Hu rau: jerry.he@wecistanche.com

Cistanche muaj cov nyhuv anti-aging

Mikhail V. Blagosklonny

1 Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA

Xa mus rau: Mikhail V. Blagosklonny, email: mikhail.blagosklonny@roswellpark.org lossis blagosklonny@rapalogs.com

Keywords: lifespan, longevity, rejuvenation, noj qab haus huv, kab mob

Tau txais: Lub Ob Hlis 17, 2017 Txais: Plaub Hlis 30, 2017 Published: May 22, 2017

Copyright: Blagosklonny et al. Qhov no yog ib tsab xov xwm qhib nkag tau muab faib raws li cov ntsiab lus ntawm Creative Commons Attribution License (CC-BY), uas tso cai rau kev siv tsis txwv, kev faib tawm, thiab luam tawm hauv ib qho nruab nrab, muab tus thawj sau thiab cov peev txheej tau txais txiaj ntsig.

Cistanche muaj cov nyhuv anti-aging

TSAB NTAWV

Inhibitors ntawm mTOR, suav nrog cov chaw kho mob muaj nyob hauv rapalogs xws li rapamycin (Sirolimus) thiab Everolimus, yog gerosuppressants, uas suppress cellular senescence. Rapamycin slows kev laus thiab ncua lub neej ncua nyob rau hauv ntau hom ntawm cab mus rau tsiaj. Rapalogs tuaj yeem tiv thaiv cov kab mob uas muaj hnub nyoog, suav nrog mob qog noj ntshav, atherosclerosis, rog rog, neurodegeneration thiab retinopathy thiab muaj peev xwm rov ua kom cov qia hlwb, tiv thaiv kab mob thiab cov metabolism. Ntawm no, kuv qhia ntxiv tias yuav ua li cas rapamycin tuaj yeem ua ke nrog metformin, inhibitors ntawm angiotensin II signaling (Losartan, Lisinopril), statins (simvastatin, atorvastatin), propranolol, aspirin thiab PDE5 inhibitor. Kev sib xyaw ua ke ntawm cov tshuaj no nrog kev tawm dag zog lub cev thiab ib qhoanti-agingnoj zaub mov (Koschei mis) tuaj yeem ua rau lawv qhov ntauanti-agingcuam ​​tshuam thiab txo cov kev mob tshwm sim.

Thaum xub thawj, lub discovery ntawm lubanti-agingCov khoom ntawm rapamycin tau ntsib nrog kev tsis ntseeg vim nws nyuaj rau dogma tias kev laus yog kev poob qis los ntawm kev puas tsuaj ntawm molecular los ntawm cov dawb radicals. Txog tam sim no, rapamycin tau raug pov thawj tias yog tshuaj tiv thaiv kev laus. Hauv qhov sib piv, cov tshuaj tiv thaiv oxidants ua tsis tiav hauv kev sim tshuaj [1-9] thiab dogma tau tawg [1, 2, 10-18]. Hauv kaum xyoo dhau los, covanti-agingCov teebmeem ntawm rapamycin tau raug lees paub. Cov koob tshuaj tiv thaiv kev laus thiab cov sij hawm tuaj yeem raug ntxiv los ntawm kev tshawb fawb tsiaj. Cov koob tshuaj tiv thaiv zoo uas muaj qhov tshwm sim tsawg kawg tuaj yeem raug txiav tawm raws li kev siv tshuaj rapalogs. Yog li qhov zooanti-agingkoob tshuaj/sijhawm yuav qhia tau. Muab hais tias rapamycin tsis tu ncua ncua sijhawm ntev tshaj plaws hauv cov nas, rapamycin yuav ua rau tib neeg los tuav cov ntaub ntawv tam sim no ntawm tib neeg lub neej, uas yog 122 xyoo. Txawm li cas los xij, rapamycin yuav tsis ncua lub neej ntev npaum li peb xav tau.

Tam sim no yog lub sijhawm rauanti-agingkev sib xyaw tshuaj. Piv txwv li, metformin tam sim no tab tom rov ua dua tshiab ua ib qhoanti-agingtus neeg sawv cev. Ob peb lwm cov tshuaj uas twb muaj lawm tuaj yeem rov ua dua. Tam sim no peb tuaj yeem tsim cov tshuaj tiv thaiv kev laus, siv cov tshuaj muaj rau tib neeg siv. Txawm li cas los xij, peb yuav tsum xub tham txog kev sib txuas ntawm kev loj hlob, kev laus thiab cov kab mob uas muaj hnub nyoog.

MTOR: los ntawm kev loj hlob mus rau kev laus

Nws yog theoretically kwv yees hais tias stimulation ntawm mitogenic / loj hlob txoj kev nyob rau hauv raug ntes los yog quiescent hlwb yuav tsum ua rau senescence [19]. Qhov kev hloov pauv no los ntawm quiescence mus rau senescence yog hu ua geroconversion [20- 22]. Cellular senescence yog kev loj hlob tsis muaj txiaj ntsig, txuas ntxiv ntawm cellular kev loj hlob thaum qhov kev loj hlob tiag tiag raug txwv [21, 23, 24]. Kev loj hlob ntawm cov hlwb raug ntes ua rau lawv cov hypertrophy thiab hyperfunctions (piv txwv li, hyper- secretory phenotype lossis SASP hauv senescent fibroblasts).

Qhov no tuaj yeem siv rau kev laus ntawm lub cev. Thaum txoj kev loj hlob tiav lawm, ces mTOR (mammalian Target of Rapamycin) thiab ib co lwm yam kev taw qhia txoj kev) drives organismal laus [1, 15, 25, 26]. Cov txheej txheem no txhawb kev ua haujlwm ntawm tes, ua rau hyperfunctions (piv txwv li, kub siab). Secondary, hyperfunctions tuaj yeem ua rau poob haujlwm [1, 27]. Hyperfunction txoj kev xav txuas kev loj hlob, kev laus thiab cov kab mob uas muaj hnub nyoog [1]. Kev tiv thaiv kev laus tiv thaiv lossis ncua cov kab mob muaj hnub nyoog [17, 28-30].

