hauv lub cev, txhawb kev tua lub peev xwm ntawm neutrophils [258].

Tsis tas li ntawd, plab hnyuv microbiota tau pom tias yuav ua rau muaj myelopoiesis los tiv thaiv cov nas tiv thaiv kab mob [259], zoo ib yam li qhov nce ntawm cov myeloid progenitors hauv cov pob txha ntawm cov nas tom qab kev cob qhia kev tiv thaiv kab mob los ntawm -glucan tswj [108]. Lwm yam microbiota-derived Cheebtsam, xws li lipopolysaccharide (LPS), flagellin, thiab -glucan, kuj tseem tuaj yeem ua rau muaj kev tiv thaiv kab mob hauv lub plab, txawm hais tias koob tshuaj ntawm qhov stimuli tseem ceeb heev rau kev tiv thaiv kab mob lossis kev ua siab ntev teb [260]. Raws li tau hais ua ntej, kev cob qhia kev tiv thaiv kab mob yog kho los ntawm cov txheej txheem metabolic thiab epigenetic. Molecules thiab metabolites tsim los ntawm commensal plab microbes thiab microbes lawv tus kheej muaj peev xwm ua rau muaj kev hloov pauv hauv ob qho tib si hauv lub cev thiab lub cev tiv thaiv kab mob [261]. Piv txwv li, txawm tias ua rau muaj kev nce ntxiv hauv cov tshuaj tiv thaiv kab mob, butyrate tsim los ntawm plab microbes muaj qhov cuam tshuam rau kev tiv thaiv kev tiv thaiv hauv macrophages, tejzaum nws tshwm sim los ntawm kev txo qis mTOR thiab inhibition ntawm HDAC3 [262].

Nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias cov hlwb tsis muaj zog, piv txwv li, fibroblasts [263], cov hlwb epithelial [264], thiab cov kab mob hauv plab hnyuv (ISCs) [265] kuj muaj peev xwm tsim lub cev tiv thaiv kab mob, uas qhia tau tias muaj kev ua haujlwm ntau ntxiv tom qab kis kab mob thib ob. Nws tau pom tias ISCs tuaj yeem tshem tawm tus kab mob sai dua thaum muaj kev sib kis los yog tsis sib xws, qhia tias muaj kev tiv thaiv kab mob [266]. Yog li ntawd, lub cev tsis muaj zog kuj ua rau homeostasis ntawm plab microbes thiab lub cev tiv thaiv kab mob.

Xav txog cov kev sib txuas muaj zog ntawm plab microbiota thiab induction ntawm lub cev tiv thaiv kab mob hauv lub cev, nws yuav muaj peev xwm xav txog tias kev tiv thaiv kab mob hauv cov neeg laus tuaj yeem ua rau dysregulated los ntawm dysbiosis hauv cov neeg laus. tuaj yeem ua rau cov kab mob pathogenesis. Txawm li cas los xij, yuav tsum muaj kev tshawb fawb ntxiv kom nkag siab tias muaj hnub nyoog li cas hloov pauv hauv microbiota cuam tshuam rau lub cev tiv thaiv kab mob.

Hla kev sib tham ntawm Immune System thiab lub hlwb

Kev laus ua rau muaj kev puas tsuaj loj hauv lub hauv nruab nrab lub paj hlwb (CNS) los ntawm kev puas tsuaj DNA, tsub zuj zuj ntawm cov khoom pov tseg, oxidative kev nyuaj siab, cuam tshuam lub zog homeostasis, thiab kev ua haujlwm tsis zoo [267]. Lub hlwb thiab lwm tus ntawm CNS tsis raug cais tawm, raws li ib zaug xav: muaj kev sib tham dav dav ntawm lub cev tiv thaiv kab mob thiab CNS. Lub hlwb homeostasis thiab rov tsim dua nyob ntawm lub cev tiv thaiv kab mob [268]. Yog li ntawd, deterioration ntawm lub cev tsis muaj zog nrog lub hnub nyoog laus pab txhawb rau thiab escalates hlwb laus thiab neurodegenerative kab mob.

Hauv CNS parenchyma, tus neeg nyob hauv lub cev tiv thaiv kab mob yog microglia, uas tshwm sim los ntawm cov kab mob macrophage thaum ntxov hauv lub yolk sac thaum ntxov [269]. Microglia tseem ceeb heev rau kev saib xyuas lub hlwb noj qab haus huv. Lawv ua cov tshuaj tiv thaiv kab mob, teb rau cov kab mob, orchestrate kev sib txuas lus nrog lub circulating lub cev tiv thaiv kab mob, tswj cov neurons, thiab lwm yam cell hom nyob rau hauv lub hlwb, phagocytose cellular khib nyiab, misfolded proteins, tshuaj lom cov khoom, thiab txawm synapses [270]. Microglia tau hloov pauv los ntawm kev laus thiab ua rau muaj hnub nyoog ntsig txog cov kab mob neurodegenerative [271]. Lawv lub peev xwm phagocytic tau txo qis nrog lub hnub nyoog nce qib, thiab lawv ua rau lub xeev ntawm kev mob qis qis. Vim qhov kev tshuaj xyuas no tsom ntsoov rau kev tiv thaiv lub cim xeeb, peb yuav tsis nkag mus rau hauv kev nthuav dav ntawm micro-glia thiab tsis txhob tsom mus rau lub luag haujlwm ntawm kev tiv thaiv kab mob thiab kev tiv thaiv kev tiv thaiv hauv cov ntsiab lus ntawm lub hlwb laus.

Ntshav-brain barrier (BBB) ​​loj heev tiv thaiv kev nkag mus ntawm lub cev tiv thaiv kab mob rau hauv lub hlwb. Txawm li cas los xij, qee yam kev tiv thaiv kab mob hauv lub cev muaj nyob hauv cerebrospinal kua (CSF) thiab cov ntshav-CSF barrier ntawm choroid plexus (CP) [272]. CP, nyob rau hauv lub hlwb lub ventricles, yog ib tug CSF-tsim epithelial cell network nrog embedded capillaries. T hlwb muaj nyob rau hauv CP, thiab lawv tswj lub cev tiv thaiv kab mob kev lag luam mus rau CSF los ntawm IFNy-dependent activation ntawm CP epithelium [273].

