Cov txiaj ntsig zoo ntawm Exogenous Ketogenic Supplements Ntawm Cov Txheej Txheem Kev Laus Thiab Cov Hnub Nyoog Txog Cov Kab Mob Neurodegenerative Part 3

2.4. Mitochondrial Dysfunction

Mitochondrial dysfunction yog txuam nrog kev poob ntawm mitochondrial kev ua ub no, xws li kev tsis haum ntawm cov kab mob ua pa, txo qis hauv ATP synthesis thiab qib, nrog rau nce ROS ntau lawm.

Ib lub cev loj hlob ntawm kev tshawb fawb qhia tau hais tias txo qis kev ua haujlwm ntawm mitochondrial tuaj yeem ua rau tib neeg nco. Mitochondria yog ib qho tseem ceeb hauv lub cell. Lawv yog lub luag hauj lwm rau hloov lub zog rau hauv cov tshuaj uas lub cell xav tau, yog li txhawb lub cell ciaj sia taus thiab muaj nuj nqi. Mitochondria tsis yog tsuas yog qhov chaw ntawm lub zog hloov dua siab tshiab xwb tab sis kuj tseem txuas nrog cov cell membranes, endoplasmic reticulum, thiab lwm cov qauv ntawm tes. Lawv ua lub luag haujlwm tseem ceeb hauv kev tswj cov cell metabolism, tswj cell homeostasis, thiab tiv thaiv cov hlwb los ntawm kev puas tsuaj oxidative kev nyuaj siab.

Kev tshawb fawb tau pom tias mitochondrial dysfunction yog ze ze rau kev nco poob. Piv txwv li, tus naj npawb thiab kev ua haujlwm ntawm mitochondria hauv hlwb hlwb ntawm Alzheimer's cov neeg mob tau txo qis, thiab mitochondrial DNA puas lossis kev hloov pauv tuaj yeem ua rau muaj qhov tshwm sim thiab kev loj hlob ntawm dementia. Tsis tas li ntawd, qee qhov kev tshawb fawb kuj tau pom tias tsis muaj zog mitochondrial antioxidant muaj peev xwm, qeeb zog metabolism, thiab tsis zoo calcium ion metabolism kuj muaj feem xyuam rau kev nco poob.

Txawm li cas los xij, peb kuj yuav tsum saib qhov zoo. Los ntawm kev txhawb nqa mitochondrial muaj nuj nqi thiab kev noj qab haus huv, peb tuaj yeem txhim kho kev nco thiab tiv thaiv ntau yam kab mob uas muaj hnub nyoog. Nov yog qee txoj hauv kev yooj yim los pab koj tswj kev noj qab haus huv mitochondria:

1. Noj zaub mov kom zoo. Cov khoom noj uas tsim nyog yuav tsum tau noj hauv cov zaub mov, suav nrog cov vitamins, minerals, proteins, carbohydrates, thiab rog. Them tshwj xeeb rau kev noj cov tshuaj antioxidants nplua nuj nyob rau hauv vitamin B, vitamin C, vitamin E, selenium, zinc, thiab lwm yam.

2. Ua kom qoj ib ce. Kev tawm dag zog nruab nrab tuaj yeem txhawb kev noj qab haus huv ntawm cov hlab plawv thiab cov hlab ntsws thiab txhim kho cov metabolism hauv kev ua haujlwm thiab kev ua haujlwm ntawm mitochondria.

3. Tsis txhob coj cwj pwm phem xws li haus ntau dhau, haus luam yeeb, noj ntau dhau, thiab lwm yam, uas yuav ua rau koj noj qab haus huv.

4. Tau pw tsaug zog zoo. Pw tsaug zog ua lub luag haujlwm tseem ceeb hauv kev rov qab los thiab kev saib xyuas ntawm mitochondrial muaj nuj nqi. Nws raug nquahu kom ua kom 7-8 teev pw tsaug zog thaum hmo ntuj, tswj lub moos lom neeg tsis tu ncua, thiab sim ua kom tsis txhob tsaug zog thaum hmo ntuj.