Cov kab mob uas muaj feem rau hnub nyoog yog qhov tshwm sim ntawm kev laus

Cov hnub nyoog ntsig txog pathologies thiab tej yam kev mob muaj xws li atherosclerosis, kub siab, osteoporosis, rog rog, insulin-tiv taus thiab hom II mob ntshav qab zib, mob qog noj ntshav, macular degeneration, Parkinson thiab Alzheimer's kab mob nrog rau cov poj niam laus, thiab ntau yam kev hloov pauv ntawm cov tsos mob uas tsis yog hu ua kab mob. (piv txwv li baldness) thiab presbyopia (ib yam mob uas zoo li pom ze ze). Mob stroke, myocardial infarction, lub plawv fibrillation, tawg lub duav, lub raum thiab lwm yam kabmob tsis ua haujlwm yog qhov tshwm sim ntawm cov hnub nyoog ntsig txog pathology [17, 28, 31].

Nyob rau hauv luv luv, cov kab mob ntsig txog hnub nyoog yog ob qho tib si tshwm sim ntawm kev laus thiab ua rau tuag. Kev laus yog qhov suav ntawm cov kab mob uas muaj hnub nyoog, cov tsos mob thiab cov tsos mob xws li wrinkles thiab presbyopia mus rau mob stroke thiab cancer metastasis. Tau kawg, cov kab mob muaj hnub nyoog tuaj yeem tshwm sim hauv cov neeg mob hluas uas muaj caj ces predisposition lossis vim muaj kev phom sij ib puag ncig. Txawm li cas los xij, txhua yam ntawm cov kab mob no yuav tsim nyob rau hauv cov kab mob laus, txawm tias tsis muaj kev phom sij thiab kev phom sij, yog tias lub cev muaj sia nyob ntev txaus. Txij li kev laus tsis yog programmed, cov kab mob no tshwm sim ntawm qhov sib txawv. Piv txwv li, menopause (hauv poj niam) thiab presbyopia loj hlob sai thiab ntaus txhua tus neeg laus. Txawm li cas los xij, tus kab mob Alzheimer tau qeeb qeeb thiab tus neeg laus tuaj yeem tuag los ntawm mob qog noj ntshav lossis mob stroke ua ntej Alzheimer kab mob tshwm sim [17, 28].

Hauv luv luv, cov tsiaj tuag los ntawm cov kab mob uas muaj hnub nyoog, uas yog qhov tshwm sim ntawm kev laus (Daim duab 1). Yog hais tias ib qho tshuaj ncua TAG NRHO cov kab mob uas muaj hnub nyoog, nws yog ib qho tshuaj tiv thaiv kev laus vim tias nws yuav ncua lub neej ntev los ntawm kev ncua kev tuag.

Dab tsi yog (thiab tsis yog) tshuaj tiv thaiv kev laus?

Ob leeg insulin thiab metformin yog siv los kho mob ntshav qab zib hom II. Insulin tuaj yeem cawm tus neeg mob hauv qhov mob ntshav qab zib coma. Metformin yuav tsis ua qhov txuj ci tseem ceeb no. Txawm li cas los xij, insulin tsis tuaj yeem tiv thaiv ntshav qab zib, thaum metformin tuaj yeem ua tau. Insulin kuj tseem tuaj yeem ua rau qee yam kab mob, thaum metformin txo qis rau lawv. (Saib nqe lus Metformin rau kev siv). Insulin tuaj yeem ua rau mob qog noj ntshav thiab rog rog. Metformin tiv thaiv kev mob qog noj ntshav thiab txo cov rog rog. Insulin qhib txoj hauv kev mTOR, txoj hauv kev tseem ceeb ntawm kev laus. Metformin indirect inhibits txoj kev mTOR. Insulin yog cov tshuaj tiv thaiv kev laus, thaum metformin yog ib qhoanti-agingtshuaj.

Cov txheej txheem rau muaj peev xwmanti-agingtshuaj

1. Ib hom tshuaj uas ua rau lub neej ntev dua hauv cov qauv kab mob zoo dua hauv cov tsiaj txhu.

2. Ib hom tshuaj tiv thaiv lossis ncua ntau yam kab mob uas muaj hnub nyoog hauv cov tsiaj.

3. Ib yam tshuaj uas suppresses cellular geroconversion los ntawm quiescence mus rau senescence

Cov txheej txheem no sib tshooj sib tshooj. Yog tias qhov kev cuam tshuam txuas ntxiv lub neej ntev, nws yuav tsum ncua cov kab mob uas muaj hnub nyoog. Tsiaj txhu tuag los ntawm cov kab mob uas muaj hnub nyoog. Piv txwv li, txwv tsis pub calories (CR) ncua txhua yam kab mob ntawm kev laus thiab ncua lub neej ntev. Ib tug yuav hais tias CR ncua lub neej ncua los ntawm kev ncua cov kab mob. Ib tug yuav hais tias CR ncua cov kab mob los ntawm kev ua kom qeeb qeeb. Ob qho kev txhais yog raug. Los ntawm txoj kev, CR deactivates txoj kev paub txog zaub mov, hu ua TOR (Target of Rapamycin) [32]. Raws li tag nrho 3 cov qauv, rapamycin thiab lwm yam rapalogs yog qhov kawganti-agingtshuaj.

Rapalogs: Rapamycin (Sirolimus/Rapamune) thiab Everalimus

Rapalogs suav nrog rapamycin, paub hauv tsev kho mob xws li Sirolimus lossis Rapamune, everolimus, temsirolimus (a rapamycin prodrug) thiab deforolimus (Ridaforolimus). Rapalogs yog cov tshuaj noj los ntawm cov neeg tau txais kev hloov pauv hauv nruab nrog cev thiab cov neeg mob qog noj ntshav.

