閱讀重磅綜述，快捷get衰老系統(tǒng)知識(shí)。大家好，這里是時(shí)光派《重磅綜述》欄目，在這里，派派為你挑選大咖中的大咖，選讀經(jīng)典中的經(jīng)典。本期的主題是，國內(nèi)學(xué)者重磅之作，衰老重要標(biāo)識(shí)表觀遺傳衰老相關(guān)綜述——《衰老的表觀遺傳調(diào)控：對衰老和疾病干預(yù)的啟示》。

衰老生物學(xué)發(fā)展近百年，衰老相關(guān)的九大標(biāo)識(shí)早已深入人心，每一個(gè)都在衰老過程中發(fā)揮著無可替代的作用，但每一個(gè)衰老表現(xiàn)、每一種干預(yù)手段，大多針對多種衰老標(biāo)識(shí)聯(lián)合作用，在和其他衰老標(biāo)識(shí)“合作”方面，表觀遺傳衰老尤為明顯。

11月初，我國著名學(xué)者劉光慧教授、朱芳芳教授、任捷教授牽頭，中國科學(xué)院和上海交通大學(xué)生物醫(yī)學(xué)研究院多名學(xué)者聯(lián)合編撰，在生物學(xué)頂刊《Nature》子刊上發(fā)文，綜述了表觀遺傳調(diào)控在衰老生物學(xué)中的堅(jiān)實(shí)理論基礎(chǔ)地位和多方向靶點(diǎn)庫作用，并就表觀遺傳的角度，為大家提供了各方面衰老干預(yù)的建議[1]。

限于篇幅，文中僅展示綜述核心內(nèi)容，想深入了解的讀者可至文末領(lǐng)取原文及全文翻譯文檔。

*該資料僅供科研學(xué)習(xí)之用，未經(jīng)授權(quán)嚴(yán)禁轉(zhuǎn)載及使用。

*如有科學(xué)謬誤敬請專家與讀者朋友聯(lián)系時(shí)光派公眾號指正。

表觀遺傳學(xué)如同它名字所表達(dá)的那樣，把“表觀”和“遺傳”聯(lián)系起來研究，代表一種在不改變基因組DNA序列的情況下調(diào)節(jié)基因組功能的可逆機(jī)制[1]。而在原因機(jī)制尚未完全被破解的衰老生物學(xué)中，這一特性尤為突顯。

1935年，衰老生物學(xué)正式起航；1953年，DNA結(jié)構(gòu)被發(fā)現(xiàn)；14年后的1967年，表觀遺傳便正式入駐衰老生物學(xué)領(lǐng)域[2]，從此開始和衰老生物學(xué)攜手并進(jìn)。

圖注：衰老相關(guān)表觀遺傳學(xué)的部分發(fā)展歷程

表觀遺傳在衰老過程中的改變主要可以分為四大類：DNA甲基化、組蛋白修飾、染色質(zhì)重塑和RNA修飾。

No.1

DNA甲基化

當(dāng)一段基因的DNA上被安裝了甲基，那么這段基因就不會(huì)表達(dá)[3-4]，而衰老的重要表現(xiàn)就是，該沉默的基因沒有安裝甲基，而該表達(dá)的基因卻被甲基扼制[5-6]。

圖注：DNA甲基化模式及其與衰老的關(guān)系

No.2

組蛋白修飾

組蛋白修飾可以細(xì)分為：甲基化、乙?；⒘姿峄?、泛素化、ADP核糖基化等[7]。其中最常見，且作為經(jīng)典案例廣為流傳的是：組蛋白乙?；L壽蛋白sirtuins[8-9]。

圖注：組蛋白乙酰化的經(jīng)典案例：長壽蛋白sirtuins

No.3

染色質(zhì)重塑

染色質(zhì)重塑是細(xì)胞核內(nèi)的一系列全基因組變化，從組蛋白成分和修飾的變化到染色質(zhì)整體結(jié)構(gòu)的改變，在細(xì)胞衰老過程中，染色質(zhì)重塑也發(fā)揮著重要的作用[10]。