Hauv luv luv, peb yuav tsum xyuam xim rau kev noj qab haus huv thiab kev ua haujlwm ntawm mitochondria thiab txhawb kev ua haujlwm ib txwm muaj thiab cov metabolism hauv mitochondria los ntawm kev tswj hwm txoj kev noj qab haus huv thiab kev noj zaub mov zoo, yog li txhim kho kev nco thiab tiv thaiv lub cev noj qab haus huv. Nws tuaj yeem pom tias peb yuav tsum txhim kho kev nco, thiab Cistanche deserticola tuaj yeem txhim kho kev nco, vim Cistanche deserticola tseem tuaj yeem tswj hwm qhov sib npaug ntawm cov neurotransmitters, xws li nce qib ntawm acetylcholine thiab kev loj hlob. Cov khoom no tseem ceeb heev rau kev nco thiab kev kawm. Tsis tas li ntawd, Cistanche deserticola kuj tseem tuaj yeem txhim kho cov ntshav khiav thiab txhawb nqa cov pa oxygen, uas tuaj yeem ua kom lub hlwb tau txais cov as-ham txaus thiab lub zog, yog li txhim kho lub hlwb tseem ceeb thiab kev ua siab ntev.

Nyem paub cov tshuaj ntxiv los txhawb kev nco

Cov cim ntawm kev laus no tuaj yeem tshwm sim los ntawm, piv txwv li, txo qis mitochondrial biogenesis, tsis zoo mitophagy, thiab mtDNA kev hloov pauv ua rau cov txheej txheem (xws li, txhim kho cov txheej txheem inflammatory), uas tuaj yeem txo txoj sia, txhim kho, thiab kev pheej hmoo ntawm cov kab mob muaj hnub nyoog [69,153 ].

Tseeb tiag, nws tau pom tias tdecrease hauv mitochondrial zog lossis kev puas tsuaj ntawm mitochondria kuj tseem nyob hauv keeb kwm ntawm kev loj hlob ntawm cov kab mob neurodegenerative [154] los ntawm ntau dhau ROSformation ua rau mob thiab genomic instability. Cov txheej txheem no tuaj yeem txhim kho cellular senescence, cov txheej txheem kev laus, thiab kev loj hlob ntawm cov kab mob uas muaj hnub nyoog [154].

Nws kuj tseem pom tau hais tias, qhov nce qib ntawm ROS tuaj yeem tsim kev tiv thaiv, homeostatic (txo) cov txheej txheem (piv txwv li, ntawm kev ua neej nyob txwv tsis pub cov txheej txheem cellular ntawm ROS-dependent, tiv thaiv, kev ntxhov siab teb), tab sis, los ntawm kev laus zuj zus, siab dua ib theem. , ROScan evoke (ua rau muaj kev puas tsuaj rau hnub nyoog) [155].

Nws tau pom tias autophagy (thiab mitophagy) tsis kam nrog lub hnub nyoog [156], uas tuaj yeem tsim kom muaj kev puas tsuaj ntawm mitochondria thiaj li ua rau mob (piv txwv li, los ntawm kev nce ROS theem-evoked activation ntawm NLRP3 / NOD-zoo li receptor pyrin domain 3 thiab NF-κB. ), kev tuag ntawm tes (piv txwv li, dhau los ntawm kev ua haujlwm ntawm caspases thiab mitochondrial permeability hloov pauv / mPT pore los ntawm ROS ntau dhau) thiab DNA puas (los ntawm ROS ua rau muaj kev nce hauv apoptotic signaling, xws li p53) [153].

Tsis tas li ntawd, nws tau pom tias qhov tsis xws luag hauv mitochondria thiab autophagy (therebyaggregation ntawm tsis yog -synuclein thiab A peptide tab sis kuj cuam tshuam mitochondria) tuaj yeem muaj lub luag haujlwm hauv kev txhim kho cov kab mob neurodegenerative, xws li Parkinson's disease thiab Alzheimer's disease [1515,156].