1. Rapamycin prolongs lifespan hauv nas [33-45] ntawm koob tshuaj uas tsis muaj kev phiv tshwm sim [46-59].

2. Rapalogs tiv thaiv cov kab mob uas muaj hnub nyoog hauv cov nas nrog rau lwm cov tsiaj txhu xws li cov tsiaj txhu uas tsis yog tib neeg thiab tib neeg. Raws li piv txwv: rapamycin tiv thaiv atherosclerosis [60-64], neurodegeneration thiab retinopathy [65-67] thiab cardiopathy [68] hauv nas. Rapalogs tiv thaiv mob qog noj ntshav hauv nas thiab tib neeg [34, 37, 38, 40, 41, 69-86]. Rapamycin txo kev rog rog hauv cov nas thiab tib neeg [87-89]. Raws li kev kwv yees [1], rapalogs rejuvenate kev tiv thaiv, txhim kho kev tiv thaiv kab mob hauv cov nas laus [90] thiab tib neeg [30, 91, 92]. Kev tiv thaiv txhua yam kab mob uas muaj hnub nyoog los ntawm rapalogs tau tham txog qhov nthuav dav [1, 2, 13, 14, 17, 18, 24, 26, 29, 32 93- 95],

3. Rapalogs suppress cellular geroconversion los ntawm quiescence mus rau senescence [20-23, 90, 96-110].

4. Rapamycin inhibits kev laus, muaj hnub nyoog ntsig txog pathologies hauv cov qauv kab mob: cov poov xab [111, 112], yoov [113-118] thiab worm [119].

Raws li tag nrho cov txheej txheem, rapalogs yoganti-agingtshuaj. Qhov tseem ceeb, rapalogs muaj kev phiv tsawg tsawg, uas tuaj yeem thim rov qab [120-122]. Hauv qee qhov kev tshawb fawb, rapamycin txhim kho cov kab mob metabolic [46, 49, 52, 56, 57, 88, 123]. Rapalogs tau siv rau hauv cov neeg ua haujlwm noj qab haus huv [124, 125] thiab txawm tias nyob hauv cov poj niam cev xeeb tub uas tsis muaj kev puas tsuaj [126, 127]. Tsis ntev los no, rapamycin tau tshawb xyuas ua ib qhoanti-agingtshuaj nyob rau hauv tib neeg [128]

Hauv cov neeg mob hloov pauv, rapalogs tiv thaiv qog noj ntshav [69- 78]. Qhov no yog ib qho zoo heev "side effect". Hauv qee hom nas, rapamycin ua rau cov tsos mob ntawm "kev tshaib kev nqhis" pseudo-diabetes piav txog 150 xyoo dhau los los ntawm Claude Bernard [129]. "Kev tshaib plab pseudo-diabetes" tsis yog kab mob. Nws yog qhov muaj txiaj ntsig zoo thaum lub sijhawm yoo mov [130, 31]. Thaum lub sijhawm tshaib plab, cov piam thaj yuav tsum tau zam rau lub hlwb, yog li lub cev ua insulin-tiv taus thiab cov tshuaj insulin txo qis. Cov kev hloov pauv hauv metabolic no muaj txiaj ntsig zoo thiab yog li kev yoo mov yog qhov zoo rau kev noj qab haus huv. Qhov tseeb, rapamycin tiv thaiv cov teeb meem ntawm ntshav qab zib mellitus (nephropathy), thaum nce qib qabzib hauv cov caj ces mob ntshav qab zib mellitus [131]. Kev tiv thaiv kev mob ntshav qab zib nrog rapamycin tau tham txog [31]. Hmoov tsis zoo, cov kws tshawb fawb yooj yim txhais tau tias kev tshaib plab-zoo li cov teebmeem ntawm rapamycin li hom 2 mob ntshav qab zib. Raws li qhov kev txhais lus tsis raug, qee tus kws kho mob gerontologists ntseeg tias qhov no txwv tsis pub siv cov tshuaj hauv tib neeg. Hmoov zoo, rapalogs twb tau siv dav hauv tib neeg. Hauv cov neeg mob hloov pauv, muaj qhov nce me ntsis ntawm cov ntshav qab zib tshwm sim hauv qee qhov kev tshawb fawb tab sis tsis yog hauv lwm cov kev tshawb fawb [132, 133]. Qhov tsim nyog, ntshav qab zib yog tshwm sim hauv cov neeg mob hloov pauv tsis hais txog kev kho mob rapalog, yog li pab pawg neeg mob no tsis yog tus sawv cev. Yuav ua li cas txog cov neeg noj qab haus huv? Kev tswj hwm mob hnyav ntawmrapamycin thim rov qab cov zaub mov-vim insulin tsis kam [134]. Hauv lwm lo lus, rapamycin nce insulin rhiab heev rau cov neeg noj qab haus huv. Tau kawg, nws muaj peev xwm hais tias kev tswj hwm mob ntev ntawm rapamycin tuaj yeem ua rau beta-cell disfunction thiab ntshav qab zib hauv qee cov noob caj noob ces, zoo li nws tau pom hauv qee hom nas [135]. Qhov no tsis txwv kev siv rapamycin ua ib qhoanti-aging. Tsuas yog, cov qib qabzib yuav tsum tau saib xyuas thiab rapamycin tuaj yeem txiav tawm, yog tias cov piam thaj nce ntxiv. Tsis zoo li cov neeg hloov pauv, cov neeg noj qab haus huv tuaj yeem txiav tawm rapamycin

thaum twg los tau. Thiab thaum kawg, txhawm rau "tso" cov kev txhawj xeeb no, rapamycin tuaj yeem ua ke nrog metformin.

Metformin

Metformin yog ib qho ntawm cov tshuaj feem ntau siv los kho mob ntshav qab zib hom II. Ua ntej metformin, nws cov tshuaj analog - phenformin - tau siv rau hom II mob ntshav qab zib. Phenformin raug tshem tawm ntawm kev ua lag luam vim qhov kev ntshai ntawm nws qhov tsis tshua muaj tshwm sim: lactic acidosis. Qhov tshwm sim ntawm lactic acidosis rau metformin yog qis dua rau phenformin.

Txij li xyoo 1972, tus kws tshawb fawb Lavxias, Vladimir Dilman, thiab nws cov npoj yaig Anisimov, Bernstein thiab lwm tus, tau qhia tias phenformin thiab metformin qeeb kev laus, txo kev rog, tiv thaiv qog noj ntshav thiab txuas ntxiv kev ua neej nyob hauv nas [136-146]. Tsis tas li ntawd, phenformin thiab metformin tau muab rau cov neeg mob qog noj ntshav [147]. Tau ntau xyoo, cov ntawv tshaj tawm no tau raug tsis quav ntsej vim nws ntseeg tias kev laus yog tsav los ntawm kev puas tsuaj ntawm molecular thiab tsis tuaj yeem cuam tshuam los ntawm cov tshuaj tiv thaiv ntshav qab zib. Kev tiv thaiv kev laus ntawm metformin thiab phenformin tau piav qhia los ntawm kev ua haujlwm siab ntawm kev laus [1].