No.4

RNA修飾

DNA轉(zhuǎn)錄成RNA，而RNA翻譯成蛋白質(zhì)，RNA承擔(dān)著基因和表型之間的紐帶的作用，所以表觀遺傳不僅包括對DNA及其結(jié)合蛋白（組蛋白）的修飾，也包含對RNA的修飾[11]。

因篇幅有限，表觀遺傳調(diào)控的原理這里不加贅述，感興趣的讀者請至文末，添加hebe即可領(lǐng)取全文翻譯。

表觀遺傳衰老為衰老生物學(xué)奠定了堅(jiān)實(shí)的理論基礎(chǔ)，同時(shí)在各種抗衰手段中，也少不了表觀遺傳調(diào)控的身影。

在這一部分，論文總結(jié)了目前主要使用的抗衰干預(yù)手段：小分子藥物、重編程、衰老細(xì)胞清除策略和健康行為干預(yù)手段，并討論了它們和表觀遺傳調(diào)控之間的相互作用。

圖注：目前常見的抗衰干預(yù)手段

No.1

小分子藥物

小分子藥物雖然靶靶點(diǎn)相對單一，但是影響的衰老途徑卻不止一條，在干預(yù)衰老和治療衰老相關(guān)疾病方面也極具潛力。

NAD+前體

大家耳熟能詳?shù)目顾パa(bǔ)劑成分NMN、NR等都是NAD+前體，在這些NAD+前體的影響下，隨年齡增加而逐漸減少的體內(nèi)NAD+可以得到補(bǔ)充，繼而通過DNA修復(fù)和表觀遺傳調(diào)控發(fā)揮增加線粒體功能、改善認(rèn)知功能等功效[12-13]，并延長線蟲、果蠅等模式生物的壽命[14]。

與表觀遺傳的相互影響

長壽蛋白sirtuins對組蛋白去乙?；挠绊懜叨纫蕾囉贜AD+，因此，NAD+在衰老表觀遺傳調(diào)控中是不可或缺的[15]。

臨床試驗(yàn)進(jìn)展

臨床試驗(yàn)結(jié)果才是抗衰相關(guān)研究的金標(biāo)準(zhǔn)，而NAD+前體已經(jīng)在臨床試驗(yàn)中證實(shí)了自己。

NMN可增加糖尿病前期女性的肌肉胰島素敏感性、胰島素信號傳導(dǎo)和肌肉重塑，并可預(yù)防與衰老相關(guān)的肌肉功能障礙，以及改善有氧能力、心血管健康、睡眠質(zhì)量、疲勞和身體機(jī)能等[16-18]；NR可抑制心力衰竭患者和降低帕金森病患者的炎性衰老情況[19]。

STACS

STACS是長壽蛋白sirtuins的激活劑[20]，目前的STACS藥物主要有白藜蘆醇、SRT1720等，能通過對sirtuins的激活發(fā)揮增加胰島素敏感性和運(yùn)動(dòng)功能、減輕血管內(nèi)皮功能障礙等功能，并延長線蟲、果蠅、蜜蜂和魚類等的壽命[21]。

與表觀遺傳的相互影響

直接激活sirtuins，改變組蛋白的去乙?；健?/p>

臨床試驗(yàn)進(jìn)展

STACS在臨床前研究中表現(xiàn)出鼓舞人心的效果，但在臨床試驗(yàn)中的結(jié)果并不那么令人滿意，沒有顯著的抗衰臨床反應(yīng)[22]。

二甲雙胍

二甲雙胍是著名的降糖藥，也是近些年熱門的抗衰潛力物質(zhì)，能通過廣泛的表觀遺傳調(diào)控發(fā)揮作用，能改善認(rèn)知障礙和神經(jīng)變性[23]、慢性腎病[24]、白內(nèi)障[25]、心臟線粒體功能障礙[26]等多種衰老相關(guān)疾病，并可延長小鼠壽命14%[27]。