Yog li, tshuaj los yog kev cuam tshuam, xws li kev txwv caloric, uas tuaj yeem txhawb autophagy thiab mitophagy, yog li inhibit mitochondrialdysfunction, ROS ntau lawm, sib sau ua ke ntawm cov proteins lom, o, cell tuag thiab cell senescence, tuaj yeem ncua hnub nyoog txog kev degeneration, ncua kev noj qab haus huv lifespan thiab alleviateneurodegenerative kab mob. [159–161].

Tseeb tiag, piv txwv li, nws tau pom tias SIRT1 muaj lub luag haujlwm hauv kev tshem tawm cov kev puas tsuaj mitochondria ntawm autophagy (los ntawm kev txhim kho ntawm autophagy proteins) [162–164] thiab hauv mitochondrial biogenesis (nce hauv mitochondrial biogenesis) los ntawm kev nce transcriptional cofactor PGC{3. }} kev ua haujlwm [87] (Daim duab 1), whereas mitochondrial deacetylase SIRT3 tswj (qis) ROS qib los ntawm kev txhim kho cov tshuaj tiv thaiv antioxidant ntawm superoxide dismutase 2 (SOD2) thaum muaj kev txwv caloric, ua rau muaj zog oxidative kev nyuaj siab [165].

Ntxiv mus, nws kuj tau pom tias nce SIRT3 kev ua haujlwm tuaj yeem cuam tshuam mPT pore tsim uas tuaj yeem tiv thaiv mitochondrial dysfunctions [166]. Nws kuj tau pom tias PGC-1 kev ua kom muaj peev xwm txhim kho mitochondrial biogenesis thiab txhim kho mitochondrial zog metabolism, yog li ua kom lub neej ntev thiab tiv thaiv cov kab mob neurodegenerative [167].

PGC-1 tuaj yeem khi thiab sib koom ua ke ntawm qhov kev hloov pauv ntawm PPAR (tshwj xeeb yog lub tsev neeg ntawm cov receptors nuclear) thiab txhawb tsis tau tsuas yog mitochondrial biogenesis tab sis kuj muaj kev ua haujlwm SOD thiab catalase, qabzib metabolism, thiab oxidative phosphorylation [162,168–170], whereas txo cov theem ntawm NF-κB thiab pro-inflammatory cytokines [171,172], nrog rau A tiam [173,174].

Qhov tseeb, qhov txo qis ntawm PGC1- tuaj yeem ua rau txo qis mitochondrial ua pa thiab txhim kho cov txheej txheem inflammatory [175]. Ntxiv mus, mitochondrial uncoupling ntawm theoverexpression ntawm uncoupling protein 1 (UCP1) kuj yuav ua rau kom lub neej [176].

2.5. Hloov Cov Kev Sib Txuas Sib Txuas Sib Txuas: Ua kom cov txheej txheem ua mob ntxiv

Cov txheej txheem kev laus kuj tseem txuas nrog dysregulation ntawm cell-cell kev sib txuas thiab kev sib txuas lus ntawm tes ua rau, ntawm lwm tus, tsis muaj menyuam (ua kom lub cev tiv thaiv kab mob tsis zoo li cov kab mob), mob ntev, qis qis (lub npe hu ua "inflammaging") nrog rau kev ua kom NF-κB. , nrog rau kev sib txuas ntxiv thiab tso tawm ntawm cov cytokines proinflammatory (piv txwv li, IL-1 thiab TNF- / qog necrosis factor-) [69,125,177,178].

Kev nce hauv cov txheej txheem inflammatory thiab proinflammatory cytokine qib kuj tuaj yeem txhim kho (ua rau muaj kev laus), piv txwv li, los ntawm kev ua kom muaj zog ntawm intracellular multiproteinsensor NLRP3 inflammasome, senescent hlwb-evoked tso tawm ntawm proinflammatory cytokinesand NF-κB qib thiab signaling [177,179,180]. Autophagy tsis ua hauj lwm hauv cov kab mob qub (xws li, txo qis hauv kev ua haujlwm ntawm autophagy), thiab hauv cov neeg mob Alzheimer's disease thiab Parkinson'sdisease [181,182] kuj tau pom.