Lub cev tiv thaiv kab mob ua rau muaj kev muaj sia nyob thiab neurogenesis thaum homeostasis, thaum raug mob, lossis nyob rau hauv cov mob neurodegenerative [272]. Kev puas tsuaj rau CNS ua rau muaj kev tiv thaiv T-cell teb uas tiv thaiv kev puas hlwb [274]. CD4 ntxiv rau lymphocytes ua lub luag haujlwm tseem ceeb tshaj plaws hauv qhov "neuroprotective immunity."

Neuroprotective T-Cell Kev Tiv Thaiv

CP harbors CD4 ntxiv rau T hlwb nrog ib qho effector-nco pheno-hom uas paub txog CNS-tus kheej-antigens[275]. Cov hlwb no tuaj yeem tau txais cov cim qhia los ntawm kev ncig ntawm lub epithelium thiab CNS los ntawm CSF thiab orchestrate ib qho kev sib koom ua ke los tswj lub hlwb homeostasis [276]. Astro-cytes, ib hom cell uas pab tswj cov synapses thiab BBB, ntawm ntau lwm yam haujlwm, xav tias muaj cov tshuaj tiv thaiv kab mob neuroprotective thiab txo cov neuronal apoptosis thaum co-cultured nrog T hlwb [277]. Thaum tus txha caj qaum raug mob, CNS-tshwj xeeb autoreactive T hlwb tsiv mus rau qhov chaw raug mob, inhibit cyst tsim, thiab pab txhawb rau kev khaws cia ntawm axons [278].

Hauv T cell-tsis muaj nas, qhov kev loj hlob ntawm progenitor hlwb raug txo, ua rau qis qis ntawm cov neurons tshiab, thaum neurogenesis tau txhawb nqa hauv cov nas transgenic nrog ntau tshaj CNS-tshwj xeeb autoreactive T hlwb [268]. Kev ntxiv ntawm T-cell-derived cytokine IFNy tuaj yeem txhim kho neurogenesis hauv cov nas qub nrog Alzheimer's kab mob [279]. CNS tshwj xeeb T hlwb kuj tseem ceeb heev rau kev kawm spatial thiab nco. Hauv cov nas uas tsis muaj zog tiv thaiv kab mob, qhov chaw nco tsis zoo tab sis tuaj yeem rov qab los nrog kev hloov kho ntawm lub cev tiv thaiv kab mob txawm tias cov nas muaj hnub nyoog [280]. Nyob rau hauv cov qauv ntawm lub cev muaj zog neuron kab mob amyotrophic lateral sclerosis (ALS), T cell deficiency accelerates tus kab mob, thaum reconstitution txhawb neuroprotection thiab ncua kab mob kev loj hlob [281-283]. Txawm li cas los xij, ntawm kev ceeb toom, T hlwb ua rau muaj kev tuag ntawm dopaminergic neurons hauv nas qauv ntawm Parkinson tus kab mob [284].

Ib txoj hauv kev los ntawm T hlwb txhim kho lub hlwb yog kev tswj hwm ntawm lub hlwb-derived neurotrophic factor (BDNF).BDNF signaling ntawm tropomyosin receptor kinase B (TrkB) plays ntau yam luag hauj lwm, piv txwv li, nyob rau hauv cov neeg laus neurogenesis [285], nco tsim , thiab retrieval [286,287], thiab yog tswj los ntawm kev kho mob los tiv thaiv kev nyuaj siab [288].BDNFlevels qis dua hauv Tcell-deficient nas [268]. BDNF cuam tshuam nrog kev nyuaj siab tus cwj pwm thiab kev txhaj tshuaj ntawm cov nas nrog myelin-derived peptide, tsim CNS-kev tiv thaiv tshwj xeeb, rov kho BDNF qib, txhim kho neurogenesis, thiab txo tus cwj pwm kev nyuaj siab [289]. Tsis tas li ntawd, cov lus teb zoo rau kev ntxhov siab hauv nas yog txuam nrog T cell lag luam hauv lub hlwb thiab qib BDNF. Tus cwj pwm ntxhov siab los ntawm kev ntxhov siab kuj raug txo los ntawm kev txhaj tshuaj nrog myelin-derived peptide [290]. Sib nrug los ntawm cov neurons thiab microglia, T hlwb lawv tus kheej tau pom tias zais BDNF [291].

Tregs kuj tau pom tias muaj kev tiv thaiv thiab ncua kev kis kab mob hauv ALS los ntawm kev txo qis microglial activation [292]. Hauv cov qauv ntawm Alzheimer's disease, Treg transplantation txhim kho kev txawj ntse thiab txo cov amyloid plaques [293]. Ntxiv mus, qhov qis Treg / Th17 piv yog cuam tshuam nrog cov kab mob hnyav dua hauv cov neeg mob uas muaj ntau yam sclerosis, ib qho kab mob autoimmune uas cuam tshuam rau cov neurons [294].

Txawm hais tias kev tiv thaiv kab mob ntau dhau yuav ua rau lub hlwb ua haujlwm tsis zoo, kev tiv thaiv kab mob T cell zoo yog qhov tseem ceeb rau kev noj qab haus huv lub hlwb homeostasis thiab rov qab los ntawm kev raug mob. Txhua qhov kev cuam tshuam rau qhov tshwm sim no yuav tsum tau ua tib zoo tswj kom tsis txhob muaj kev puas tsuaj; Txawm li cas los xij, kev nkag siab txog kev hloov pauv kev tiv thaiv lub luag haujlwm hauv lub hlwb kev noj qab haus huv qhib txoj hauv kev tshiab los tiv thaiv lub hlwb raug mob lossis muaj hnub nyoog txog cov kab mob neurodegenerative.

