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联合国（UN）曾预测，到2050年，全球超过65岁的人口将占总人数的六分之一，老龄化已然成为无法避免的趋势。然而，随医疗技术的进步，我们的平均寿命虽然得到显著增加，但“健康寿命”并没有跟上延寿的步伐，衰老及其伴随的众多慢性疾病仍是目前难以解决的人体负担和医疗挑战。 如何减缓衰老进程、促进“健康老龄化”（将机体健康功能维持到老年）成为了亟待解决的社会难题。  近日，《中国科学：生命科学》英文版（SCIENCE CHINA Life Sciences）在线发表了由中国科学院动物研究所刘光慧和北京大学韩敬东统筹，中国科学院动物研究所宋默识、杭州师范大学刘俊平、武汉大学刘勇、四川大学肖智雄、南昌大学田小利、上海生物化学与细胞生物学研究所邹卫国、中国科学技术大学刘强、中国科学院昆明动物研究所孔庆鹏、同济大学毛志勇、中国科学院上海营养与健康研究所孙宇、上海交通大学医学院叶静、广州国际生物岛实验室胡苹、清华大学王戈林、中国科学院遗传与发育生物学研究所田烨、中国科学院上海营养与健康研究所肖意传、清华大学王建伟、中国科学院动物研究所曲静、北京大学谢正伟、中国科学院北京基因组研究所张维绮、中国科学院微生物研究所王军、中国科学院上海营养与健康研究所张亮、中国科学院北京基因组研究所任捷、中国科学技术大学宋晓元、首都医科大学宣武医院王思、北京干细胞与再生医学研究院马帅等53位科研人员联合撰写的衰老全景综述——“The landscape of aging”。 该综述参考了逾千篇衰老领域研究文献，以超5万字、20张插图和5张表格的篇幅，从衰老机制、器官衰老特征和衰老干预三个方面系统总结了衰老领域的经典理论和近年来衰老研究取得的重要进展，是目前国际上最为详尽的衰老研究综述之一。  图：衰老全景图。这张图从细胞(底部)、组织、器官和系统(中间)、机体(顶部)各个层面描绘了衰老的全景。以及辅助衰老研究的新技术(左侧)和干预和恢复策略(右侧) 综述发布后，时光派第一时间组织内部集体学习。为方便广大读者、同道一起学习进步，现将内部编译资料分享如下（共1.9万字，建议收藏）。 此外，为庆祝国内衰老自主研究成果涌现，编辑部奋战中秋，日夜兼程，对综述进行了全文翻译（图片、表格均已汉化，全文共13万字，260余页文档，远超微信推文字数限制），愿无偿分享，领取方式详见文末。  *时间仓促，难免疏漏，如有科学谬误敬请专家与读者朋友联系时光派公众号指正。  一直以来，细胞衰老被认为是衰老的主要原因，也是联系衰老与诸多老龄化疾病之间的桥梁，然而细胞衰老和衰老的关系一直未得到明晰，因此，在本节中，派派将为大家一一揭示细胞衰老的分子机制。 No.1 干细胞衰老 什么是干细胞衰老 干细胞作为维持体内稳态和可塑性的万能细胞，可以在体内终生存在，然而随年龄的增长，干细胞容易受到核DNA和线粒体DNA损伤、表观遗传变化、细胞周期改变、氧化应激和线粒体功能障碍、蛋白质稳态破坏、信号通路改变、外部和系统性变化、自噬和代谢失调的多方影响，并积累损伤，最终导致衰老或功能衰退，因此干细胞衰老也被认为是机体衰老的重要表现之一[1,2]。 干细胞衰老机制 一方面，人体中每个干细胞在其整个生命周期中，都会经历数十万次来自内源性代谢副产物（如ROS和炎症）和外源性物质（如环境中的辐射和化学物质）的毒性损害，而这些物质会进一步破坏DNA结构和功能[3]。