與表觀遺傳的相互影響

二甲雙胍可以通過改變S-腺苷甲硫氨酸（SAMe）/S-腺苷同型半胱氨酸（SAH）的比例來影響組蛋白甲基化[28]；增加Bdnf基因的DNA甲基化水平[29]；還可以調(diào)整小鼠和人類的microRNA表達(dá)水平[30-31]。

臨床試驗(yàn)進(jìn)展

臨床數(shù)據(jù)顯示，二甲雙胍可以降低糖尿病、心血管疾病、脆弱和認(rèn)知障礙的發(fā)病率，并改善外周血單核細(xì)胞中潛在的長壽效應(yīng)因子[32]。

雷帕霉素

雷帕霉素是21世紀(jì)以來炙手可熱的抗衰藥物、美國抗衰金字項(xiàng)目ITP計(jì)劃的招牌成果，已被證實(shí)可以改善一系列衰老相關(guān)病理狀況，包括心血管功能障礙[33]、神經(jīng)變性[34]、骨骼肌老化[35]、卵巢衰老[36]、衰老相關(guān)聽力損失[37]等，并能以劑量依賴的方式延長雄性和雌性小鼠的中位和最大壽命[38]。

與表觀遺傳的相互作用

雷帕霉素能減弱大腦結(jié)構(gòu)中與衰老相關(guān)的DNA甲基化變化，影響大腦衰老，還能減緩肝臟衰老的表觀遺傳特征[39]。

臨床試驗(yàn)進(jìn)展

盡管雷帕霉素在臨床前研究中顯示出令人興奮的效果，但在臨床試驗(yàn)中卻不盡人意，雷帕霉素并沒有改善人類受試者的認(rèn)知功能或身體機(jī)能[40]，也就意味著，雷帕霉素仍需要更多的實(shí)驗(yàn)研究。

圖注：各種抗衰小分子藥物的抗衰延壽效果

除了上述幾種，其他多種小分子藥物也都存在巨大的抗衰潛力，如抗糖尿病藥物（鈉-葡萄糖共轉(zhuǎn)運(yùn)蛋白-2抑制劑、阿卡波糖)、天然化合物（沒食子酸、槲皮素）、抗氧化分子（N-乙?；?L-半胱氨酸（NAC）、維生素C 、亞甲藍(lán)）、抗高血壓藥物（血管緊張素轉(zhuǎn)換酶抑制劑和血管緊張素受體阻滯劑），氯喹、阿司匹林、尿苷等等，但它們和表觀遺傳之間的關(guān)系還有待進(jìn)一步研究。

No.2

細(xì)胞重編程策略

細(xì)胞重編程是近兩年最具潛力、研發(fā)經(jīng)費(fèi)最充足的抗衰干預(yù)手段，通過將體細(xì)胞逆轉(zhuǎn)到年輕狀態(tài)來達(dá)到機(jī)體抗衰老的目的。

短短時(shí)間內(nèi)，細(xì)胞重編程也的確取得了驚人的抗衰效果：為期13天的細(xì)胞重編程顯著降低了人成纖維細(xì)胞的表觀遺傳年齡[41]，生命早期的瞬時(shí)重編程也足以將轉(zhuǎn)基因早衰小鼠的壽命延長15%[42]。

與表觀遺傳的相互作用

細(xì)胞重編程關(guān)鍵基因OSKM的持久表達(dá)可導(dǎo)致廣泛的染色質(zhì)重塑，從而逆轉(zhuǎn)細(xì)胞狀態(tài)，使其年輕化[43]。

圖注：染色質(zhì)重塑在衰老過程中的作用機(jī)制

No.3

健康行為干預(yù)

和小分子藥物和細(xì)胞重編程相比，健康行為干預(yù)才是延緩衰老的最有效和最簡單的方法，隨著人們對積極健康干預(yù)的認(rèn)識(shí)不斷提高，各種研究表明，健康的生活方式可以改善不同動(dòng)物和人類的衰老相關(guān)特征。