Qhov tseeb, metformin nce lifespan hauv nas [143] thiab C. elegans [148, 149]. Metformin tiv thaiv kev mob qog noj ntshav thiab qee yam kab mob ntsig txog hnub nyoog hauv tib neeg. [150-161]. Tsis tas li ntawd, metformin txo qis tag nrho-ua rau kev tuag hauv cov neeg mob ntshav qab zib [156] thiab txo qhov kev pheej hmoo ntawm kev paub txog kev poob qis thiab dementia [157]. Tsis tas li ntawd, metformin yog siv los ua kom muaj menyuam [162,163].

Yog li, metformin (a) ncua lub neej ntev ntawm cov kab mob thiab nas thiab txo qis txhua qhov kev tuag ntawm tib neeg (b) tiv thaiv ntau yam kab mob uas muaj hnub nyoog hauv cov nas thiab tib neeg. Txawm li cas los xij, metformin tsis tau ua kom muaj sia nyob hauv qee cov qauv kab mob. Nws tsis nce lifespan hauv nas hauv qee qhov kev tshawb fawb. Lub spectrum ntawm metformin-responsive kab mob yog nqaim dua li cov rapamycin. Raws li kev kho mob monotherapy, cov txiaj ntsig txuas ntxiv ntawm lub neej ntawm metformin tuaj yeem sib txawv, tab sis nws tuaj yeem ua ke nrog rapamycin thiab lwm yam tshuaj.

Ob tus neeg sawv cev kuj tseem tuaj yeem tso tseg ib leeg cov kev mob tshwm sim. Piv txwv li, thaum metformin tuaj yeem nce lactate ntau lawm, rapamycin txo nws [164]. Qhov no yog qhov tseem ceeb vim tias phenformin raug tshem tawm ntawm kev ua lag luam vim kev ntshai ntawm lactate acidosis, tshwm sim los ntawm lactate ntau lawm. Ntawm qhov tod tes, metformin yuav tsum txo qis qhov tshwm sim ntawm cov piam thaj tsis txaus ntseeg, yog tias rapamycin yuav ua rau cov tsos mob no, hauv cov neeg tsawg. Ib qho kev sib xyaw ntawm Rapamycin thiab metformin kuj tau kawm rau kev kho mob qog noj ntshav [165, 166].

Inhibitors ntawm angiotensin II

Angiotensin II receptor blockers (ARB) xws li Valsartan, Telmisartan, Losartan thiab angiotensin- converting enzyme (ACE) inhibitors xws li Captopril, Lisinopril, Enalapril, Ramipril yog dav siv los kho ntshav siab. Ntshav siab yog ib yam kab mob uas ua kom pom tseeb ntawm hyperfunction. Angiotensin II, ib yam tshuaj hormones, muaj feem xyuam rau cov kab mob muaj hnub nyoog hauv cov tsiaj nyeg [167, 168]. Kev cuam tshuam ntawm angiotensin II receptor tsub kom lub neej ntev hauv cov nas [169]. Kev hloov pauv ntawm angiotensin II receptor noob yog txuam nrog kev ua neej nyob ntev hauv tib neeg [170]. Inhibitors ntawm angiotensin II ob lub neej ntev ntawm cov nas hypertensive [171, 172]. Qhov kev ua yeeb yam no (100 feem pua) nce yog ib feem ntawm cov nyhuv anti-hypertensive. Txawm li cas los xij, hauv kev noj qab haus huv (cov neeg uas muaj ntshav siab) nas, kev kho mob ntev nrog enalapril txo qhov hnyav thiab ua rau lub neej ntev heev [173]. Hauv tib neeg, inhibitors ntawm angiotensin II tiv thaiv kev mob plawv hypertrophy thiab organ fibrosis [168], [174], ib qho cim ntawm kev laus. Hauv qee qhov kev tshawb fawb, kev siv ARBs mus ntev tau cuam tshuam nrog kev mob qog noj ntshav qis dua [175]. Enalapril thiab perindopril tsis txo cov ntshav siab hauv cov neeg mob uas muaj ntshav siab [176]. Qhov tseem ceeb, angiotensin-hloov enzyme inhibitors lossis angiotensin receptor blockers tau txais txiaj ntsig zoo rau cov neeg mob atherosclerotic normotensive [177].

Aspirin

Aspirin los yog acetylsalicylic acid, ib qho inhibitor ntawm cyclooxygenase (COX), yog ib qho ntawm feem ntau siv cov tshuaj uas tsis yog tshuaj. Aspirin inhibits qhov mob. Pro- o (piv txwv ntawm hyperfunction) yog ib qho cim ntawm kev laus [178, 179]. Aspirin kuj inhibits hyper-functional platelets, tiv thaiv thrombosis thiab atherosclerosis. Inhibition ntawm hyper-active platelets tiv thaiv kab mob plawv thiab mob qog noj ntshav [180].

Aspirin prolongs lifespan nyob rau hauv Drosophila [181], C elegans [182, 183] thiab nas [184]. Aspirin thim rov qab cov piam thaj intolerance hauv cov nas [185].Anti-agingCov dej num ntawm cov tshuaj aspirin tau tham txog [105, 186,187].

