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聯(lián)合國(guó)（UN）曾預(yù)測(cè)，到2050年，全球超過(guò)65歲的人口將占總?cè)藬?shù)的六分之一，老齡化已然成為無(wú)法避免的趨勢(shì)。然而，隨醫(yī)療技術(shù)的進(jìn)步，我們的平均壽命雖然得到顯著增加，但“健康壽命”并沒(méi)有跟上延壽的步伐，衰老及其伴隨的眾多慢性疾病仍是目前難以解決的人體負(fù)擔(dān)和醫(yī)療挑戰(zhàn)。 如何減緩衰老進(jìn)程、促進(jìn)“健康老齡化”（將機(jī)體健康功能維持到老年）成為了亟待解決的社會(huì)難題。  近日，《中國(guó)科學(xué)：生命科學(xué)》英文版（SCIENCE CHINA Life Sciences）在線發(fā)表了由中國(guó)科學(xué)院動(dòng)物研究所劉光慧和北京大學(xué)韓敬東統(tǒng)籌，中國(guó)科學(xué)院動(dòng)物研究所宋默識(shí)、杭州師范大學(xué)劉俊平、武漢大學(xué)劉勇、四川大學(xué)肖智雄、南昌大學(xué)田小利、上海生物化學(xué)與細(xì)胞生物學(xué)研究所鄒衛(wèi)國(guó)、中國(guó)科學(xué)技術(shù)大學(xué)劉強(qiáng)、中國(guó)科學(xué)院昆明動(dòng)物研究所孔慶鵬、同濟(jì)大學(xué)毛志勇、中國(guó)科學(xué)院上海營(yíng)養(yǎng)與健康研究所孫宇、上海交通大學(xué)醫(yī)學(xué)院葉靜、廣州國(guó)際生物島實(shí)驗(yàn)室胡蘋(píng)、清華大學(xué)王戈林、中國(guó)科學(xué)院遺傳與發(fā)育生物學(xué)研究所田燁、中國(guó)科學(xué)院上海營(yíng)養(yǎng)與健康研究所肖意傳、清華大學(xué)王建偉、中國(guó)科學(xué)院動(dòng)物研究所曲靜、北京大學(xué)謝正偉、中國(guó)科學(xué)院北京基因組研究所張維綺、中國(guó)科學(xué)院微生物研究所王軍、中國(guó)科學(xué)院上海營(yíng)養(yǎng)與健康研究所張亮、中國(guó)科學(xué)院北京基因組研究所任捷、中國(guó)科學(xué)技術(shù)大學(xué)宋曉元、首都醫(yī)科大學(xué)宣武醫(yī)院王思、北京干細(xì)胞與再生醫(yī)學(xué)研究院馬帥等53位科研人員聯(lián)合撰寫(xiě)的衰老全景綜述——“The landscape of aging”。 該綜述參考了逾千篇衰老領(lǐng)域研究文獻(xiàn)，以超5萬(wàn)字、20張插圖和5張表格的篇幅，從衰老機(jī)制、器官衰老特征和衰老干預(yù)三個(gè)方面系統(tǒng)總結(jié)了衰老領(lǐng)域的經(jīng)典理論和近年來(lái)衰老研究取得的重要進(jìn)展，是目前國(guó)際上最為詳盡的衰老研究綜述之一。  圖：衰老全景圖。這張圖從細(xì)胞(底部)、組織、器官和系統(tǒng)(中間)、機(jī)體(頂部)各個(gè)層面描繪了衰老的全景。以及輔助衰老研究的新技術(shù)(左側(cè))和干預(yù)和恢復(fù)策略(右側(cè)) 綜述發(fā)布后，時(shí)光派第一時(shí)間組織內(nèi)部集體學(xué)習(xí)。為方便廣大讀者、同道一起學(xué)習(xí)進(jìn)步，現(xiàn)將內(nèi)部編譯資料分享如下（共1.9萬(wàn)字，建議收藏）。 此外，為慶祝國(guó)內(nèi)衰老自主研究成果涌現(xiàn)，編輯部奮戰(zhàn)中秋，日夜兼程，對(duì)綜述進(jìn)行了全文翻譯（圖片、表格均已漢化，全文共13萬(wàn)字，260余頁(yè)文檔，遠(yuǎn)超微信推文字?jǐn)?shù)限制），愿無(wú)償分享，領(lǐng)取方式詳見(jiàn)文末。  *時(shí)間倉(cāng)促，難免疏漏，如有科學(xué)謬誤敬請(qǐng)專家與讀者朋友聯(lián)系時(shí)光派公眾號(hào)指正。  