Kev cob qhia kev tiv thaiv kab mob hauv Microglia

Cov kev tshawb fawb tsis ntev los no qhia tias kev tiv thaiv kab mob hauv lub cev tuaj yeem raug ntxias hauv microglial hlwb. Ib txoj kev tshawb nrhiav pom epigenetic reprogramming hauv microglia tam sim no tsawg kawg 6 lub hlis raws li kev tswj hwm LPS [295]. Interestingly, thaum ib zaug LPS txhaj induced ib tug kawm phenotype nyob rau hauv microglia, rov LPS txhaj coj mus rau induction ntawm kam rau ua. Ib yam li ntawd, kev tswj hwm qis TNF kuj tau pom los txhawb kev cob qhia microglia. Nyob rau hauv tus qauv nas ntawm Alzheimer's kab mob, kev cob qhia kev tiv thaiv kab mob ua rau tus kab mob hnyav dua thaum kev ua siab ntev txo nws. Ib txoj kev tshawb fawb tsis ntev los no tau lees paub qhov kev tshawb pom ntawm LPS-vim kev cob qhia thiab pom tau tias kev tswj hwm-glucan tseem tuaj yeem ua rau muaj kev tiv thaiv kab mob hauv microglia [296]. Txawm li cas los xij, qhov kev kawm phenotype ntawm microglia tsuas yog pom ob hnub tom qab priming thiab tsis muaj nyob rau hnub 7, tejzaum nws qhia tias tsis muaj kev txhawb nqa epigenetic reprogramming. Yog li ntawd, nws yog tsim nyog los soj ntsuam lub zog thiab persistence ntawm kev cob qhia nrog sib txawv koob tshuaj thiab txawv kev txhaj tshuaj regimens.

Lub hlwb laus

Ntau lub hlwb ua haujlwm tsis zoo nrog kev laus, nrog qee tus txawm pib poob qis tom qab xyoo thib peb ntawm lub neej [297]. Cov haujlwm ua haujlwm tsis zoo suav nrog kev ua haujlwm nrawm, daws teeb meem, kev xav ua kua dej, muaj peev xwm nkag siab, hais lus zoo, thiab ua haujlwm nco. Txawm li cas los xij, qhov kev puas tsuaj tsis tas yuav cuam tshuam nrog lub hnub nyoog chronological. Nws yog qhov tshwm sim ntawm kev xav tau kev saib xyuas ntau ntxiv los ntawm kev sib sau ntawm kev puas tsuaj thiab tsis muaj peev xwm ntawm lub cev tiv thaiv kab mob los saib xyuas lub hlwb kom ua tau raws li cov kev xav tau no. Tau kawg, kev laus ua rau muaj kev xav tau thiab qhov tsis muaj peev xwm ntawm lub cev tiv thaiv kab mob los ntawm cov txheej txheem tau tham ua ntej.

Lub hnub nyoog microglia tsim ib qho phenotype pro-inflammatory [298]. Tom qab raug mob taub hau lossis kis kab mob, lawv tsim cov cytokines ntau dhau rau lub sijhawm ntev dua piv rau lub hlwb hluas [299]. Lub xeev inflammatory no ua rau inhibited neurogenesis [300, 301]. Ib puag ncig tiv thaiv kab mob kuj inhibits modulators ntawm kev nco mus sij hawm ntev xws li BDNF thiab kev ua haujlwm-dependent cytoskeletal-associated protein thiab ua rau kev nco tsis ua haujlwm [299]. Circulating BDNF qib txo qis nrog lub hnub nyoog ntawm tib neeg, thiab lub hlwb theem tau pom tias poob qis hauv cov qauv nas [302], uas yuav cuam tshuam txog hnub nyoog cuam tshuam hauv T cell thiab kev ua haujlwm.

Kev laus kuj tseem cuam tshuam nrog nce kev nrhiav neeg ua haujlwm nco CD8 ntxiv rau T hlwb mus rau CP thiab meninges - cov membranes npog lub hlwb [303]. Cov hlwb no tau pom tias ua rau tsis zoo rau microglial kev ua haujlwm thaum lub sijhawm homeostasis tab sis txhim kho pro-inflammatory cytokine ntau lawm thaum raug mob. Ntxiv mus, Treg cov lej tau nce siab hauv cov neeg laus; Txawm li cas los xij, lawv lub peev xwm tsiv teb tsaws chaw thiab kev ua haujlwm zoo li cuam tshuam vim lawv tsis muaj peev xwm tswj tau neurodegeneration. Piv txwv li, Tregs ntawm ntau tus neeg mob sclerosis muaj lub peev xwm tiv thaiv kab mob tsawg dua thiab tsis tuaj yeem muaj sia nyob hauv cov kab mob sclerotic hauv lub hlwb [304].

Nyob rau hauv cov ntaub ntawv ntawm mob o, thaum lub cev tsis muaj zog tiv thaiv kab mob feem ntau tso cai rau txo qis cytokine ntau lawm, microglia tau txais ib qho primed los nthuav tawm cov phenotype ntau dua, ua rau kev nkag siab tsis zoo [305] . Tsis tas li ntawd, cov qib siab ntawm TNFa tau pom hauv cov kab mob hnub nyoog. kuj tseem tuaj yeem ua rau muaj kev puas tsuaj los ntawm kev txhawb nqa kev tiv thaiv kab mob hauv microglia, raws li tau tham saum toj no. Yog li ntawd, kev tiv thaiv zoo hauv lub cev yog qhov tseem ceeb rau kev noj qab haus huv ntawm lub hlwb raws li kev tiv thaiv kab mob.

Tackling Immune Aging Los Ntawm Txhua Lub Hlis

Kev siv zog kom qeeb lossis thim rov qab kev laus yog qhov tsis tshua muaj. Txawm li cas los xij, cov txiaj ntsig tau ntsuas los ntawm cov kev tshawb fawb feem ntau raug txwv hauv kev nkag siab tias lawv tsis muaj kev nkag siab txog kev siv tshuab lossis tsom rau cov txheej txheem tshwj xeeb. Txawm li cas los xij, qee qhov kev cuam tshuam zoo siab, suav nrog kev txwv caloric, metformin, thiab kev tawm dag zog lub cev, cuam tshuam kev laus ntawm ntau qib uas suav nrog kev tiv thaiv kab mob, metabolism, epigenetics, microbiota, thiab lub paj hlwb (Fig. 2). Cov tshooj hauv qab no sib tham