另一方面，随年龄的增长，干细胞中DNA修复能力（如核苷酸切除修复（NER）在内的修复途径）逐渐下降，基因组损伤积累会损害正常干细胞的功能，破坏组织稳态[4]。 并且，长寿相关的SIRT3和SIRT7蛋白也易随干细胞衰老而减少，导致核膜蛋白和异染色质相关蛋白的复合物的形成受损，而脂蛋白颗粒的载脂蛋白(APOE)又在衰老的干细胞中积累，并作为异染色质的去稳定剂而发挥作用，进一步驱动细胞衰老[5]。异染色质稳定性的变化，也会改变机体在表观遗传修饰方面的表达。 在细胞水平上，干细胞功能会因年龄增长而发生慢性炎症而受损，并表现出一系列衰老标志物，包括衰老相关的β-半乳糖苷酶(SA-β-gal)活性升高、Rb-p16和p53-p21通路上调、持续性DNA损伤以及生长因子、蛋白酶和细胞因子分泌[6]。 在代谢水平上，衰老会使干细胞的自噬功能受损，导致蛋白质稳态的丧失，从而促进线粒体质量和活性下降，线粒体的功能障碍反过来继续诱导干细胞中发生蛋白质聚集，造成代谢失调[7]。  图:导致再生能力受损的干细胞衰老机制 No.2 衰老细胞与SASP 什么是SASP 衰老(senescence)是细胞的一种归宿，其特征是生长潜力的丧失和表型改变，还会分泌由多种细胞因子、趋化因子、生物活性脂质、损伤相关分子模式（DAMP，也称警报素）共同组成的衰老相关分泌表型（SASP）。 在局部微环境中，SASP会非自主地作用于细胞，以改变相邻细胞的生物学行为，造成负面影响[8]。然而，衰老细胞分泌的特异性SASP因子还可以参与组织修复、创面愈合和再生过程，因此在二元论与拮抗多效性进化理论中，SASP还可被看做衰老程序中的有益功能[9]。 SASP在衰老细胞中的调控机制 衰老细胞可以在转录、mRNA稳定性、翻译和细胞外分泌等多个水平上调节SASP的表达[10]。在细胞质和核因子的调节过程中，转录因子GATA4在衰老细胞中积累并诱导上调IL1α和TRAF3IP2（编码E3的泛素连接酶），而细胞膜又与促炎蛋白白细胞介素1α(IL-1α)相结合，它们共同激活炎症相关NF-κB信号并放大SASP表达[11]。 此外，衰老细胞还可以通过先天免疫感应机制来触发SASP。释放到细胞质中的大量DNA片段通过募集平衡免疫反应的cGAS酶，通过cGAS-STING通路招募IRF3进行磷酸化[12]。磷酸化的IRF3二聚体进入细胞核，激活NF-κB信号通路从而产生I型IFNs，并启动其他免疫调节基因的转录，从而促进SASP的表达[13]。  图：衰老细胞的分子特征 No.3 线粒体衰老 什么是线粒体 线粒体作为细胞的“发电站”，可产生大量的三磷酸腺苷(ATP)应用于机体产能过程，其还可作为生物能量和生物合成等各种生物事件的信号枢纽，在大分子的生物合成、细胞凋亡、先天免疫反应和对压力的适应中发挥重要作用[14]。 线粒体衰老的机制 衰老细胞中的线粒体，往往会出现生物合成减少、形态网络改变、氧化磷酸化(OXPHOS)活性效率降低、mtDNA突变积累和ROS增加等生物反应[15]。并且受到损伤的线粒体又会通过改变分解和合成代谢反应的速率，从而导致ATP、烟酰胺腺嘌呤二核苷酸(NAD+)、α-酮戊二酸(α-KG)和ROS等代谢物发生含量变化，诱导细胞进一步衰老[16]。