Nws tau pom tias kev laus (piv txwv li, txo qis autophagy los ntawm lub hnub nyoog) tuaj yeem txhawb nqa NF-κB signaling, uas qhov kev hloov pauv ntawm NF-κB (zoo li nce hauv ROS los ntawm mitochondria thiab aggregation ntawm A) txhawb cov txheej txheem inflammatory, piv txwv li, los ntawm kev nce NLRP3 qhia thiab IL-1 tso tawm [161,179,183–185], whereas autophagic uptake ntawm puas mitochondria (ua rau txo qis hauv ROS theem) supresses NLRP3 stimulation [161]. Yog li, nws tau pom tias autophagy tuaj yeem tsim cov tshuaj tiv thaiv kab mob los ntawm inhibition ntawm NLRP3 inflammasome yog li txo NLRP3-evoked cleavage ntawm pro-IL-1 rau nws daim ntawv nquag / IL-1 los ntawm caspase -1 [186,187] ua rau ncua kev laus [180].

Ntxiv mus, qhov kev teb ntawm AMPK signaling txo qis nrog lub hnub nyoog [180,188], uas txo nws txoj haujlwm inhibitory ntawm NF-κB signaling [82] (Daim duab 1) thiab impairs autophagicactivity ua rau muaj zog oxidative kev nyuaj siab thiab ua kom inflammasomes [180] thiab tuaj yeem attenuate lifespan. ].

Raws li mTORC1 muaj peev xwm inhibit autophagy (piv txwv li, mitophagy lossis macroautophagy ntawm cov protein hloov pauv) txhua yam tshuaj lossis kev cuam tshuam, uas tuaj yeem inhibitmTORC1 (piv txwv li, txwv tsis pub caloric ua rau mTOR inhibition) tuaj yeem ua rau muaj zog qeeb ntawm cov txheej txheem kev laus thiab txhim kho lub neej ntawm inhibition ntawm o [180 ] (Daim duab 1), uas tuaj yeem daws tsis tau tsuas yog neuroinflammation tab sis kuj neurodegeneration thiab kab mob ntsig txog, xws li Alzheimer's disease, Parkinson's disease thiab amyotrophic lateralsclerosis [183,189]. Tseeb tiag, inhibition ntawm NF-κB signaling muaj peev xwm tiv thaiv lub hnub nyoog-kev koom nrog hauv cov qauv nas txuas lawv lub neej ntev [190].

2.6. Cellular Senescence

Cellular senescence tuaj yeem tshwm sim los ntawm intracellular thiab extracellular, genomic andepigenomic teeb meem stimuli thiab kev puas tsuaj uas ua rau cov cim ntawm kev laus (xws li, muaj hnub nyoog txog kev ntxhov siab: oxidative kev nyuaj siab thiab telomere shortening; metabolic, nrog rau ER kev nyuaj siab; mitochondrial dysfunction ntawm protasis. 191–193] ib.

Ib qho ntawm cov yam ntxwv tseem ceeb ntawm kev laus yog kev txhim kho ntawm cellular senescence (irreversible cell-cycle ntes tswj los ntawm, xws li, telomere attrition/DNA puas-evoked p53-dependent DNA-kev puas tsuaj teb, nyob rau hauv whichp53 yog qhib).

Kev sib sau ntau dhau ntawm cov hlwb senescent, uas cov hlwb txo cov qog nqaij hlav thiab tiv taus apoptosis (piv txwv li, los ntawm kev tswj hwm ntawm antiapoptotic Bcl-2/Bcell lymphoma-2 tsev neeg cov proteins uas ua rau muaj kev tiv thaiv apoptosis-inducing signals), tuaj yeem tsim teeb meem. cov txheej txheem ntawm cov hlwb nyob ib puag ncig los ntawm kev tso tawm ntawm cov tshuaj tiv thaiv proinflammatory (SASP yam, xws li IL-1 ,) thiab lwm yam khoom (piv txwv li, IGF-1) [2,191,194,195].