一直以來(lái)，細(xì)胞衰老被認(rèn)為是衰老的主要原因，也是聯(lián)系衰老與諸多老齡化疾病之間的橋梁，然而細(xì)胞衰老和衰老的關(guān)系一直未得到明晰，因此，在本節(jié)中，派派將為大家一一揭示細(xì)胞衰老的分子機(jī)制。 No.1 干細(xì)胞衰老 什么是干細(xì)胞衰老 干細(xì)胞作為維持體內(nèi)穩(wěn)態(tài)和可塑性的萬(wàn)能細(xì)胞，可以在體內(nèi)終生存在，然而隨年齡的增長(zhǎng)，干細(xì)胞容易受到核DNA和線粒體DNA損傷、表觀遺傳變化、細(xì)胞周期改變、氧化應(yīng)激和線粒體功能障礙、蛋白質(zhì)穩(wěn)態(tài)破壞、信號(hào)通路改變、外部和系統(tǒng)性變化、自噬和代謝失調(diào)的多方影響，并積累損傷，最終導(dǎo)致衰老或功能衰退，因此干細(xì)胞衰老也被認(rèn)為是機(jī)體衰老的重要表現(xiàn)之一[1,2]。 干細(xì)胞衰老機(jī)制 一方面，人體中每個(gè)干細(xì)胞在其整個(gè)生命周期中，都會(huì)經(jīng)歷數(shù)十萬(wàn)次來(lái)自內(nèi)源性代謝副產(chǎn)物（如ROS和炎癥）和外源性物質(zhì)（如環(huán)境中的輻射和化學(xué)物質(zhì)）的毒性損害，而這些物質(zhì)會(huì)進(jìn)一步破壞DNA結(jié)構(gòu)和功能[3]。另一方面，隨年齡的增長(zhǎng)，干細(xì)胞中DNA修復(fù)能力（如核苷酸切除修復(fù)（NER）在內(nèi)的修復(fù)途徑）逐漸下降，基因組損傷積累會(huì)損害正常干細(xì)胞的功能，破壞組織穩(wěn)態(tài)[4]。 并且，長(zhǎng)壽相關(guān)的SIRT3和SIRT7蛋白也易隨干細(xì)胞衰老而減少，導(dǎo)致核膜蛋白和異染色質(zhì)相關(guān)蛋白的復(fù)合物的形成受損，而脂蛋白顆粒的載脂蛋白(APOE)又在衰老的干細(xì)胞中積累，并作為異染色質(zhì)的去穩(wěn)定劑而發(fā)揮作用，進(jìn)一步驅(qū)動(dòng)細(xì)胞衰老[5]。異染色質(zhì)穩(wěn)定性的變化，也會(huì)改變機(jī)體在表觀遺傳修飾方面的表達(dá)。 在細(xì)胞水平上，干細(xì)胞功能會(huì)因年齡增長(zhǎng)而發(fā)生慢性炎癥而受損，并表現(xiàn)出一系列衰老標(biāo)志物，包括衰老相關(guān)的β-半乳糖苷酶(SA-β-gal)活性升高、Rb-p16和p53-p21通路上調(diào)、持續(xù)性DNA損傷以及生長(zhǎng)因子、蛋白酶和細(xì)胞因子分泌[6]。 在代謝水平上，衰老會(huì)使干細(xì)胞的自噬功能受損，導(dǎo)致蛋白質(zhì)穩(wěn)態(tài)的喪失，從而促進(jìn)線粒體質(zhì)量和活性下降，線粒體的功能障礙反過(guò)來(lái)繼續(xù)誘導(dǎo)干細(xì)胞中發(fā)生蛋白質(zhì)聚集，造成代謝失調(diào)[7]。  圖:導(dǎo)致再生能力受損的干細(xì)胞衰老機(jī)制 No.2 衰老細(xì)胞與SASP 什么是SASP 衰老(senescence)是細(xì)胞的一種歸宿，其特征是生長(zhǎng)潛力的喪失和表型改變，還會(huì)分泌由多種細(xì)胞因子、趨化因子、生物活性脂質(zhì)、損傷相關(guān)分子模式（DAMP，也稱警報(bào)素）共同組成的衰老相關(guān)分泌表型（SASP）。 在局部微環(huán)境中，SASP會(huì)非自主地作用于細(xì)胞，以改變相鄰細(xì)胞的生物學(xué)行為，造成負(fù)面影響[8]。然而，衰老細(xì)胞分泌的特異性SASP因子還可以參與組織修復(fù)、創(chuàng)面愈合和再生過(guò)程，因此在二元論與拮抗多效性進(jìn)化理論中，SASP還可被看做衰老程序中的有益功能[9]。 SASP在衰老細(xì)胞中的調(diào)控機(jī)制 衰老細(xì)胞可以在轉(zhuǎn)錄、mRNA穩(wěn)定性、翻譯和細(xì)胞外分泌等多個(gè)水平上調(diào)節(jié)SASP的表達(dá)[10]。