 图：线粒体功能和衰老 No.4 代谢和内质网应激（营养感知） 营养感知途径诱导衰老 在衰老过程中，mTOR、AMPK和Sirtuins等营养传感机制，和胰岛素/IGF途径激素信号途径，以及内质网未折叠蛋白反应(UPR)等应激反应途径之间，发生持续的生理相互作用，多种内源性代谢物和分泌蛋白通过信号传导，破坏机体的代谢稳态，诱导衰老[20]。 诱导衰老的机制
 图：衰老和长寿代谢控制中的营养感知和内质网应激反应 No.5 表观遗传学 什么是表观遗传学定义的衰老 表观遗传学所定义的衰老是“在不改变主要DNA序列的条件下，基因表达的可遗传和可逆变化，其中包括DNA甲基化、染色质重塑、组蛋白修饰、组蛋白变体和非编码RNA调控[26]。 表观遗传学涉及机制
 图：衰老表观基因组示意图 No.6 端粒 为何可作为衰老标识 在衰老的过程中，由于细胞的末端DNA无法通过常规方法进行复制，导致端粒DNA经历一次次的细胞分裂过程而逐渐缩短，最终导致复制性衰老。也正是因为端粒一直处于不断缩短的动态发育过程中，因此它也被认为是衰老的驱动力[29]。 端粒和衰老间的作用机制 不健康的生活方式、压力、环境变化和感染等情况的出现，均会导致端粒缩短或结构受损，从而引发DNA损伤、氧化应激、基因表达改变、基因组不稳定性和细胞衰老等后果，并且当含有受损端粒的细胞在体内堆积时，又易导致激素失衡、炎症、免疫缺陷、代谢紊乱和加速衰老等问题[30]。
 图：通过发育程序衰老的端粒生物学 No.7 基因组稳定性 基因组不稳定 随年龄的增加，基因组稳定性的保护机制逐渐遭到破坏，发生DNA损伤、反转录转座子激活、端粒磨损和复制应激等基因组不稳定现象，从而加速衰老过程[37]。 基因组不稳定机制
 图：基因组稳定性和衰老的调节 通过第一章的学习，我们已经了解到，衰老与机体细胞稳态和功能的下降有关。因此在本章中，文章将进一步为我们讲述，随年龄增长，身体中多个组织/器官会发生怎样的特异性衰老，并探讨它们的衰老机制和有效干预措施。 No.1 血管 血管老化 循环系统可为身体中所有细胞输送氧气和营养物质，并带走组织器官中的二氧化碳和废物，对于维持内环境稳态至关重要。但伴随着年龄的增加，血管也开始呈现出形态、功能和分子标记方面的老化现象[41]。 在形态上，老化血管中的转化细胞（失去正常细胞特点）开始无限增殖，血管中弹性蛋白的断裂和胶原蛋白的沉积，使血管内膜层增厚，导致血管腔被扩大[37]。在功能上，老化血管的硬度会增加，收缩压升高，血管对内外源刺激的反应也逐渐下降[42]。在分子标识方面，老化血管上观察到端粒磨损、其他衰老标志物（如p53、p21、p16、ROS）和SASP相关基因的异常表达等现象[41]。 干预措施
图：血管衰老和干预 No.2 大脑细胞的特异性老化 大脑的功能在衰老过程中会体现出学习和记忆力的下降，而脑细胞，包括神经元细胞和星形胶质细胞等非神经元细胞，也在衰老过程中表现出各自独特的衰老特征[47]。