Piv txwv li, cov kev tshawb fawb yav dhau los qhia tau hais tias kev tswj xyuas mob hnyav ntawm IGF-1 tuaj yeem txhawb nqa cell proliferation thiab ciaj sia taus thaum lub sij hawm kev tswj hwm ntawm IGF-1 txhawb nqa kev loj hlob ntawm tes thiab senescence (thiab tom kawg, txhim kho cov txheej txheem kev laus thiab inhibits tumorigenesis) los ntawm SIRT1 inhibition thiab nce p53 kev ua haujlwm (los ntawm kev nce acetylation) [196] thiab kev tawm tsam ntawm autophagy (piv txwv li, ntawm mTOR) [197] (Daim duab 1).
Tseeb, SIRT1 tuaj yeem cuam tshuam tsis yog DNA kev puas tsuaj nkaus xwb tab sis kuj tseem muaj cellular senescence ntawm deacetylation (inhibition) ntawm p53 uas ua rau muaj kev tiv thaiv kev laus [198]. Hauv kev sib piv nrog cellular senescence, cellular quiescenceoccurs thaum cov khoom noj khoom haus lossis kev loj hlob theem qis heev (lossis tsis muaj) ua rau rov qab mus rau lub voj voog ntawm tes. Hauv lub xeev no, te lub hlwb tuaj yeem cuam tshuam qhov pib ntawm cell senescence [199] thiab muaj lub luag haujlwm hauv kev saib xyuas ntawm stemness [200]. Txawm li cas los tswj cellularbalance, lub senescence ntawm hlwb yog ob-edged ntaj [2].

Piv txwv li, cellular senescence tuaj yeem txo daim siab fibrosis [201], txhawb kev kho cov ntaub so ntswg, thiab muaj lub luag haujlwm tsis yog lub cev nqaij daim tawv xwb, tab sis kuj muaj cov txheej txheem pathophysiological (xws li, embryogenesis thiab kho qhov txhab) [195] thiab tiv thaiv kev mob qog noj ntshav [202], tab sis exaggerated. attenuation ntawm cov txheej txheem ntawm cellenescence thiab tsub zuj zuj ntawm senescent hlwb tuaj yeem tsim (los yog txhim kho) kev laus, thiab, raws li qhov tshwm sim, kev loj hlob ntawm cov kab mob muaj hnub nyoog, xws li Alzheimer's kab mob thiab mob qog noj ntshav [192,195,203-205].

Yog li, tshuaj rau cellular senescence yuav tsum tau ceev faj. Nyob rau hauv cov xwm txheej uas tsis muaj qabzib, AMPK-induced p53 activation potentiates cellularsurvival (p53-dependent metabolic arrest), tab sis ntau dhau (ntev) AMPK activation leadsto enhanced p53-dependent cellular senescence [206,207]. Txawm li cas los xij, tsis yog SIRT nkaus xwb tab sis kuj AMPK ua kom muaj peev xwm txhim kho cellular senescence ntawm, piv txwv li, inhibition ofproinflammatory mediators [5,81,82] (Daim duab 1).

2.7. Poob Proteostasis thiab Stem Cell Exhaustion

Impaired protein homeostasis (poob ntawm proteostasis) los ntawm lub hnub nyoog kuj tseem nyob rau hauv keeb kwm ntawm kev laus thiab lwm yam kab mob (xws li, neurodegenerative kab mob) ua rau dysregulation ntawm protein synthesis, degradation, thiab protein aggregation, disaggregation, sib dhos, folding, thiab kev lag luam [208 ].

Piv txwv li, qhov kev ua ntawm f ubiquitin-proteasome system thiab autophagy poob qis nrog lub hnub nyoog [209], qhov kev ua haujlwm ntawm f proteostasis network (xws li, txhim kho autophagy) txuas ntxiv kev noj qab haus huv ncua sij hawm thiab lifespan [210]. Inhibition ntawm mTORpathways (piv txwv li, los ntawm kev txwv caloric los ntawm kev txo cov protein synthesis thiab ua kom cov autophagy) tuaj yeem txhim kho cov protein homeostasis thiab txuas ntxiv lub neej [211,212] (Daim duab 1).