Fig.2 Promising anti-aging interventions that target multiple facets of the aging process. Metformin ncua sij hawm qia cell laus, txhim kho mitochondrial muaj nuj nqi, tiv thaiv telomere shortening, thim rov qab cov hnub nyoog ntsig txog kev hloov pauv ntawm epigenetic, thiab txo qis plab thiab dysbiosis. Kev tawm dag zog lub cev, txawm tias pib lig hauv lub neej, txhim kho lub cev tiv thaiv kab mob thiab kev ua haujlwm, rov ua kom cov metabolism hauv mitochondrial, tiv thaiv cellular senescence, tiv thaiv kev paub tsis meej, thiab txo cov kev pheej hmoo rau cov kab mob neurodegenerative. Resveratrol, muaj nyob rau hauv txiv hmab txiv ntoo thiab caw liab, ua raws li ib tug antioxidant, ncua lifespan nyob rau hauv ntau yam qauv kab mob, attenuates systemic o, thiab slows epigenetic laus. Kev txwv caloric los ntawm 20-40 feem pua ​​​​ txhim kho txoj sia nyob thiab txo qis tag nrho cov neeg tuag nyob rau hauv cov tsiaj tsis yog tib neeg primates, ncua kev laus epigenetic, restores plab microbiota, thiab slows kev txawj ntse poob. Cov txheej txheem ntawm tes sib koom los ntawm cov kev kho mob no suav nrog kev txwv ntawm mTOR / AKT axis thiab ua kom AMPK thiab SIRT1 nyob rau hauv ntau txoj hauv kev los daws qhov teeb meem kev laus thiab nthuav dav cov txheej txheem ntawm kev kho mob tiv thaiv kev laus tshaj plaws.

Kev cuam tshuam metabolic

Rau feem ntau ntawm cov tib neeg evolution, cov as-ham tsis tshua muaj, thiab muaj ntau yam ntawm lub cev ua si yuav tsum tau txais lawv. Yog li ntawd, tib neeg tau hloov kho kom haum rau cov xwm txheej ntawd. Peb tam sim no sedentary txoj kev ua neej nrog ib tug overabundance ntawm cov as-ham yog npaj siab yuav ua rau siab heev ntawm cov kab mob metabolic, xws li rog, ntshav qab zib, thiab kab mob plawv [306]. Tsis tas li ntawd, lub hnub nyoog yog qhov muaj feem pheej hmoo rau cov mob no, raws li tau hais ua ntej, thiab kev tiv thaiv kab mob muaj ntau yam nrog cov kab mob metabolic. Yog li ntawd, tsom mus rau cov kev cuam tshuam hauv metabolic yog ib txoj hauv kev zoo los daws cov kev laus thiab cov kab mob metabolic ib txhij. Caloric txwv (CR) thiab kev tawm dag zog, coj peb los ze zog rau cov poj koob yawm txwv tej yam kev mob, ua tus thawj coj hauv kab kev tshawb fawb no.

CR hais txog kev txo qis tag nrho cov calories kom tsawg los ntawm 20-40 feem pua ​​. Los ntawm cov poov xab mus rau cov tsis yog primates, CR tau rov ua dua qhia tias yuav txhim kho txoj sia [307].Nyob rau hauv rhesus liab, CR pib los ntawm cov neeg laus txo qhov kev pheej hmoo ntawm kev tuag uas cuam tshuam txog hnub nyoog cuam tshuam los ntawm peb npaug thiab tag nrho cov neeg tuag los ntawm 1. {6}}fold [308].Hauv lwm txoj kev tshawb fawb, CR txo qhov tshwm sim ntawm ntshav qab zib, mob qog noj ntshav, thiab kab mob plawv thaum tseem ncua cov kab mob pib [309]. Ib txoj kev tshawb fawb sib piv tau qhia tias tsis muaj kev txhim kho hauv kev ciaj sia, txawm hais tias qhov xwm txheej ntawm mob qog noj ntshav thiab ntshav qab zib tau txo qis [310].

Hauv kev sim randomized tswj ntawm 218 tus neeg tsis rog rog, 2- xyoo CR noj zaub mov txo qis TNF qib thiab txo qis cov cim kev pheej hmoo plawv, xws li cov roj cholesterol thiab triglycerides, yam tsis muaj kev cuam tshuam txog kev cuam tshuam [311]. Txog tam sim no, tsis muaj tib neeg txoj kev tshawb fawb qhia txog qhov cuam tshuam tseem ceeb ntawm CR ntawm kev ua neej ntev. Cov kev tshawb fawb loj thiab dav nrog cov noob caj noob ces yog qhov xav tau los ua kom cov lus cog tseg ntawm CR hauv tib neeg.

Ntau yam kev cuam tshuam ntawm metabolic ntawm CR suav nrog kev txo qis ntawm mTOR thiab insulin signaling thiab ua kom SIRT1, uas txhua tus muaj feem cuam tshuam rau lub cev tiv thaiv kab mob [312]. CR tau pom tias ncua T cell senescence hauv rhesus liab [313]. Tsis tas li ntawd, CD4t thiab CD8 ntxiv rau cov pas dej tsis zoo Tcell tau nthuav dav, thiab cov zis thymic thiab T cell proliferation tau nce, tab sis IFNy ntau lawm los ntawm CD8 ntxiv cov hlwb raug txo tom qab CR. Txawm hais tias txo tus naj npawb ntawm calories noj zoo li thim rov qab lub hnub nyoog cuam tshuam kev hloov pauv hauv cov metabolism thiab txhim kho kev noj qab haus huv thiab kev noj qab haus huv, nws yog ib qho tseem ceeb uas yuav tsum nco ntsoov tias ob peb txoj kev tshawb fawb hauv cov nas tau qhia txog qhov tsis zoo ntawm cov lus teb thiab kev tuag ntau ntxiv tiv thaiv kab mob khaub thuas A thiab West Nile cov kab mob hauv cov tsiaj laus. tom qab CR [314,315]. Txawm li cas los xij, kev tshawb fawb nas tsis ntev los no tau qhia txog kev tiv thaiv CR tiv thaiv kab mob M.tuberculosis. Cov txiaj ntsig no tau cuam tshuam nrog kev hloov pauv hauv metabolic yam ntxwv los ntawm mTOR inhibition tab sis txhim kho glycolysis thiab txo FAO, nrog rau

nce autophagy [316] .mTOR inhibitor rapamycin ua ke nrog CR thiab ntxiv txhim kho autophagy, ua rau muaj txiaj ntsig zoo inhibition ntawm M. tuberculosis.