在細(xì)胞質(zhì)和核因子的調(diào)節(jié)過(guò)程中，轉(zhuǎn)錄因子GATA4在衰老細(xì)胞中積累并誘導(dǎo)上調(diào)IL1α和TRAF3IP2（編碼E3的泛素連接酶），而細(xì)胞膜又與促炎蛋白白細(xì)胞介素1α(IL-1α)相結(jié)合，它們共同激活炎癥相關(guān)NF-κB信號(hào)并放大SASP表達(dá)[11]。 此外，衰老細(xì)胞還可以通過(guò)先天免疫感應(yīng)機(jī)制來(lái)觸發(fā)SASP。釋放到細(xì)胞質(zhì)中的大量DNA片段通過(guò)募集平衡免疫反應(yīng)的cGAS酶，通過(guò)cGAS-STING通路招募IRF3進(jìn)行磷酸化[12]。磷酸化的IRF3二聚體進(jìn)入細(xì)胞核，激活NF-κB信號(hào)通路從而產(chǎn)生I型IFNs，并啟動(dòng)其他免疫調(diào)節(jié)基因的轉(zhuǎn)錄，從而促進(jìn)SASP的表達(dá)[13]。  圖：衰老細(xì)胞的分子特征 No.3 線粒體衰老 什么是線粒體 線粒體作為細(xì)胞的“發(fā)電站”，可產(chǎn)生大量的三磷酸腺苷(ATP)應(yīng)用于機(jī)體產(chǎn)能過(guò)程，其還可作為生物能量和生物合成等各種生物事件的信號(hào)樞紐，在大分子的生物合成、細(xì)胞凋亡、先天免疫反應(yīng)和對(duì)壓力的適應(yīng)中發(fā)揮重要作用[14]。 線粒體衰老的機(jī)制 衰老細(xì)胞中的線粒體，往往會(huì)出現(xiàn)生物合成減少、形態(tài)網(wǎng)絡(luò)改變、氧化磷酸化(OXPHOS)活性效率降低、mtDNA突變積累和ROS增加等生物反應(yīng)[15]。并且受到損傷的線粒體又會(huì)通過(guò)改變分解和合成代謝反應(yīng)的速率，從而導(dǎo)致ATP、煙酰胺腺嘌呤二核苷酸(NAD+)、α-酮戊二酸(α-KG)和ROS等代謝物發(fā)生含量變化，誘導(dǎo)細(xì)胞進(jìn)一步衰老[16]。
 圖：線粒體功能和衰老 No.4 代謝和內(nèi)質(zhì)網(wǎng)應(yīng)激（營(yíng)養(yǎng)感知） 營(yíng)養(yǎng)感知途徑誘導(dǎo)衰老 在衰老過(guò)程中，mTOR、AMPK和Sirtuins等營(yíng)養(yǎng)傳感機(jī)制，和胰島素/IGF途徑激素信號(hào)途徑，以及內(nèi)質(zhì)網(wǎng)未折疊蛋白反應(yīng)(UPR)等應(yīng)激反應(yīng)途徑之間，發(fā)生持續(xù)的生理相互作用，多種內(nèi)源性代謝物和分泌蛋白通過(guò)信號(hào)傳導(dǎo)，破壞機(jī)體的代謝穩(wěn)態(tài)，誘導(dǎo)衰老[20]。 誘導(dǎo)衰老的機(jī)制
 圖：衰老和長(zhǎng)壽代謝控制中的營(yíng)養(yǎng)感知和內(nèi)質(zhì)網(wǎng)應(yīng)激反應(yīng) No.5 表觀遺傳學(xué) 什么是表觀遺傳學(xué)定義的衰老 表觀遺傳學(xué)所定義的衰老是“在不改變主要DNA序列的條件下，基因表達(dá)的可遺傳和可逆變化，其中包括DNA甲基化、染色質(zhì)重塑、組蛋白修飾、組蛋白變體和非編碼RNA調(diào)控[26]。 表觀遺傳學(xué)涉及機(jī)制
 圖：衰老表觀基因組示意圖 No.6 端粒 為何可作為衰老標(biāo)識(shí) 在衰老的過(guò)程中，由于細(xì)胞的末端DNA無(wú)法通過(guò)常規(guī)方法進(jìn)行復(fù)制，導(dǎo)致端粒DNA經(jīng)歷一次次的細(xì)胞分裂過(guò)程而逐漸縮短，最終導(dǎo)致復(fù)制性衰老。也正是因?yàn)槎肆Ｒ恢碧幱诓粩嗫s短的動(dòng)態(tài)發(fā)育過(guò)程中，因此它也被認(rèn)為是衰老的驅(qū)動(dòng)力[29]。 端粒和衰老間的作用機(jī)制 不健康的生活方式、壓力、環(huán)境變化和感染等情況的出現(xiàn)，均會(huì)導(dǎo)致端?？s短或結(jié)構(gòu)受損，從而引發(fā)DNA損傷、氧化應(yīng)激、基因表達(dá)改變、基因組不穩(wěn)定性和細(xì)胞衰老等后果，并且當(dāng)含有受損端粒的細(xì)胞在體內(nèi)堆積時(shí)，又易導(dǎo)致激素失衡、炎癥、免疫缺陷、代謝紊亂和加速衰老等問(wèn)題[30]。