Aspirin yog siv los tiv thaiv cov kab mob uas muaj hnub nyoog xws li kab mob plawv thiab mob qog noj ntshav hauv tib neeg. Ntau qhov kev tshawb fawb tau pom cov txiaj ntsig, txawm tias koob tshuaj thiab lub sijhawm ntawm kev kho mob tseem tsis paub meej. Piv txwv li, 600 mg aspirin ib hnub twg rau 25 lub hlis txo qis qhov tshwm sim ntawm mob qog noj ntshav hauv cov neeg muaj kab mob qog noj ntshav [188]. Hauv lwm txoj kev tshawb fawb, 300 mg ib hnub rau 5 xyoos tiv thaiv kab mob qog noj ntshav [189]. Kev siv cov tshuaj aspirin ntev niaj hnub ua rau txo qis qhov tshwm sim ntawm cov qog nqaij hlav hauv plab, prostate, thiab mob qog noj ntshav [190]. Hauv qee qhov kev tshawb fawb, kev siv tshuaj aspirin ntev li niaj zaus txo qhov kev pheej hmoo ntawm mob qog nqaij hlav hauv plab [191], thaum, hauv lwm cov kev tshawb fawb, qee zaus siv cov tshuaj aspirin tiv thaiv kab mob vascular thiab mob qog noj ntshav [192]. Hauv ib qho ntawm cov kev tshawb fawb zoo tshaj plaws, cov tshuaj aspirin ntawm koob tshuaj ntawm 75 thiab 325 mg / hnub rau 5 xyoos txo qis kev mob qog noj ntshav [192]. Nws me ntsis yuav ua rau mob plab hnyuv [192, 193]. Nws tau kwv yees tias, los ntawm kev tiv thaiv kev mob qog noj ntshav, tshuaj aspirin tuaj yeem cawm tau ntau dua li lub neej ploj vim muaj kev phiv tshwm sim [192. 193] ib.

Statins

Statins, xws li atorvastatin (Lipitor), simvastatin thiab lovastatin, txo cov roj cholesterol hauv cov ntshav thiab yog li txo qis atherosclerosis, tiv thaiv kab mob plawv [194]. Statins muaj txiaj ntsig zoo hauv kev kub siab [195- 197]. Statins tuaj yeem txo qhov tshwm sim ntawm qee cov qog nqaij hlav [198]. Simvastatin nce qhov nruab nrab thiab siab tshaj lub neej ntawm Drosophila [199]. Statins nce lub neej ncua ntawm cov nas progeroid [200]. Txawm li cas los xij, hauv lwm txoj kev tshawb fawb, ib qho statin tsis ua rau lub neej ntev hauv cov nas [36]. Statins ncua lub neej los ntawm 2 xyoos hauv tib neeg kho thaum muaj hnub nyoog 78 txog 85 [194]. Ntawm cov laus heev, qhov txuas ntxiv ntawm lub neej yog ywj siab ntawm qib roj cholesterol [201].

Qhov tsim nyog, statins tuaj yeem tiv thaiv rapamycin-induced dyslipidemia [202]. Qhov zoo siab dyslipidemia no yog tshwm sim los ntawm lipolysis thiab inhibition ntawm lipoproteins uptake los ntawm cov ntaub so ntswg (saib daim duab 2 hauv [94]). Dyslipidemia yog thim rov qab los ntawm nws tus kheej [64]. Txawm li cas los xij, nws yooj yim dua los ua ke rapamycin thiab statins dua los ua pov thawj tias dyslipidemia tsis muaj teeb meem kiag li. Statins tuaj yeem "txo qhov kev ntshai" ntawm rapamycin-induced "side effect". Statins muaj cov kev mob tshwm sim, uas yog, qee zaum, txaus ntshai. Statins, uas yog cov tshuaj kws kho mob, muaj nyob rau hauv cov khw muag khoom noj yam tsis muaj tshuaj raws li cov khoom ntuj tsim. Lovastatin yog ib qho khoom siv ntuj tsim muaj nyob hauv cov nceb oyster thiab cov poov xab liab, cov khoom noj ntxiv. Cov poov xab liab feem ntau ua ke nrog berberine thiab policosanol, cov khoom noj khoom haus ntuj.

Beta-blockers

Beta-blockers tau dav siv los kho mob ntshav siab thiab kab mob plawv. Propranolol, uas tsis yog xaiv beta-adrenergic blocker, tiv thaiv mob qog noj ntshav [203-206] thiab

Daim duab 1: Schema ntawm kev laus thiab nws cov tshuaj tua kab mob. Kev laus yog qhov nce ntawm qhov tshwm sim ntawm kev tuag. Kev laus yog qhov txuas ntxiv ntawm kev loj hlob, thaum txoj kev loj hlob raug nres tab sis cov kev taw qhia (xws li mTOR) tseem ua haujlwm. Cov kab mob cellular overactivation nce cellular zog (secretion, synthesis, metabolism, contraction, aggregation, lipid tsub zuj zuj thiab lwm yam), ua rau lub cev hyperfuntions xws li kub siab thiab lwm yam kab mob ntawm kev laus. Hyperfunction, tshwm sim raws li cov kab mob muaj hnub nyoog, ua rau lub cev puas tsuaj thiab tsis ua haujlwm. Kev laus muaj los ntawm subclinical hyperfunction, kab mob thiab tsis ua haujlwm / lub cev tsis ua haujlwm. Cov tshuaj tiv thaiv kev laus inhibit qhov kev taw qhia txoj hauv kev, txo qis kev ua haujlwm siab, qeeb kev laus thiab ncua cov kab mob thiab kev tuag. Cov tshuaj tseem ceeb tshaj plaws yog pom hauv cov ntawv loj dua.

hepatic steatosis [207]. Propranolol yog siv tawm ntawm daim ntawv lo kom txo kev ntxhov siab. Metoprolol thiab nebivolol nce qhov nruab nrab thiab nruab nrab lub neej ncua ntawm txiv neej nas, los ntawm 10 feem pua ​​​​thiab 6.4 feem pua ​​​​thiab txuas ntxiv Drosophila lub neej [208].

PDE5 inhibitors kev loj hlob thiab metastasis hauv nas [223, 224]. Qhov tseem ceeb, doxycycline yog ib feem ntawm cov tshuaj tiv thaiv metastatic ua ke, uas suav nrog doxycyclin, aspirin, lisin thiab mifepristone [225].