图：大脑中不同细胞类型的衰老特征 No.3 肺部 人体的肺部功能从35岁开始逐渐下降，并出现气体交换受损、粘液纤毛清除力降低和免疫能力下降等肺部功能障碍[51]。其中，肺泡上皮细胞（尤其是I型肺泡上皮细胞(AEC1)和II型肺泡上皮细胞（AEC2）都容易受到与衰老相关的可持续性影响，使它们的数量减少，且间质沉积增加。目前已有研究表明，随年龄的增加，AEC1的增殖与凋亡比率会随之变化，并且AEC2的再生、自我更新和分化能力会逐渐下降[52]。 同时，协调肺部免疫反应的肺泡巨噬细胞(AMs)和间质巨噬细胞(IM)，也随着年龄的增长，表现出吞噬和清除能力下降、干扰素(IFN)受到顽固性激活等免疫降低迹象，并且肺部免疫细胞出现炎细胞浸润，从而诱导衰老[53]。 当然，还有更多的机制研究表明，端粒缩短、DNA损伤应答（DDR）、表观遗传改变、氧化应激反应和线粒体功能障碍所引起的干细胞衰竭，也是导致肺部细胞衰老的一大诱因[54]。 图：肺衰老的细胞表型 No.4 心脏 心脏老化 首先，心脏中占总重一半以上并维持收缩和舒张功能的心肌细胞，其数量会随年龄的增加而逐渐减少，与此同时，成纤维细胞的不断增殖又导致胶原蛋白沉淀的累积，大大促进了心脏纤维化和心脏功能障碍[55]。 此外，心脏衰老还涉及多种分子机制。其中最核心的原因就是蛋白质稳态失衡，随时间的增加，错误折叠蛋白逐渐增多、积累，导致伴侣蛋白、蛋白酶体、核糖体和线粒体蛋白的表达降低，和氧化应激相关蛋白的上调[56]。此时，大量产生的ROS开始伺机而动，打破线粒体融合和裂变的平衡，进一步破坏线粒体稳态，使心脏线粒体功能障碍和氧化损伤的风险增加[57]。 终生积累的遗传损伤会成为心脏衰老的导火索。除端粒缩短和端粒功能障碍已被证实会影响心脏的正常生理功能外，表观遗传改变也被发现会破坏心脏的氧化应激、血管生成和细胞代谢相关的转录程序，诱发炎症，从而促进心脏衰老[58]。 干预措施 目前，靶向线粒体功能障碍的抗氧化肽，已被证明可有效改善高血压性心肌病，而在动物模型中，热量限制也被发现对缓解心脏衰老和改善纤维化程度有显著疗效[59]。此外，还有小分子化合物、靶向抗衰老药物、干细胞疗法、不同形式的运动等多种心脏抗衰干预方法也正被应于临床。 表：https:///中列举出的与年龄相关的心脏病的临床实验数据 No.5 骨骼 骨骼衰老 骨骼结构会随着年龄的增长而退化，作为衰老过程的一个普遍特征，骨骼中胶原蛋白间的交联就会在衰老过程中发生变化，或者因晚期糖基化终产物的积累而受损。然而对于骨骼来说，发生在其上最常见的衰老相关的衰退性疾病，还当属骨质疏松症[84]。 在细胞层面，在绝经后骨质疏松症模型中发现，破骨细胞分泌的semaphin4D特异性抗体(SEMA4D)会介导破骨细胞与成骨细胞之间的交流，从而有效刺激成骨细胞的骨形成。并且，衰老过程会引起人体骨骼干细胞中去乙酰化酶1(SIRT1)表达的缺失，降低骨骼干细胞的分化潜能；此外，机体内已被老化的免疫细胞也会分泌促进炎症的大钙素(GCA)，使骨骼细胞受到炎症浸润而变性，大大增加骨骼细胞维持青春的难度[85]。 在基因层面，当DNA甲基化或组蛋白乙酰化和甲基化的改变时，例如H3K9me和H3K27me3的缺失，可诱导导致衰老过程的表观遗传变化[86]。 干预措施 长期以来，双膦酸盐和地诺塞麦这类可降低骨骼吸收、抑制破骨细胞活性的药物，被广泛应用于骨质疏松症的治疗，但它们同时具有骨形成减少和骨脆性增加的副作用。 目前，干细胞疗法已作为治疗骨质疏松症的有效方法。然而骨骼治疗过程中仍会存在炎症性衰老，影响干细胞活性。因此学界尝试在骨科手术之前选择性服用如非甾体类的抗炎药(NSAID)，以提高干细胞数量，并已在阻断骨细胞衰老、提高骨细胞合成代谢和提高干细胞数量等方面初见成效[87]。 