 圖：通過(guò)發(fā)育程序衰老的端粒生物學(xué) No.7 基因組穩(wěn)定性 基因組不穩(wěn)定 隨年齡的增加，基因組穩(wěn)定性的保護(hù)機(jī)制逐漸遭到破壞，發(fā)生DNA損傷、反轉(zhuǎn)錄轉(zhuǎn)座子激活、端粒磨損和復(fù)制應(yīng)激等基因組不穩(wěn)定現(xiàn)象，從而加速衰老過(guò)程[37]。 基因組不穩(wěn)定機(jī)制
 圖：基因組穩(wěn)定性和衰老的調(diào)節(jié) 通過(guò)第一章的學(xué)習(xí)，我們已經(jīng)了解到，衰老與機(jī)體細(xì)胞穩(wěn)態(tài)和功能的下降有關(guān)。因此在本章中，文章將進(jìn)一步為我們講述，隨年齡增長(zhǎng)，身體中多個(gè)組織/器官會(huì)發(fā)生怎樣的特異性衰老，并探討它們的衰老機(jī)制和有效干預(yù)措施。 No.1 血管 血管老化 循環(huán)系統(tǒng)可為身體中所有細(xì)胞輸送氧氣和營(yíng)養(yǎng)物質(zhì)，并帶走組織器官中的二氧化碳和廢物，對(duì)于維持內(nèi)環(huán)境穩(wěn)態(tài)至關(guān)重要。但伴隨著年齡的增加，血管也開(kāi)始呈現(xiàn)出形態(tài)、功能和分子標(biāo)記方面的老化現(xiàn)象[41]。 在形態(tài)上，老化血管中的轉(zhuǎn)化細(xì)胞（失去正常細(xì)胞特點(diǎn)）開(kāi)始無(wú)限增殖，血管中彈性蛋白的斷裂和膠原蛋白的沉積，使血管內(nèi)膜層增厚，導(dǎo)致血管腔被擴(kuò)大[37]。在功能上，老化血管的硬度會(huì)增加，收縮壓升高，血管對(duì)內(nèi)外源刺激的反應(yīng)也逐漸下降[42]。在分子標(biāo)識(shí)方面，老化血管上觀察到端粒磨損、其他衰老標(biāo)志物（如p53、p21、p16、ROS）和SASP相關(guān)基因的異常表達(dá)等現(xiàn)象[41]。 干預(yù)措施
圖：血管衰老和干預(yù) No.2 大腦細(xì)胞的特異性老化 大腦的功能在衰老過(guò)程中會(huì)體現(xiàn)出學(xué)習(xí)和記憶力的下降，而腦細(xì)胞，包括神經(jīng)元細(xì)胞和星形膠質(zhì)細(xì)胞等非神經(jīng)元細(xì)胞，也在衰老過(guò)程中表現(xiàn)出各自獨(dú)特的衰老特征[47]。
圖：大腦中不同細(xì)胞類型的衰老特征 No.3 肺部 人體的肺部功能從35歲開(kāi)始逐漸下降，并出現(xiàn)氣體交換受損、粘液纖毛清除力降低和免疫能力下降等肺部功能障礙[51]。其中，肺泡上皮細(xì)胞（尤其是I型肺泡上皮細(xì)胞(AEC1)和II型肺泡上皮細(xì)胞（AEC2）都容易受到與衰老相關(guān)的可持續(xù)性影響，使它們的數(shù)量減少，且間質(zhì)沉積增加。目前已有研究表明，隨年齡的增加，AEC1的增殖與凋亡比率會(huì)隨之變化，并且AEC2的再生、自我更新和分化能力會(huì)逐漸下降[52]。 同時(shí)，協(xié)調(diào)肺部免疫反應(yīng)的肺泡巨噬細(xì)胞(AMs)和間質(zhì)巨噬細(xì)胞(IM)，也隨著年齡的增長(zhǎng)，表現(xiàn)出吞噬和清除能力下降、干擾素(IFN)受到頑固性激活等免疫降低跡象，并且肺部免疫細(xì)胞出現(xiàn)炎細(xì)胞浸潤(rùn)，從而誘導(dǎo)衰老[53]。 當(dāng)然，還有更多的機(jī)制研究表明，端?？s短、DNA損傷應(yīng)答（DDR）、表觀遺傳改變、氧化應(yīng)激反應(yīng)和線粒體功能障礙所引起的干細(xì)胞衰竭，也是導(dǎo)致肺部細(xì)胞衰老的一大誘因[54]。 