Melatonin

Phosphodiesterase 5 (PDE5) degrades cGMP. PDE5 inhibitors, suav nrog sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), thiab avanafil (Stendra), yog dav paub txog kev kho mob erectile kawg (ED). Thaum kev sib deev stimulation ua rau cGMP synthesis, PDE5 inhibitors ua rau nws tsub zuj zuj, relaxing corpus cavernosum thiab penile hlab ntsha. Tsis tas li ntawd, cGMP relaxes lub suab ntawm prostate leeg hlwb thiab txo qis prostate o. Tadalafil yog qhov ua tau zoo thiab zam kev kho mob rau benign prostate hyperplasia (BPH) [209]. PDE5 inhibitors, xws li tadalafil ua haujlwm ntev, tuaj yeem ntxiv rau cov tshuaj tiv thaiv kev laus vim tias ED thiab BPH yog qhov muaj feem cuam tshuam txog hnub nyoog ntawm cov txiv neej laus. Tsis tas li, muaj qhov laj thawj tseem ceeb los txiav txim siab PDE5 inhibitors ua cov tshuaj tiv thaiv kev laus (hauv txiv neej thiab poj niam). Lo lus tseem ceeb yog "so". Senescent hlwb yog nruj thiab ntxhov siab. Cellular senescence yog tshwm sim los ntawm hyper-function. Nyob rau hauv lub cev theem hyper-function yog txhais nyob rau hauv kub siab, hyperplasia, hyperlipidemia thiab hais txog. Los ntawm 'txo qhov nro', PDE5 inhibitors tuaj yeem ua rau qeeb senescent-sociated pathology. PFE5 inhibitors ua rau muaj kev tiv thaiv vasoconstriction, tiv thaiv proliferative thiab anti-inflammatory teebmeem. Tsis yog ib qho xwm txheej, PDE5 inhibitors twb tau pom zoo los yog tshawb xyuas rau kev kho mob ntawm cov hnub nyoog sib txawv thiab cov xwm txheej. Sildenafil thiab tadalafil tau pom zoo rau pulmonary arterial hypertension [210]. PDE5 inhibitors tab tom tshawb nrhiav rau lub plawv hypertrophy, myocardial infarction, mob qog noj ntshav, kab mob neurodegenerative, cystic fibrosis, ntshav qab zib, rog rog thiab metabolic syndrome [210-213]. Inhibition ntawm PDE5 nce qib ntawm cGMP thiab hydrogen sulfate. Cov kev taw qhia cov molecules nce lub neej ncua hauv C elegans [214, 215].

PDE5 inhibitors muaj kev nyab xeeb zoo heev rau kev siv txhua hnub rau lub sijhawm ntev. Hauv feem ntau cov kev tshawb fawb, 5 mg tadalafil ib hnub ib zaug muaj kev phiv tsawg thiab txhim kho BPH thiab ED [216]. Tsis tas li ntawd, txawm tias 40 mg ntawm tadalafil yog siv rau hauv kev kho mob pulmonary arterial hypertension tsis muaj kev phiv loj [217]. PDE5 inhibition txhim kho beta-cell muaj nuj nqi hauv metabolic syndrome [218, 219]. Qhov no tuaj yeem txo cov kev mob tshwm sim ntawm Rapamycin ntawm beta-cells.

Doxocycline, broad-spectrum tshuaj tua kab mob ntawm cov chav kawm tetracycline, txuas lub neej ntev hauv C elegans [220] thiab Drosophila [221, 222]. Doxycycline suppresses qog

Melatonin, ib yam tshuaj hormones, uas yog muag raws li cov tshuaj uas tsis yog tshuaj tsaug zog, ua rau kom lub neej ntev thiab txo qhov mob qog noj ntshav hauv cov tsiaj hauv qee qhov kev tshawb fawb [226]-229]. Txawm li cas los xij, lwm cov kev tshawb fawb tsis tau lees paub.

Kev sim gerosuppressants

Zoo li rapalogs, pan-mTOR inhibitors suppress geroconversion [107-109, 110, 230]. Lawv txwv geroconversion ntawm cov concentrations qis dua li cov tshuaj tiv thaiv kab mob [230]. Cov koob tshuaj tsawg ntawm pan-mTOR inhibitors tseem tsis tau sim hauv cov nas kom txiav txim siab txog kev ua neej ntev. Txij li cov tshuaj no tseem tsis tau pom zoo rau tib neeg siv, peb yuav tsis tham txog lawv ntawm no. MDM-2 inhibitors [96, 231] MEK inhibitors [232] thiab S6K inhibitors [233] kuj tseem cuam tshuam geroconversion hauv cell hom tshwj xeeb. Gerosuppression thiab qog-suppression yog ob sab ntawm ib lub npib, yog li tsis xav tsis thoob, lawv tau npaj los ua tshuaj tiv thaiv kab mob [234-236]. Ntawm cov koob tshuaj tiv thaiv kab mob, gerosuppressants inhibit cell proliferation. Yog li, koob tshuaj tiv thaiv kev laus yuav tsum qis dua li cov tshuaj tiv thaiv kab mob qog noj ntshav. Xwb, gerosuppressants yuav tsum tau siv tsis tu ncua: cov tshuaj kho mob siab ua raws li lub sijhawm kho tsis pub dawb.

Polypill

Polypill yog ib qho kev sib xyaw ua ke ntawm cov tshuaj tiv thaiv kab mob (aspirin), tshuaj tiv thaiv ntshav siab (lisinopril thiab beta-blocker), thiab statin [237-239]. Polypill kuj tseem tuaj yeem suav nrog cov tshuaj tiv thaiv ntshav siab ntxiv [240] nrog rau folic acid [237]. Polypill tau qhia txog kev ua neej ntev hauv cov neeg laus uas muaj kev pheej hmoo siab [241, 242]. Nws tau suav tias polypill tuaj yeem txo cov mob stroke thiab ischemic plawv mob los ntawm ntau dua 80 feem pua ​​​​ntawm cov tib neeg uas muaj kev pheej hmoo rau cov kab mob plawv [242]. Polypill tuaj yeem tiv thaiv kab mob plawv thiab mob stroke [243, 244]. Polypill suav nrog 4 cov tshuaj tiv thaiv kev laus (statin, aspirin, beta-blocker, angiotensin II inhibitor xws li lisinopril). Txawm li cas los xij, qhov kev sib xyaw ua ke no tau tsim los tiv thaiv kab mob plawv, tsis ua rau kev laus qeeb. Yog li, Polypill tsis suav nrog ob lub ntsiab tiv thaiv kev laus: rapalog thiab metformin. Txawm li cas los xij, Polypill yog siv rau hauv 'kev noj qab haus huv' cov neeg laus txhawm rau txhawm rau txuas lub neej ntev los ntawm kev tiv thaiv kab mob. Nws yuav tsum tau ua ke nrog rapamycin thiab metformin, txhawm rau ua kom lub neej ntev ntev.