当然，学界特别建议绝经后的女性和老年男性要注重日常运动[88]，可以在提高骨骼强度的同时减少脂肪量。 图：导致骨衰老的细胞机制示意图 No.6 骨骼肌 骨骼肌是由单核细胞和多核细胞（肌纤维）共同组成的细胞群，而骨骼肌细胞的衰老会引发肌肉质量和功能下降，并导致机体运动、呼吸、视力、热平衡、代谢稳态和免疫调节的失调[89]。 从细胞层面来看。随着年龄的增长，身为多核细胞的肌纤维的大小和收缩能力会随之下降，导致肌肉质量和功能的整体缺失。衰老的肌纤维中出现的代谢失衡（合成代谢减少和分解代谢增加）现象，导致肌原纤维蛋白被降解，进而会加重骨骼肌衰老[90]。 而单核细胞中，具有高度分化能力的肌肉干细胞（MuSCs），其上的衰老相关p38、MAPK信号通路被激活后，细胞周期抑制剂p16（INK4）也得到提高，导致MuSCs发生不对称分裂和自我更新受损，最终使骨骼肌的再生能力急剧下降[91]。 从基因层面来看。据统计，人体的MuSCs每年都会有13个基因组发生突变，随年龄的增长，不断累积的DNA突变导致DNA损伤效应，这时，DNA甲基化开始调节肌源基因的表达，抑制性染色质修饰基因H3K27me3在MuSCs中逐渐增加，MuSCs中的部分重要功能基因被抑制，最终使MuSCs出现功能障碍[92]。 而除了内源性变化引发骨骼肌细胞衰老外，其他微环境因子如NF-κB、IL-33和CCL-2水平的变化也会导致MuSCs的增殖和分化缺陷，导致衰老过程中肌肉损伤后的再生能力下降[93]。 图：骨骼肌衰老的主要机制 No.7 皮肤 皮肤作为人体最外层、最直观的器官，承担着保护、温度调节、感觉、免疫、社交等多种重要功能[45]。在组织学水平上，它的老化被分为以下形式：
图：皮肤衰老特征和机制的示意图 No.8 生殖系统 生殖系统衰老 生殖系统可以通过维持机体内分泌的稳态，保证健康后代的孕育并协调生理功能。对于女性来说，生殖系统的衰老往往出现在更年期，会表现在内分泌失调和代谢疾病风险的提高方面[98]。而男性的生殖衰老，则体现在随年龄的增长而逐渐下降的生育能力上[99]。
表：两性生殖系统衰老的潜在机制 干预措施
No.9 肠道和微生物菌群 肠道的衰老过程，往往会伴随肠道菌群失调和肠道功能紊乱，而老化的肠道会体现出肠上皮干细胞（IESCs）过度增殖和功能障碍。而肠道衰老的另一个方面则是肠道屏障受损，其特征包含肠道通透性增加、结肠粘液层变薄和慢性炎症水平升高等特征[117]。 IESCs是位于肠隐窝处底部的多能细胞，调控着上皮细胞的更新和维持肠道稳态，研究发现，衰老果蝇肠道中存在IESCs的增殖升高和错误分化，以及ROS和ROS相关通路(如c-JunN-末端激酶(JNK)信号通路)的过度表达，这可能会破坏肠道稳态[118]。 此外，随年龄的变化，老化肠道内的微生物菌群也易发生失调，刺激肠道出现代谢紊乱，并提高患其他慢性疾病的风险[119]。 图：衰老的肠道和微生物群 No.10 免疫 衰老往往会伴随诸多老龄化疾病的出现，其原因就在于炎性的累积降低了机体对外来抗原和有害细胞的抵抗力，从而增加了患衰老相关疾病的风险，因此，这种随年龄的增加而引发的免疫功能障碍，被定义为生理性免疫衰老（PHIS）[120]。此外，还有一种通过病理性微环境诱导免疫细胞表现出同PHIS相似的衰老表型的途径，被称为病理性免疫衰老（PAIS）[121]。 