圖：肺衰老的細(xì)胞表型 No.4 心臟 心臟老化 首先，心臟中占總重一半以上并維持收縮和舒張功能的心肌細(xì)胞，其數(shù)量會(huì)隨年齡的增加而逐漸減少，與此同時(shí)，成纖維細(xì)胞的不斷增殖又導(dǎo)致膠原蛋白沉淀的累積，大大促進(jìn)了心臟纖維化和心臟功能障礙[55]。 此外，心臟衰老還涉及多種分子機(jī)制。其中最核心的原因就是蛋白質(zhì)穩(wěn)態(tài)失衡，隨時(shí)間的增加，錯(cuò)誤折疊蛋白逐漸增多、積累，導(dǎo)致伴侶蛋白、蛋白酶體、核糖體和線粒體蛋白的表達(dá)降低，和氧化應(yīng)激相關(guān)蛋白的上調(diào)[56]。此時(shí)，大量產(chǎn)生的ROS開(kāi)始伺機(jī)而動(dòng)，打破線粒體融合和裂變的平衡，進(jìn)一步破壞線粒體穩(wěn)態(tài)，使心臟線粒體功能障礙和氧化損傷的風(fēng)險(xiǎn)增加[57]。 終生積累的遺傳損傷會(huì)成為心臟衰老的導(dǎo)火索。除端?？s短和端粒功能障礙已被證實(shí)會(huì)影響心臟的正常生理功能外，表觀遺傳改變也被發(fā)現(xiàn)會(huì)破壞心臟的氧化應(yīng)激、血管生成和細(xì)胞代謝相關(guān)的轉(zhuǎn)錄程序，誘發(fā)炎癥，從而促進(jìn)心臟衰老[58]。 干預(yù)措施 目前，靶向線粒體功能障礙的抗氧化肽，已被證明可有效改善高血壓性心肌病，而在動(dòng)物模型中，熱量限制也被發(fā)現(xiàn)對(duì)緩解心臟衰老和改善纖維化程度有顯著療效[59]。此外，還有小分子化合物、靶向抗衰老藥物、干細(xì)胞療法、不同形式的運(yùn)動(dòng)等多種心臟抗衰干預(yù)方法也正被應(yīng)于臨床。 表：https:///中列舉出的與年齡相關(guān)的心臟病的臨床實(shí)驗(yàn)數(shù)據(jù) No.5 骨骼 骨骼衰老 骨骼結(jié)構(gòu)會(huì)隨著年齡的增長(zhǎng)而退化，作為衰老過(guò)程的一個(gè)普遍特征，骨骼中膠原蛋白間的交聯(lián)就會(huì)在衰老過(guò)程中發(fā)生變化，或者因晚期糖基化終產(chǎn)物的積累而受損。然而對(duì)于骨骼來(lái)說(shuō)，發(fā)生在其上最常見(jiàn)的衰老相關(guān)的衰退性疾病，還當(dāng)屬骨質(zhì)疏松癥[84]。 在細(xì)胞層面，在絕經(jīng)后骨質(zhì)疏松癥模型中發(fā)現(xiàn)，破骨細(xì)胞分泌的semaphin4D特異性抗體(SEMA4D)會(huì)介導(dǎo)破骨細(xì)胞與成骨細(xì)胞之間的交流，從而有效刺激成骨細(xì)胞的骨形成。并且，衰老過(guò)程會(huì)引起人體骨骼干細(xì)胞中去乙?；?(SIRT1)表達(dá)的缺失，降低骨骼干細(xì)胞的分化潛能；此外，機(jī)體內(nèi)已被老化的免疫細(xì)胞也會(huì)分泌促進(jìn)炎癥的大鈣素(GCA)，使骨骼細(xì)胞受到炎癥浸潤(rùn)而變性，大大增加骨骼細(xì)胞維持青春的難度[85]。 在基因?qū)用妫?dāng)DNA甲基化或組蛋白乙?；图谆母淖儠r(shí)，例如H3K9me和H3K27me3的缺失，可誘導(dǎo)導(dǎo)致衰老過(guò)程的表觀遺傳變化[86]。 干預(yù)措施 長(zhǎng)期以來(lái)，雙膦酸鹽和地諾塞麥這類可降低骨骼吸收、抑制破骨細(xì)胞活性的藥物，被廣泛應(yīng)用于骨質(zhì)疏松癥的治療，但它們同時(shí)具有骨形成減少和骨脆性增加的副作用。 目前，干細(xì)胞療法已作為治療骨質(zhì)疏松癥的有效方法。然而骨骼治療過(guò)程中仍會(huì)存在炎癥性衰老，影響干細(xì)胞活性。因此學(xué)界嘗試在骨科手術(shù)之前選擇性服用如非甾體類的抗炎藥(NSAID)，以提高干細(xì)胞數(shù)量，并已在阻斷骨細(xì)胞衰老、提高骨細(xì)胞合成代謝和提高干細(xì)胞數(shù)量等方面初見(jiàn)成效[87]。 