Anti-aging ua ke

Rapamycin (los yog lwm yam rapalog) yuav tsum yog lub hauv paus ntawmanti-agingua ke (Daim duab 1), muab nws universalanti-agingnyhuv thiab muaj peev xwm ncua yuav luag tag nrho cov kab mob ntawm kev laus.

Rapamycin thiab metformin: Ob qho tshuaj txuas ntxiv txoj sia nyob hauv cov tsiaj thiab tsis muaj kev cuam tshuam sib tshooj. Tsis tas li ntawd, lawv tuaj yeem, nyob rau hauv txoj kev xav, tshem tawm cov kev cuam tshuam metabolic ntawm ib leeg. Raws li peb tau tham ntawm no (saib ntu rapamycin) nrog rau hauv [31, 130], rapamycin nyob rau hauv ntau qhov chaw tuaj yeem nce lossis txo cov tshuaj insulin. Ib yam li ntawd, txwv tsis pub calorie ntau ntxiv rau insulin rhiab heev, qhov txwv tsis pub calorie hnyav (kev tshaib plab) txo nws [129, 245]. Txawm li cas los xij, rapamycin ncua lub neej ntev, qhia tias insulin tsis kam yog qhov zoo [130]. Hmoov tsis zoo, qhov kev ntshai ntawm qhov zoo siab 'kev mob tshwm sim' yog ncua kev siv rapamycin rau kev tiv thaiv kab mob uas muaj hnub nyoog. Txoj hauv kev yooj yim tshaj plaws yog saib xyuas cov piam thaj hauv cov tib neeg noj rapamycin. Tsis tas li ntawd, metformin, tshuaj tiv thaiv kab mob ntshav qab zib mellitus, tuaj yeem ua ke nrog rapamycin.

Thiab lwm nqe lus, metformin tuaj yeem ua rau cov ntshav lactate nce ntxiv. Rapamycin txo qis lactate ntau lawm [164]. Txhua cov tshuaj prolongs lifespan nyob rau hauv nas, tiv thaiv mob qog noj ntshav, atherosclerosis, thiab lwm yam kab mob ntawm kev laus.

Rapamycin thiab statins: Rapamycin txhawb nqa lipolysis nce ntshav cov roj ntsha. Qhov no, nyob rau hauv lem, nce qib ntawm lipoproteins uas tsim los ntawm lub siab. Rapamycin-induced hyperlipidemia yog qhov ua tau zoo thiab thim rov qab. Tseem, statins twb tau siv los tiv thaiv rapamycin-induced hyperlipidemia [202, 246, 247]

Rapamycin thiab kev tawm dag zog lub cev: Ib yam li ntawd, kev tawm dag zog lub cev yuav muaj txiaj ntsig los tiv thaiv rapamycin-induced hyperlipidemia vim tias cov roj ntsha siv los ntawm cov leeg thaum lub cev qoj ib ce.

Rapamycin thiab kev noj zaub mov tsawg-calorie lossis kev yoo mov tsis sib xws:

ib. Thaum lub sij hawm yoo mov, cov kab mob nyob ntawm lipolysis thiab ketogenesis. Rapamycin txhawb cov txheej txheem no. Fatty acids thiab ketone lub cev yuav siv los ntawm cov leeg thiab lub hlwb, raws li.

b. Kev yoo mov yuav txo cov piam thaj, uas tuaj yeem txo qhov ua tau rapamycin-induced hyperglycemia.

Cov teebmeem ntawm rapamycin thiab kev txwv calorie tsis zoo ib yam thiab tej zaum yuav yog additive [248, 249]. Kev txwv calories thiab kev yoo mov tsis tu ncua ncua lub neej ntev. Kev noj zaub mov tsis muaj calorie tuaj yeem ntxiv nrog cov vitamins (poly-vitamins ntxiv, B3, B12 thiab D3), cov zaub mov thiab txawm tias tseem ceeb amino thiab fatty acids, yog tias xav tau, kom tsis txhob muaj khoom noj khoom haus.

Nws yog feem ntau pom zoo tias qee yam khoom noj muaj txiaj ntsig vim tias nws yog nplua nuj nyob rau hauv qee cov khoom xyaw 'pab': tshuaj tiv thaiv oxidants, vitamins, minerals, fatty acids tseem ceeb. Txawm li cas los xij, zaub mov kuj muaj calorie ntau ntau. Siv cov tshuaj ntxiv, tsis tas yuav noj zaub mov vim nws "nplua nuj nyob rau hauv ib yam dab tsi" (vitamin C, D los yog promega-3). Kev noj zaub mov rau txhua yam tseem ceeb yuav coj calories nrog rau cov khoom tseem ceeb. Cov zaub mov nplua nuj nyob hauv cov vitamins tuaj yeem hloov nrog cov vitamins ib leeg.

Rapamycin thiab PDE5 inhibitors Cialis tau pom zoo rau kev kho BPH thiab rapamycin kho BPH hauv kev tshawb fawb ua ntej. Rapamycin tuaj yeem txo qis beta-cell muaj nuj nqi, qhov PDE5 inhibitors tuaj yeem nce nws.

Rapamycin-based sib tov:

A. Rapamycin ntxiv rau metformin (tshwj xeeb tshaj yog nyob rau hauv cov neeg mob insulin-resistant thiab rog, metformin yog qhia).

B. Rapamycin ntxiv rau Lisinopril (los yog lwm yam angiotensin II-inhibitor) ntxiv rau propranolol. Zoo li hauv Polypill, cov tshuaj no yuav siv tau ntawm ½ koob tshuaj rau cov tib neeg uas tsis muaj zog. Cov neeg mob ntshav siab yuav tsum tau txhaj tshuaj tas li.