Ithas tau pom tias khaws cia mitochondrial proteostasis ntev lifespan thiab txo A protein aggregation hauv Alzheimer tus kab mob qauv [213]. Ntxiv mus, kev txo qis ntawm f autophagy-lysosomal txoj hauv kev tuaj yeem muaj lub luag haujlwm hauv kev txhim kho ob leeg Alzheimer's kab mob thiab Parkinson's kab mob thiab lwm yam kab mob neurodegenerative [77].

Tseeb tiag, kev ua kom cov mitophagy (los ntawm qhov uas autophagy-lysosomal pathwaremovesve puas / dysfunctional mitochondria) muaj peev xwm ua rau kom muaj sia nyob hauv cov kab mob thiab rov qab tsis txaus ntseeg hauv cov qauv ntawm Alzheimer's disease [214,215]. AMPK kev ua kom muaj zog tuaj yeem koom nrog kev saib xyuas ntawm proteostasis los ntawm inhibition ntawm mTOR thiab phosphorylation ntawm eIF2 (eukaryotic pib tshwm sim 2; ua rau txo qis ntawm cov protein synthesis) thiab los ntawm kev ua kom autophagy [79,80] (Daim duab 1). Ntxiv mus, nws kuj tau pom tias autophagymay yuav txhim kho los ntawm inhibition ntawm mTOR los ntawm SIRT1 [216] (Daim duab 1).

Yog li, kev ua haujlwm ntawm AMPK / SIRT1 thiab inhibition ntawm mTOR (mTORC1, tab sis tsis yog mTORC2 vim tias tom kawg xav tau rau autophagy) kev ua haujlwm yuav yog lub hom phiaj tseem ceeb hauv kev kho kev laus [77].Qhov tseeb, kev laus thiab cov kab mob muaj hnub nyoog muaj peev xwm upregulate mTORC1 [ 69].Stem cell qaug zog tuaj yeem muaj lub luag haujlwm hauv kev laus anthe d zoo li cov kab mob uas muaj hnub nyoog dhau los ntawm kev poob ntawm f regenerative muaj peev xwm ntawm cov hlwb, cov ntaub so ntswg, es, thiab cov kabmob.

Piv txwv li, cov kev ua thiab tus naj npawb ntawm cov hematopoietic hlwb thiab cov kab mob hauv plab hnyuv tau txo qis nrog lub hnub nyoog ua rau txo qis hauv lymphoid cell xov tooj thiab hloov lub cev tiv thaiv kab mob, ua rau muaj kev pheej hmoo ntawm kev txhim kho ntshav qab zib thiab myeloid cell xov tooj, nrog rau kev ua haujlwm tsis zoo hauv cov hnyuv [217,218] . Ntxiv mus, qhov muaj hnub nyoog-nyob ntawm qhov txo qis hauv n kev ua haujlwm ntawm lwm cov qia hlwb, xws li cov kab mob neuronal qia kuj tau pom [71].

Nws tau pom tias kev laus ntawm qia cell tuaj yeem tshwm sim los ntawm ntau yam, xws li DNA puas thiab hloov pauv, cellular senescence, tsis xws luag hauv proteostasis, mitochondrial dysfunction, thiab telomere attrition [63,71].

Yog li, peb tuaj yeem txiav txim siab tias kev ua haujlwm ntawm AMPK / SIRTs-modulated signaling pathways, inhibition of mTOR teebmeem (xws li, los ntawm inhibition ntawm IIS txoj kev) thiab kev hloov pauv ntawm cov geneexpression (xws li, los ntawm HDAC inhibitors) tuaj yeem txo cov txheej txheem kev laus (hallmarks) los ntawm kev ncaj thiab tsis ncaj. yam (xws li, kev txhim kho ntawm ib qho ntawm cov cim kev laus, xws li telomere attrition tuaj yeem txhim kho lwm yam kev laus, xws li senescence thiab mitochondrialdysfunction), uas ua rau kom ncua lub neej ntev thiab ncua cov tsos mob ntawm cov kab mob neurodegenerative.

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