飲食/熱量限制

作為“不打針不吃藥”的抗衰干預(yù)方法典范，飲食/熱量限制早在上個(gè)世紀(jì)衰老生物學(xué)伊始的時(shí)候便取得了世人的青睞。經(jīng)過近一百年的錘煉，飲食/熱量限制已被證明能減緩生物衰老，改善肝臟功能，減少氧化應(yīng)激和衰老相關(guān)疾病的發(fā)病率[44]，并延長實(shí)驗(yàn)動(dòng)物的壽命[45]。

與表觀遺傳的相互作用

熱量限制能顯著抑制RNAm6A閱讀蛋白的衰老相關(guān)下調(diào)[46]，且在相關(guān)實(shí)驗(yàn)中，受試動(dòng)物也能表現(xiàn)出表觀遺傳年齡的降低。

臨床試驗(yàn)進(jìn)展

飲食/熱量限制早已被應(yīng)用在人類身上，臨床試驗(yàn)結(jié)果表明，熱量限制可以減弱與衰老有關(guān)的生物標(biāo)志物，如降低體重、增強(qiáng)胰島素敏感性和葡萄糖耐受性，并改善主要的心臟代謝危險(xiǎn)因素[47]；同時(shí)，飲食干預(yù)已被證明可以減緩基于DNA甲基化的衰老生物標(biāo)志物[48]。

運(yùn)動(dòng)

運(yùn)動(dòng)則是行為干預(yù)中的另一大“巨頭”，雖然簡單易行，但抗衰效果多多。通過運(yùn)動(dòng)，生物體能恢復(fù)活力[49]、并有益于保護(hù)神經(jīng)[50]和延長壽命[51]。

與表觀遺傳的相互作用

運(yùn)動(dòng)可重塑骨骼肌中關(guān)鍵基因啟動(dòng)子上的DNA甲基化情況[52]，還可通過通過抑制組蛋白去乙?；瘺]的功能來影響基因表達(dá)模式[53]，此外，運(yùn)動(dòng)還可以調(diào)節(jié)幾種有益miRNA的表達(dá)[54]。

臨床試驗(yàn)進(jìn)展

運(yùn)動(dòng)相關(guān)的臨床干預(yù)研究中發(fā)現(xiàn)，運(yùn)動(dòng)可以逆轉(zhuǎn)一系列與衰老有關(guān)的疾病，包括心力衰竭[55]、認(rèn)知能力下降[56]、動(dòng)脈粥樣硬化[57]和胰島素抵抗[58]等，并在改善的過程中與表觀遺傳調(diào)控密切相關(guān)[59]。

圖注：飲食限制和運(yùn)動(dòng)等行為干預(yù)手段在抗衰中的作用

除飲食限制和運(yùn)動(dòng)外，健康行為干預(yù)中，晝夜節(jié)律的調(diào)整也能廣泛影響生物的衰老進(jìn)程和速度，但是它和表觀遺傳調(diào)控之間的相互作用尚不明確，還需要更多的研究來發(fā)現(xiàn)和證實(shí)。

除了小分子藥物、細(xì)胞重編程和健康行為干預(yù)，衰老細(xì)胞清除策略（senolytics）也是抗衰干預(yù)手段中十分重要的一種，能達(dá)到非常顯著的抗衰延壽功效，但其和表觀遺傳調(diào)控的關(guān)系相對較弱，仍需要進(jìn)一步研究。

———///———

與其說是重要的衰老標(biāo)識(shí)之一，表觀遺傳衰老更像是一根貫穿衰老的線，在這根線上，不僅掛滿了衰老的原理、機(jī)制和作用靶點(diǎn)，也連接了很多抗衰老干預(yù)手段。

但是其他衰老標(biāo)識(shí)是不是也會(huì)像表觀遺傳衰老一樣，成為串起衰老的一根根線呢？表觀遺傳衰老這根線和其他衰老標(biāo)識(shí)之間，又存在哪些連結(jié)和串?dāng)_呢？這些都還需要未來的研究來探索，當(dāng)我們理清了衰老這張“網(wǎng)”，或許那時(shí)破解衰老便指日可待。

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