Zoo ib yam li CR, kev tawm dag zog tau cog lus tias yuav cuam tshuam nrog kev tiv thaiv kab mob. Kev qoj ib ce tsis tu ncua ntawm cov poj niam laus tau zoo dua NK thiab T cell ua haujlwm piv rau cov poj niam uas muaj hnub nyoog sib tw [317]. Naive T cell naj npawb thiab thymic tso zis ntau dua nyob rau hauv lub cev muaj zog cov neeg laus, zoo ib yam li cov hluas, piv rau sedentary sawv daws yuav [318]. Lawv kuj muaj qis dua IL-6 thiab siab dua IL-7, uas yog qhov tseem ceeb rau kev txhim kho T cell. Txawm li cas los xij, senescent CD8 ntxiv rau T cell tooj tsis txawv ntawm pawg. Tom qab ib qho kev qhia 8-lub lim tiam, lub cev tiv thaiv kab mob ntawm cov neeg laus cov neeg laus tau nthuav tawm kev txhim kho autophagy thiab downregulated NLRP3 inflammasome [319]. Kev tawm dag zog kuj tau txhim kho mitophagy thiab mitochondrial biogenesis hauv cov leeg nqaij pob txha thiab lub cev tiv thaiv kab mob zoo ib yam, rov ua kom cov cellular metabolic cuam tshuam los ntawm kev laus [320].

Sib nrug los ntawm kev cuam tshuam hauv kev ua neej, tshuaj lom neeg cov tshuaj metabolic tseem raug tshawb xyuas rau lawv cov peev xwm tiv thaiv kev laus. Metformin, kev nyab xeeb siv rau tib neeg rau ntau dua 60 xyoo rau nws cov txiaj ntsig txo qis, txo cov hnub nyoog cuam tshuam nrog ntau yam ntawm cov txheej txheem. Cov no suav nrog kev ua kom AMPK, inhibition ntawm mTORCl, txhim kho mitochondrial biogenesis, downregulation ntawm insulin / IGF1 signaling, thiab ua kom SIRT1 [321]. Tsis tas li ntawd, met-formin ncua sij hawm qia cell aging thiab txo telomere shortening. Zuag qhia tag nrho, nws zoo li ua rau tag nrho cov cim ntawm kev laus. Kev sim tshuaj loj ntawm ntau dua 3000 tus neeg muaj hnub nyoog 65-79 tam sim no tau npaj los ntsuas qhov kev tiv thaiv kev laus ntawm metformin (https://www.afar.org/tame-trial).

Everolimus, lwm tus mTOR inhibitor, txo qis kev tiv thaiv kab mob thiab txhim kho cov tshuaj tiv thaiv kab mob rau kev txhaj tshuaj tiv thaiv kab mob khaub thuas hauv cov neeg laus [322]. Txawm hais tias feem ntau cov kab mob tiv thaiv kab mob tsis tau hloov pauv hauv txoj kev tshawb no, T hlwb zoo rau programmed cell death protein 1 (PD-1), ib qho cim ntawm kev qaug zog, tau txo qis. Ib txoj kev tshawb nrhiav tom qab nrog 264 tus neeg laus cov neeg laus tau tshaj tawm txog kev qhia tshuaj tiv thaiv kab mob, txhim kho cov lus teb rau kev txhaj tshuaj tiv thaiv kab mob khaub thuas, thiab tag nrho cov kab mob tsawg dua [323]. Kev ua kom SIRT1 yog lwm txoj hauv kev los tiv thaiv kev tiv thaiv kab mob. Nws paub tias txhim kho B cell proliferation thiab ua haujlwm, thiab yog li ntawd tuaj yeem pab txhim kho cov tshuaj tiv thaiv kab mob hauv lub hnub nyoog [324]. SIRT1 tuaj yeem hloov kho cov txheej txheem metabolic los ntawm cov protein thiab histone deacetylation [325]. Cov hom phiaj ntawm SIRTl suav nrog NF-KB, hypoxia-inducible factor 1-alpha (HIFla), thiab FOXO transcription factor. Ntxiv mus, SIRT1 activation potentiates BCG-induced cob qhia kev tiv thaiv teb [326]. Txawm hais tias cov kev tshawb fawb nas nrog SIRT1- cov activators qhia ncua sij hawm muaj hnub nyoog phenotypes thiab nce lifespan [327, 328], tsis muaj pov thawj qhia tias SIRTl cuam tshuam nrog kev ua neej nyob ntev hauv tib neeg [329].

Resveratrol, polyphenol compound pom nyob rau hauv liab caw, yog ib tug muaj zog activator ntawm SIRT1 [330]. Nws kuj tseem pom tias yuav qhib AMPK, yog li ntawd nws yuav txwv tsis pub mTOR signaling [331]. Sib nrug los ntawm cov kev tshawb fawb hauv vitro thiab cov qauv kab mob uas qhia txog resveratrol cov tshuaj tiv thaiv kab mob antioxidant thiab tiv thaiv kab mob [332], ntau cov kev tshawb fawb nas qhia nws cov kab mob antiviral capac-ity [333,334]. noj qab nyob zoo nas [327,335]. Txawm li cas los xij, hauv cov nas uas tau noj nrog cov khoom noj muaj calorie ntau, resveratrol tau hloov pauv cov ntaub ntawv ntawm cov nas uas tau noj cov qauv [336]. Nws kuj tseem txhim kho cov tshuaj insulin rhiab heev thiab ua kom muaj sia nyob. Cov txiaj ntsig zoo sib xws tau pom hauv rhesus liab ntawm kev noj zaub mov muaj rog, qab zib siab [337]. Peb caug hnub ntxiv ntawm cov txiv neej rog rog nrog resveratrol induced metabolic kev hloov pauv los ntawm AMPK-SIRT1 axis thiab txo cov kab mob hauv lub cev, qabzib, thiab qib triglyceride [338]. Txawm li cas los xij, ib qho kev tshawb fawb zoo sib xws tsis tau tshaj tawm cov txiaj ntsig zoo ntawm resveratrol [339].

Zuag qhia tag nrho, muaj kev cog lus zoo heev rau kev kho mob rau cov kab mob metabolic hauv qab kev tiv thaiv kab mob thiab cov kab mob uas muaj hnub nyoog cuam tshuam nrog metabolic. Txawm li cas los xij, qhov kev sim ntsuas loj loj hauv tib neeg yuav tsum tau saib seb cov kev soj ntsuam zoo siab no hauv cov tsiaj tsis yog tib neeg thiab cov qauv me me puas tau txhais tau rau tib neeg siv.