當(dāng)然，學(xué)界特別建議絕經(jīng)后的女性和老年男性要注重日常運(yùn)動(dòng)[88]，可以在提高骨骼強(qiáng)度的同時(shí)減少脂肪量。 圖：導(dǎo)致骨衰老的細(xì)胞機(jī)制示意圖 No.6 骨骼肌 骨骼肌是由單核細(xì)胞和多核細(xì)胞（肌纖維）共同組成的細(xì)胞群，而骨骼肌細(xì)胞的衰老會(huì)引發(fā)肌肉質(zhì)量和功能下降，并導(dǎo)致機(jī)體運(yùn)動(dòng)、呼吸、視力、熱平衡、代謝穩(wěn)態(tài)和免疫調(diào)節(jié)的失調(diào)[89]。 從細(xì)胞層面來(lái)看。隨著年齡的增長(zhǎng)，身為多核細(xì)胞的肌纖維的大小和收縮能力會(huì)隨之下降，導(dǎo)致肌肉質(zhì)量和功能的整體缺失。衰老的肌纖維中出現(xiàn)的代謝失衡（合成代謝減少和分解代謝增加）現(xiàn)象，導(dǎo)致肌原纖維蛋白被降解，進(jìn)而會(huì)加重骨骼肌衰老[90]。 而單核細(xì)胞中，具有高度分化能力的肌肉干細(xì)胞（MuSCs），其上的衰老相關(guān)p38、MAPK信號(hào)通路被激活后，細(xì)胞周期抑制劑p16（INK4）也得到提高，導(dǎo)致MuSCs發(fā)生不對(duì)稱分裂和自我更新受損，最終使骨骼肌的再生能力急劇下降[91]。 從基因?qū)用鎭?lái)看。據(jù)統(tǒng)計(jì)，人體的MuSCs每年都會(huì)有13個(gè)基因組發(fā)生突變，隨年齡的增長(zhǎng)，不斷累積的DNA突變導(dǎo)致DNA損傷效應(yīng)，這時(shí)，DNA甲基化開(kāi)始調(diào)節(jié)肌源基因的表達(dá)，抑制性染色質(zhì)修飾基因H3K27me3在MuSCs中逐漸增加，MuSCs中的部分重要功能基因被抑制，最終使MuSCs出現(xiàn)功能障礙[92]。 而除了內(nèi)源性變化引發(fā)骨骼肌細(xì)胞衰老外，其他微環(huán)境因子如NF-κB、IL-33和CCL-2水平的變化也會(huì)導(dǎo)致MuSCs的增殖和分化缺陷，導(dǎo)致衰老過(guò)程中肌肉損傷后的再生能力下降[93]。 圖：骨骼肌衰老的主要機(jī)制 No.7 皮膚 皮膚作為人體最外層、最直觀的器官，承擔(dān)著保護(hù)、溫度調(diào)節(jié)、感覺(jué)、免疫、社交等多種重要功能[45]。在組織學(xué)水平上，它的老化被分為以下形式：
圖：皮膚衰老特征和機(jī)制的示意圖 No.8 生殖系統(tǒng) 生殖系統(tǒng)衰老 生殖系統(tǒng)可以通過(guò)維持機(jī)體內(nèi)分泌的穩(wěn)態(tài)，保證健康后代的孕育并協(xié)調(diào)生理功能。對(duì)于女性來(lái)說(shuō)，生殖系統(tǒng)的衰老往往出現(xiàn)在更年期，會(huì)表現(xiàn)在內(nèi)分泌失調(diào)和代謝疾病風(fēng)險(xiǎn)的提高方面[98]。而男性的生殖衰老，則體現(xiàn)在隨年齡的增長(zhǎng)而逐漸下降的生育能力上[99]。
表：兩性生殖系統(tǒng)衰老的潛在機(jī)制 干預(yù)措施
No.9 腸道和微生物菌群 腸道的衰老過(guò)程，往往會(huì)伴隨腸道菌群失調(diào)和腸道功能紊亂，而老化的腸道會(huì)體現(xiàn)出腸上皮干細(xì)胞（IESCs）過(guò)度增殖和功能障礙。而腸道衰老的另一個(gè)方面則是腸道屏障受損，其特征包含腸道通透性增加、結(jié)腸粘液層變薄和慢性炎癥水平升高等特征[117]。 IESCs是位于腸隱窩處底部的多能細(xì)胞，調(diào)控著上皮細(xì)胞的更新和維持腸道穩(wěn)態(tài)，研究發(fā)現(xiàn)，衰老果蠅腸道中存在IESCs的增殖升高和錯(cuò)誤分化，以及ROS和ROS相關(guān)通路(如c-JunN-末端激酶(JNK)信號(hào)通路)的過(guò)度表達(dá)，這可能會(huì)破壞腸道穩(wěn)態(tài)[118]。 