C. Rapamycin plus Statin (xws li lovastatin, simvastatin thiab atorvastatin)

D. Rapamycin plus Statin plus metformin. Qhov kev sib xyaw ua ke no nrog rapamycin tuaj yeem yog qhov txaus nyiam tshaj plaws rau cov neeg uas muaj kev hloov pauv hauv metabolic: hyperlipidemia, rog rog, insulin tsis kam.

E. Rapamycin plus polypill zoo li ua ke (Lisinopril, propranolol, aspirin, statin). Qhov no yog tshwj xeeb tshaj yog txaus nyiam rau cov neeg uas muaj atherosclerosis muab rapamycin tiv thaiv atherosclerosis ib yam nkaus.

F. Rapamycin ntxiv rau Lisinopril (los yog lwm yam Angiotensin II-inhibitor) ntxiv rau propranolol ntxiv rau aspirin ntxiv rau statin ntxiv rau metformin ntxiv rau PDE5inhibitor. Qhov no yog kev sib xyaw ua ke ntawm 7- yeeb tshuaj.

Cov koob tshuaj thiab cov sijhawm teem tseg

Hauv 7-cov tshuaj tiv thaiv kev laus ua ke, rapamycin, metformin, lisinopril (lossis nws qhov sib npaug), statin, PDE5 inhibitor thiab propranolol yog cov tshuaj noj (hauv Tebchaws Meskas). Yog li kuv yuav tsis tham txog koob tshuaj thiab sijhawm teem sijhawm ntawm no. Lawv yuav tsum tau txiav txim siab rau txhua tus ntawm tus kheej. Polypill muaj pes tsawg leeg muab cov lus qhia ntawm koob tshuaj 4 tshuaj hauv cov tib neeg noj qab haus huv. Cov koob tshuaj ntawm rapamycin yog dhau ntawm cov kab lus no. Kev sib xyaw ntawm cov tshuaj tiv thaiv kev laus yuav tsum tau ua ntxiv nrog kev tawm dag zog lub cev thiab kev noj zaub mov tsawg lossis kev noj zaub mov tsis sib haum. Cov tshuaj ntxiv xws li melatonin yuav raug txiav txim siab. 7-Cov tshuaj sib xyaw ua ke tuaj yeem kuaj tau hauv cov nas, tshwj xeeb tshaj yog nyob rau hauv cov nas noj zaub mov muaj roj ntau thiab hauv cov nas uas mob qog noj ntshav. Yog tias pib lig hauv lub neej, qhov kev sim yuav siv sijhawm li ob peb lub hlis los ntsuas cov txiaj ntsig ntawm lub neej thiab kev mob qog noj ntshav nrog rau qhov hnyav, ntshav siab, piam thaj, insulin, triglycerides thiab leptin. Hauv tib neeg, txoj kev kho mob tuaj yeem pib tsis hais txog kev tshawb fawb ua ntej, vim tias tag nrho 7 cov tshuaj tau pom zoo rau tib neeg siv thiab qee yam xws li tshuaj aspirin thiab statin tau siv dav rau kev tiv thaiv kab mob ib yam nkaus. Qhov tsuas yog qhov xav tau yog saib xyuas cov kev mob tshwm sim. Tshwj xeeb, lub plawv dhia, ntshav siab thiab qib qabzib yuav tsum tau saib xyuas.

Los ntawm yav dhau los mus rau yav tom ntej

Raws li tau hais hauv xyoo 2006, "… rapamycin, twb tau pom zoo rau kev siv tshuaj kho mob, muaj thiab siv tau tam sim ntawd ... txhawm rau txo qis qis thiab tiv thaiv kab mob."[1]. Nws tau pom tias nyob rau hauv cov sij hawm tsis sib xws, rapamycin yuav ua tau zoo, tab sis tsis muaj kev phiv. Pulse-kev kho mob tau pom zoo los txhim kho qhov txhab zoo thiab rov ua kom cov qia hlwb thiab tiv thaiv kab mob [1, 27]. Tom qab 10 xyoo, qhov kev pom zoo no tseem tsis hloov pauv. Kev siv tshuaj tiv thaiv kev laus kom muaj sia nyob ntev dua thiab ncua kev muaj hnub nyoog cov kab mob tau sib tham kom ntxaws [94, 250, 251].

Tam sim no, lub sijhawm yog rau cov tshuaj tiv thaiv kev laus, uas ua ke ib ncig ntawm 7 tshuaj nrog kev noj haus thiab kev tawm dag zog lub cev. Cov tshuaj tiv thaiv kev laus yog npaj rau tib neeg siv. Yog hais tias ib tug yuav tos kom txog thaum lub neej-extending nyhuv yuav tshwm sim nyob rau hauv lwm tus neeg, tus neeg no yuav tsis ciaj sia los ntawm lub sij hawm ntawm qhov tshwm sim. Tib neeg kev sim tshuaj yuav tsum tau ua kom zoo dua cov koob tshuaj thiab cov sijhawm teem sijhawm. Txawm li cas los xij, tshwj tsis yog peb koom nrog kev sim tshuaj peb tus kheej, peb yuav tsis paub tias cov neeg koom yuav nyob ntev npaum li cas vim lawv xav tias yuav muaj sia nyob tsis muaj neeg koom nrog. Yog tias peb xav nyob ntev peb yuav tsum koom nrog hauv kev sim tshuaj. Hauv qhov xwm txheej zoo tshaj plaws, qhov no yuav ua rau peb nyob ntev txaus kom tau txais txiaj ntsig los ntawm kev tshawb pom yav tom ntej ntawm cov tshuaj tiv thaiv kev laus. Kev sim tshuaj tiv thaiv kev laus xws li pan-mTOR inhibitors tej zaum yuav raug pom zoo rau cov qauv tshuaj tiv thaiv kev laus yav tom ntej. Thaum kawg, yog tias mTOR-driven aging yuav raug tshem tawm, cov tshuaj tiv thaiv oxidants yuav pab tau rau kev kho mob tom qab kev laus [245]. Thiab step-by-step, tib neeg yuav ncua lub neej ncua.

Kev tsis sib haum xeeb ntawm kev txaus siab

Tus sau tsis muaj qhov cuam tshuam txog kev txaus siab los nthuav tawm.