Tswvyim Modulating Epigenetics

Epigenetic kev cuam tshuam tau ua haujlwm rau ntau yam kab mob uas muaj hnub nyoog, xws li mob qog noj ntshav, ntshav qab zib mellitus, thiab Alzheimer's disease; Txawm li cas los xij, tsuas yog qee qhov kev tshawb fawb tshwj xeeb tsom rau cov hnub nyoog hloov pauv hauv cov qauv epigenetic [340]. Hloov chaw, cov kev cuam tshuam metabolic ua haujlwm los tiv thaiv kev tiv thaiv kab mob kuj ua haujlwm los ntawm kev hloov pauv cov hnub nyoog cuam tshuam nrog epigenetic toj roob hauv pes. Resveratrol, CR, thiab metformin yog peb qhov kev cog lus kho mob rau kev kho cov hnub nyoog DNA methylation thiab hloov histone hauv cov neeg laus.

Ib qho kev tshawb fawb zoo tshaj plaws tau nthuav tawm tias kev tsim cov thymus rov ua rau muaj 2 xyoos 5- xyoo yau epigenetic muaj hnub nyoog [341]. Cov neeg koom nrog hnub nyoog ntawm 51 thiab 65 xyoo tau txais kev kho mob 1- xyoo nrog kev sib txuas ntawm tib neeg txoj kev loj hlob hormone, dehydroepiandrosterone (DHEA), uas yog steroid hormone precursor, thiab metformin. Kev kho mob tau ua rau rov qab ua haujlwm thymic huab hwm coj, kev hloov pauv hauv lub cev tiv thaiv kab mob sub-sets, thiab cytokine ntau lawm, nrog rau kev hloov pauv epigenetic profile, uas cuam tshuam nrog cov hnub nyoog yau.

Rhesus liab, uas raug rau 40 feem pua ​​​​kwv yees txwv, tau lig los qhia cov kev hloov pauv methylation pom hauv cov laus laus [342]. Txawm hais tias txoj kev tshawb no tsis muab pov thawj ncaj qha ntawm lub neej ntev dua cuam tshuam nrog kev ncua methylation drift, nws qhia tias CR tuaj yeem siv los ua kom cov txheej txheem kev laus qeeb. Nyob rau hauv txoj kab nrog qhov no, kev txhim kho lub neej ntawm nas nrog resveratrol lossis CR ua rau qeeb qeeb epigenetic aging [343]. Lub neej ntev CR kuj tau pom tias tiv thaiv hnub nyoog DNA methylation hloov hauv lub hlwb, muab kev tiv thaiv neuroprotection [344].

Qee qhov kev tshawb fawb piav qhia tias CR tuaj yeem cuam tshuam li cas ntawm epigenetics. Cov txheej txheem no suav nrog txo qis histone acetylation kho los ntawm kev nce SIRTI kev qhia, siab dua DNA methyltransferase (DNMT) kev ua, thiab hypermethylation ntawm kev tswj cov noob caj noob ces, xws li Ras [340]. Ib yam li ntawd, metformin ua rau cov cim epigenetic los ntawm kev ua kom SIRT1 thiab inhibiting HDACs [345]. Rau peb txoj kev paub, tsis muaj kev tshawb fawb soj ntsuam txog qhov cuam tshuam ntawm CR ntawm kev laus-txog kev hloov pauv ntawm epigenetic, tej zaum vim muaj kev txwv ntawm kev siv cov kev cuam tshuam mus sij hawm ntev rau tib neeg.

Muaj peev xwm kho tau Targeting Microbiota

Txij li thaum plab microbiota tswj hwm tus tswv tsev metabolism, kev tiv thaiv kev laus tiv thaiv cov metabolism hauv inevitably cuam tshuam rau plab microbiota. Raws li ib qho piv txwv, ntxiv rau kev ua haujlwm ntawm txoj hauv kev metabolic, metformin hloov kho lub plab microbiota. Ib txoj kev tshawb nrhiav qhov cuam tshuam ntawm metformin hauv cov nas rog rog thiab cov laus pom qhov txo qis hauv IL-1 thiab IL-6 hauv cov rog epididymal, uas cuam tshuam nrog kev hloov pauv hauv plab hnyuv microbes [346]. Tsis tas li ntawd, cov neeg mob ntshav qab zib hom 2 uas noj metformin muaj ntau dua ntawm Akkermansia hauv lawv lub plab [347], uas cuam tshuam nrog cov kab mob qis dua thiab kev pheej hmoo ntawm dysbiosis [348].Raws li cov no, metformin txo cov hnub nyoog ntsig txog lub plab thiab. mob hauv nas [349]

Lwm txoj kev kho mob los tiv thaiv kev tiv thaiv kab mob los ntawm kev tsom mus rau microbiota yog kev siv cov pro-thiab prebiotics. Probiotics yog cov tshuaj uas muaj cov kab mob nyob, thaum prebiotics yog substrates uas cov kab mob tuaj yeem siv rau kev ua neej [350]. Txawm hais tias muaj pov thawj tsis sib haum, cov kev tshawb fawb qhia tias kev siv probiotic tsis tu ncua tuaj yeem hloov kho qhov sib txawv thiab ntau ntawm cov kab mob hauv plab, txo qis qhov tshwm sim ntawm dysbiosis [351,352]. Probiotics cuam tshuam nrog kev txhim kho lub cev tiv thaiv kab mob tshwm sim los ntawm kev nce B thiab T cell suav, txhim kho NK cell kev ua haujlwm [353], thiab ntau dua IgA tsim tawm tsam tus kab mob khaub thuas hauv cov neeg laus [354]. Tsis tas li ntawd, ntxiv nrog cov tshuaj probiotics tau pab txo qis kev loj hlob ntawm cov kab mob opportunistic Clostridium dif-file ntawm cov neeg laus [355]. Tsis zoo li cov kev tshawb pom no, ib qho kev soj ntsuam ntawm 10 randomized tswj cov kev tshawb fawb pom tias tsis muaj txiaj ntsig zoo ntawm probiotics ntawm kev txo qis inflammatory cytokine ntau lawm [356].