此外，隨年齡的變化，老化腸道內(nèi)的微生物菌群也易發(fā)生失調(diào)，刺激腸道出現(xiàn)代謝紊亂，并提高患其他慢性疾病的風(fēng)險(xiǎn)[119]。 圖：衰老的腸道和微生物群 No.10 免疫 衰老往往會(huì)伴隨諸多老齡化疾病的出現(xiàn)，其原因就在于炎性的累積降低了機(jī)體對(duì)外來(lái)抗原和有害細(xì)胞的抵抗力，從而增加了患衰老相關(guān)疾病的風(fēng)險(xiǎn)，因此，這種隨年齡的增加而引發(fā)的免疫功能障礙，被定義為生理性免疫衰老（PHIS）[120]。此外，還有一種通過(guò)病理性微環(huán)境誘導(dǎo)免疫細(xì)胞表現(xiàn)出同PHIS相似的衰老表型的途徑，被稱為病理性免疫衰老（PAIS）[121]。 PHIS的典型特征，表現(xiàn)為血液和組織中促炎標(biāo)志物以及其他內(nèi)源性損傷產(chǎn)物（如ATP、尿酸或循環(huán)DNA）水平的提高（俗稱“炎癥”）。炎癥會(huì)促進(jìn)細(xì)胞分泌IL-1、TNF、IL-6、IL-8、IL-13、IL-18、IFNα、IFNβ和TGF-β等一系列SASP，而SASP又可營(yíng)造病理性微環(huán)境，導(dǎo)致免疫細(xì)胞群出現(xiàn)PAIS，從而促進(jìn)疾病和衰老進(jìn)展[120]。 圖：免疫衰老的誘因、特征和后果 No.11 造血干細(xì)胞 造血干細(xì)胞（HSC）的衰老，主要由復(fù)制應(yīng)激和DNA損傷、有毒副產(chǎn)物（如ROS）的積累、表觀遺傳修飾、微環(huán)境炎癥等生物過(guò)程間的相互作用所導(dǎo)致[121]。
圖：HSC衰老的標(biāo)志 了解衰老，除了能更好地打破我們對(duì)“衰”和“老”的未知恐懼，并以科學(xué)性、系統(tǒng)性的思想對(duì)待衰老外，還能有力地推進(jìn)衰老干預(yù)研究的進(jìn)行。衰老研究的目標(biāo)之一，就是能夠?qū)崿F(xiàn)對(duì)各種與年齡相關(guān)疾病的預(yù)防或干預(yù)，并延長(zhǎng)健康壽命。 因此，本文也為我們總結(jié)了極具臨床應(yīng)用潛力的抗衰干預(yù)手段，例如使用基因療法改變與衰老相關(guān)的基因、清除衰老細(xì)胞、人工智能（AI）預(yù)測(cè)。除此之外，本文還對(duì)可預(yù)測(cè)衰老的新技術(shù)領(lǐng)域進(jìn)行了展望。 No.1 基因療法 過(guò)去二十年間，基因編輯技術(shù)已能實(shí)現(xiàn)在基因組特定位置添加、刪除或改變核苷酸序列；如今，它的應(yīng)用拓展到了“延長(zhǎng)壽命或健康期” [126]： 表：衰老干預(yù)的基因治療方法 目前，基因療法在靶向遞送策略仍然是一個(gè)重大挑戰(zhàn)，因此也在一定程度上限制了基因療法的實(shí)際應(yīng)用[52]。本文認(rèn)為，雖然取得了許多有力的數(shù)據(jù)支撐，但將基因療法運(yùn)用于臨床實(shí)踐仍有很長(zhǎng)的路要走。 No.2 抗衰藥物 隨著衰老研究的不斷深入，許多小分子在延緩衰老的同時(shí)也加深了人們對(duì)衰老過(guò)程和機(jī)制的認(rèn)識(shí)。然而，衰老是一個(gè)由多因素共同作用的復(fù)雜過(guò)程。目前，被學(xué)界廣泛接受的衰老干預(yù)方向包括NAD+、VEGF、AMPK、衰老細(xì)胞、炎癥、FOXO家族、胰島素/IGF-1信號(hào)通路、PI3K-AKT信號(hào)通路、p16、p21等。下表列舉了當(dāng)前主要的衰老干預(yù)分子及其主要靶點(diǎn)： 表：抗衰藥物和補(bǔ)劑 No.3 人工智能 面對(duì)無(wú)可避免的衰老，除了盡可能延長(zhǎng)機(jī)體的健康壽命外，如果能對(duì)年齡和適用方式進(jìn)行正確的篩選和預(yù)測(cè)，也將助力實(shí)現(xiàn)對(duì)衰老的有效干預(yù)。目前，人工智能和系統(tǒng)生物學(xué)已開(kāi)始應(yīng)用于抗衰藥物的篩選：
圖：基于人工智能和系統(tǒng)生物學(xué)的衰老干預(yù)藥物篩選的兩個(gè)平行和協(xié)同方向 文章認(rèn)為，隨著數(shù)字化時(shí)代的到來(lái)，大眾對(duì)于衰老領(lǐng)域的輔助研究和藥物篩選的重視程度逐漸上升，未來(lái)，人工智能和生物學(xué)技術(shù)將會(huì)成為研究的熱門(mén)方向和大熱發(fā)展趨勢(shì)[45]。 No.4 新技術(shù)領(lǐng)域 隨技術(shù)的不斷進(jìn)步，現(xiàn)在針對(duì)抗衰的干預(yù)也出現(xiàn)了諸多先進(jìn)技術(shù)，可以幫助我們更加深入地對(duì)單個(gè)分子到整個(gè)有機(jī)體的復(fù)雜衰老過(guò)程進(jìn)行了解，并提供了一系列有效干預(yù)方案。 模型： 通過(guò)建立疾病和衰老相關(guān)的細(xì)胞、器官、組織和動(dòng)物模型等，實(shí)現(xiàn)便捷的體外實(shí)驗(yàn)操作，可快速進(jìn)行衰老機(jī)制研究和干預(yù)手段評(píng)估[150]。 單細(xì)胞組學(xué)技術(shù)： 衰老在不同個(gè)體、組織和細(xì)胞之間的體現(xiàn)具有極大差異，因此需要更精準(zhǔn)的方式去剖析生物衰老中的異質(zhì)性[151]。迄今為止，單細(xì)胞RNA測(cè)序技術(shù)已廣泛應(yīng)用于衰老研究，并幫助我們揭示了衰老在跨組織和物種之間的相互影響[152]。盡管單細(xì)胞蛋白質(zhì)組學(xué)和代謝組學(xué)技術(shù)尚未應(yīng)用于衰老的研究領(lǐng)域，但文章認(rèn)為，它們?cè)谖磥?lái)極有望實(shí)現(xiàn)對(duì)衰老過(guò)程進(jìn)行深入機(jī)制理解的有效手段。 成像技術(shù)： 細(xì)胞衰老是一種復(fù)雜的現(xiàn)象，而成像技術(shù)可以最直觀了解細(xì)胞衰老的發(fā)生和進(jìn)展過(guò)程。目前，用于檢測(cè)衰老細(xì)胞的主要成像技術(shù)是體內(nèi)探針（細(xì)胞衰老的一般生物標(biāo)志物）的實(shí)時(shí)跟蹤[153]。此外，還有將成像結(jié)果與基因表達(dá)數(shù)據(jù)相結(jié)合的方式，也叫ST分析法，可以更加深入了解到細(xì)胞衰老的時(shí)空變化，目前，已應(yīng)用成熟的ST分析技術(shù)有：下一代測(cè)序技術(shù)(NGS)、現(xiàn)場(chǎng)測(cè)序技術(shù)（ISS）和現(xiàn)場(chǎng)基于雜交的測(cè)序技術(shù)（ISH）[154]。 算法： 將多組學(xué)數(shù)據(jù)結(jié)合機(jī)器學(xué)習(xí)算法，可以通過(guò)對(duì)豐富的數(shù)據(jù)資源的開(kāi)發(fā)，識(shí)別出潛在的生物標(biāo)志物和干預(yù)目標(biāo)，從而為衰老生物學(xué)的發(fā)展提供新見(jiàn)解[155] 時(shí)光派點(diǎn)評(píng) 在各領(lǐng)域研究學(xué)者的共同努力下，我們現(xiàn)在已經(jīng)進(jìn)入了一個(gè)最好的老齡化研究時(shí)代，眾多預(yù)防、延緩甚至在某些情況下逆轉(zhuǎn)衰老跡象的方式均得到有力證實(shí)。雖然本世紀(jì)能否通過(guò)生物醫(yī)藥技術(shù)實(shí)現(xiàn)人類壽命的延長(zhǎng)仍是一個(gè)懸而未決的問(wèn)題，但派派和眾多學(xué)者們堅(jiān)信，預(yù)防衰老、延緩人類健康壽命終必會(huì)在不久的將來(lái)真正實(shí)現(xiàn)。 愿世人“年老而不衰,智盡而不亂”。 由于篇幅所限，無(wú)法傳達(dá)更多精彩內(nèi)容，我們特將研究全文翻譯，以饗大眾。 掃碼添加助理 —— TIMEPIE —— 參考文獻(xiàn) [1]C López-Otín, Blasco, M. 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