Kev sib xyaw ntawm probiotics nrog prebiotics, piv txwv li, synbiotics, kuj muaj txiaj ntsig zoo, zoo li probiotics supplementation. Ob lub hlis ntawm kev kho mob hauv cov neeg laus uas muaj cov qauv synbiotic tau txhim kho cov kab mob metabolic tsis zoo hauv kev ncig thiab txo qis cov protein, xws li TNF thiab C-reactive protein [357]. Ob qhov muag tsis pom kev 4-lub lim tiam kev kho mob symbiotic txoj kev tshawb fawb qhia txog kev nce hauv Bifidobacteria, Actinobacteria, Firmicutes, thiab cov metabolite butyrate hauv pawg kho mob piv rau cov placebo, thaum Proteobacteria thiab pro-inflammatory cytokines qis dua [358].

Kev txwv caloric tuaj yeem yog lwm lub tswv yim kho mob los txhim kho kev paub txog kev ua haujlwm, metabolic tsis, thiab plab microbiota hauv cov neeg laus. CR ua rau qeeb qhov kev paub txog kev poob qis hauv tus qauv nas ntawm Alzheimer's kab mob, cuam tshuam nrog nce Bacteroides hauv plab. Cov nas muaj hnub nyoog tau txais 30 feem pua ​​​​tsawg calories rau 2 lub hlis tau pom qhov hloov pauv tseem ceeb hauv lawv cov microbiota mus rau qhov sib npaug sib npaug zoo ib yam li cov nas hluas [359]. Lifelong CR induced ntau qhov kev hloov pauv hauv microbiota, txo cov concentration ntawm inflammatory peptides, thiab nce lub neej ntawm nas [360]. Txawm li cas los xij, ib txoj kev tshawb fawb tsis ntev los no tau qhia tias qhov hnyav CR, ntau dua 50 feem pua, cuam tshuam qhov sib txawv ntawm microbiota thiab ua rau kev loj hlob ntawm cov kab mob pathogenic C. difficile [361]. Yog li, nws yog ib qho tseem ceeb kom ua tib zoo txiav txim siab qhov ntev thiab ntev ntawm CR.

Kev cuam tshuam rau Brain Aging

Kev tawm dag zog lub cev yog ib txoj hauv kev zoo tshaj plaws los txhawb lub hlwb kev noj qab haus huv. Kev tawm dag zog tiv thaiv kev puas hlwb, txo qis kev pheej hmoo dementia, txhim kho kev nco, thiab txhim kho neuroplasticity [362]. Kev ua si lub cev tuaj yeem ua rau txo qis qhov cuam tshuam ntawm kev pheej hmoo alleles rau kev nco tsis zoo [363] thiab tiv thaiv kev txhim kho ntawm Alzheimer's disease [364,365]. Kev tshuaj xyuas zoo ntawm 16 txoj kev tshawb fawb nrog tag nrho 163,797 tus neeg koom qhia tias kev tawm dag zog ib txwm ua rau 28 feem pua ​​​​thiab 45 feem pua ​​​​kev pheej hmoo txo ​​qis hauv dementia thiab Alzheimer's, feem [366]. Ntawm qhov kev ceeb toom, qhov kev pheej hmoo ntawm kev tawm dag zog tau pom nyob rau hauv feem ntau ntawm cov kev tshawb fawb ntawm tus kheej tsis hais txog qhov zaus thiab qhov hnyav ntawm qhov kev tawm dag zog.

Cov kev tshawb fawb qhia txog cov tshuaj tiv thaiv kab mob antioxidant thiab tiv thaiv kab mob ntawm kev tawm dag zog raws li cov txheej txheem muaj peev xwm tom qab neuroprotection [367,368]. Kev tiv thaiv kev mob tshwm sim ntawm kev tawm dag zog suav nrog txo qis IL-6 tab sis nce IL-10 thiab IL-1RA, qis dua ntawm Treg, ntau dua ntawm cov kab mob inflammatory monocytes hauv kev ncig, thiab inhibited monocyte muaj nuj nqi [ 369] ib. Dhau li ntawm cov no, kev tawm dag zog lub cev yog txuam nrog txo qis T hlwb, nce NK cell cytotoxicity thiab neutrophil phagocytosis, thiab ntev telomeres hauv leukocytes [370]. Tsis tas li ntawd, kev ua haujlwm nruab nrab ntawm cov hlab plawv tau txhim kho seroprotection tom qab txhaj tshuaj tiv thaiv kab mob khaub thuas hauv cov neeg laus [371]. Kev txo qis hauv kev tiv thaiv kab mob yuav txwv tsis pub lub hlwb laus thiab kev txawj ntse poob los ntawm kev txhim kho kev tiv thaiv kab mob thiab kho CNS.

Ntxiv mus, txawm tias ib qho kev tawm dag zog ib zaug nce BDNF qib uas tau txhim kho ntxiv nrog kev tawm dag zog ib txwm [372]. Qhov zoo siab, qhov kev tawm dag zog ntsig txog kev nce hauv BDNF tau tshaj tawm hauv cov txiv neej piv rau poj niam. Ketone lub cev kuj tau pom tias ua rau BDNF qhia [373,374], muaj peev xwm ua rau muaj kev tiv thaiv neuroprotective ntawm ketogenic noj zaub mov hauv cov kab mob neurological [375].

CR yog lwm qhov kev cuam tshuam tau pom los tiv thaiv kev puas tsuaj neuronal. Nws ua rau nce BDNF qhia thiab txhim kho neurogenesis [376], ua rau muaj zog hloov pauv ntawm glycolysis mus rau kev siv lub cev ketone, tiv thaiv cov teeb meem dawb, thiab txhim kho kev nco mus ntev hauv nas [377]. Hauv cov nas, ib qho kev hloov pauv-hnub CR kev tswj hwm txhawb nqa neuronal tsis kam mus rau kev puas tsuaj rau tshuaj lom [378]. Ib lub tswv yim ntawm CR-induced neuroprotection yog qhov zoo li vim yog kev cuam tshuam ntawm oxidative kev nyuaj siab hauv lub hlwb [379,380]. Txawm li cas los xij, CR hnyav nrog 50 feem pua ​​​​ntawm cov calorie kom tsawg tau tshaj tawm ua rau muaj kev ntxhov siab hauv cov nas [381].Hauv nas qauv ntawm Alzheimer's kab mob, CR muaj peev xwm txwv amyloid plaque deposition [382,383], tejzaum nws los ntawm ib tug mechanism uas muaj SIRT1 activation. [384].

Txawm hais tias tag nrho cov txiaj ntsig zoo hauv cov nas, cov teebmeem neuroprotective ntawm CR tsis meej heev hauv cov neeg tsis yog tib neeg primates, thaum loj tib neeg kev tshawb fawb tsis muaj [385]. Txawm li cas los xij, ib qho me me randomized tswj kev sim nrog tib neeg ua rau tsis muaj kev txhim kho tseem ceeb hauv kev txawj ntse [386]. Lwm qhov kev tshawb fawb soj ntsuam ntawm cov neeg laus tau pom cov qhab nia nco tau zoo dua tom qab 3 lub hlis ntawm CR [387]. Txhim kho kev nco, nrog rau kev sib txuas ua haujlwm siab dua hauv hippocampus, tau tshaj tawm hauv cov poj niam rog rog uas tau txais kev noj zaub mov 3- hli CR [388]. Ntau qhov kev tshawb fawb tib neeg nrog CR yog qhov tsim nyog kom nkag siab txog qhov cuam tshuam ntawm neuroprotective.

Qhov zoo siab, kev txhaj tshuaj BCG tsis ntev los no tau pom tias txo qis kev pheej hmoo ntawm Alzheimer's thiab Parkinson's kab mob hauv cov neeg mob qog noj ntshav zais zis tau kho nrog BCG immunotherapy, piv rau cov neeg mob tsis kho [389, 390]. Hauv kev kho mob qog noj ntshav ntawm lub zais zis, BCG tau siv ncaj qha rau hauv lub zais zis, tsis yog txoj hauv kev ua haujlwm ntawm kev tswj hwm ib txwm muaj. Zoo siab rau yav tom ntej kev tshawb fawb tej yaam num yuav tau soj ntsuam cov teebmeem ntawm intradermal BCG ntawm cov kab mob neurodegenerative thiab tshawb xyuas cov txheej txheem hauv qab kom paub seb puas muaj kev tiv thaiv kab mob ua lub luag haujlwm hauv cov teebmeem neuroprotective. Tam sim no, kev sim tshuaj ntsuam xyuas tab tom siv kev txhaj tshuaj intra-dermal BCG hauv cov neeg mob Alzheimer's lig (NCT04449926).

Cov lus xaus

Biological aging yog ib tug complex txheej txheem nrog rau tag nrho cov kab mob ntawm lub cev. Lub cev tiv thaiv kab mob yog nyob hauv nruab nrab ntawm nws, cuam tshuam nrog tag nrho lwm tus. Kev laus lub cev tsis muaj zog yog qhov ua txhaum rau qhov kev pheej hmoo siab ntawm cov neeg laus rau cov kab mob thiab cov hnub nyoog ntsig txog cov kab mob metabolic thiab neurodegenerative, thiab lwm yam. Yog li ntawd, kev txhim kho lub cev thiab yoog raws kev tiv thaiv kab mob yog qhov tseem ceeb heev los txo cov kab mob ntsig txog kab mob thiab kev tuag thiab txhim kho cov tshuaj tiv thaiv kab mob hauv cov neeg laus. Ntawm no, peb kuj tau nthuav tawm lub cev loj ntawm kev tshawb fawb hinting rau lub luag haujlwm tshiab ntawm kev tiv thaiv kab mob hauv cov kab mob metabolic thiab tswj kev noj qab haus huv hauv nruab nrab paj hlwb. Nkag mus rau kev laus los ntawm txhua lub ces kaum, nrog kev tiv thaiv kev tiv thaiv raws li lub hauv paus node, thiab tsim kev tiv thaiv kev laus los tiv thaiv cov txheej txheem uas cuam tshuam los ntawm kev laus yog ib txoj hauv kev zoo rau kev tshawb fawb ntxiv. Kev coj tus cwj pwm xws li kev txwv caloric thiab kev tawm dag zog lub cev nrog rau cov tshuaj siv tshuaj xws li metformin thiab resveratrol tuaj yeem tswj hwm ntau yam ntawm kev laus thiab tau txais txiaj ntsig zoo hauv cov qauv tsiaj thiab tib neeg. Lub tswv yim dav dav yog qhov tseem ceeb rau tib neeg siv zog ua lub neej ntev nrog lub siab noj qab haus huv, lub hlwb ua haujlwm, thiab tsis muaj kab mob hnyav.

Cov lus tshaj tawm

Tsis sib haum xeeb ntawm kev txaus siab Cov neeg sau ntawv tshaj tawm tsis muaj kev sib tw txaus siab.

Qhib Kev Nkag Mus Kab lus no tau tso cai raws li Creative Commons Attribution 4.0 Daim ntawv tso cai thoob ntiaj teb, uas tso cai siv, sib koom, hloov kho, faib, thiab luam tawm hauv ib qho nruab nrab lossis hom ntawv, tsuav yog koj muab credit tsim nyog rau tus sau thawj (s) thiab qhov chaw, muab qhov txuas mus rau Creative Commons daim ntawv tso cai, thiab qhia seb puas tau hloov pauv. Cov duab lossis lwm yam khoom siv thib peb hauv tsab xov xwm no suav nrog hauv tsab xov xwm Creative Commons daim ntawv tso cai tshwj tsis yog tau qhia lwm yam hauv kab qiv nyiaj rau cov khoom siv. Yog tias cov ntaub ntawv tsis suav nrog hauv tsab xov xwm Creative Commons daim ntawv tso cai thiab koj qhov kev npaj siv tsis raug tso cai los ntawm txoj cai lij choj lossis tshaj qhov kev tso cai siv, koj yuav tsum tau txais kev tso cai ncaj qha los ntawm tus tuav ntaub ntawv. Txhawm rau saib daim ntawv tso cai no, mus saib http://creativecommons.org/licenses/by/4.0/.

Kab lus no yog muab rho tawm los ntawm Kev Tshuaj Ntsuam Xyuas Hauv Kev Ua xua & Immunology https://doi.org/10.1007/s12016-021-08905-x