PHIS的典型特征，表现为血液和组织中促炎标志物以及其他内源性损伤产物（如ATP、尿酸或循环DNA）水平的提高（俗称“炎症”）。炎症会促进细胞分泌IL-1、TNF、IL-6、IL-8、IL-13、IL-18、IFNα、IFNβ和TGF-β等一系列SASP，而SASP又可营造病理性微环境，导致免疫细胞群出现PAIS，从而促进疾病和衰老进展[120]。 图：免疫衰老的诱因、特征和后果 No.11 造血干细胞 造血干细胞（HSC）的衰老，主要由复制应激和DNA损伤、有毒副产物（如ROS）的积累、表观遗传修饰、微环境炎症等生物过程间的相互作用所导致[121]。
图：HSC衰老的标志 了解衰老，除了能更好地打破我们对“衰”和“老”的未知恐惧，并以科学性、系统性的思想对待衰老外，还能有力地推进衰老干预研究的进行。衰老研究的目标之一，就是能够实现对各种与年龄相关疾病的预防或干预，并延长健康寿命。 因此，本文也为我们总结了极具临床应用潜力的抗衰干预手段，例如使用基因疗法改变与衰老相关的基因、清除衰老细胞、人工智能（AI）预测。除此之外，本文还对可预测衰老的新技术领域进行了展望。 No.1 基因疗法 过去二十年间，基因编辑技术已能实现在基因组特定位置添加、删除或改变核苷酸序列；如今，它的应用拓展到了“延长寿命或健康期” [126]： 表：衰老干预的基因治疗方法 目前，基因疗法在靶向递送策略仍然是一个重大挑战，因此也在一定程度上限制了基因疗法的实际应用[52]。本文认为，虽然取得了许多有力的数据支撑，但将基因疗法运用于临床实践仍有很长的路要走。 No.2 抗衰药物 随着衰老研究的不断深入，许多小分子在延缓衰老的同时也加深了人们对衰老过程和机制的认识。然而，衰老是一个由多因素共同作用的复杂过程。目前，被学界广泛接受的衰老干预方向包括NAD+、VEGF、AMPK、衰老细胞、炎症、FOXO家族、胰岛素/IGF-1信号通路、PI3K-AKT信号通路、p16、p21等。下表列举了当前主要的衰老干预分子及其主要靶点： 表：抗衰药物和补剂 No.3 人工智能 面对无可避免的衰老，除了尽可能延长机体的健康寿命外，如果能对年龄和适用方式进行正确的筛选和预测，也将助力实现对衰老的有效干预。目前，人工智能和系统生物学已开始应用于抗衰药物的筛选：
图：基于人工智能和系统生物学的衰老干预药物筛选的两个平行和协同方向 文章认为，随着数字化时代的到来，大众对于衰老领域的辅助研究和药物筛选的重视程度逐渐上升，未来，人工智能和生物学技术将会成为研究的热门方向和大热发展趋势[45]。 No.4 新技术领域 随技术的不断进步，现在针对抗衰的干预也出现了诸多先进技术，可以帮助我们更加深入地对单个分子到整个有机体的复杂衰老过程进行了解，并提供了一系列有效干预方案。 模型： 通过建立疾病和衰老相关的细胞、器官、组织和动物模型等，实现便捷的体外实验操作，可快速进行衰老机制研究和干预手段评估[150]。 单细胞组学技术： 衰老在不同个体、组织和细胞之间的体现具有极大差异，因此需要更精准的方式去剖析生物衰老中的异质性[151]。迄今为止，单细胞RNA测序技术已广泛应用于衰老研究，并帮助我们揭示了衰老在跨组织和物种之间的相互影响[152]。尽管单细胞蛋白质组学和代谢组学技术尚未应用于衰老的研究领域，但文章认为，它们在未来极有望实现对衰老过程进行深入机制理解的有效手段。 成像技术： 细胞衰老是一种复杂的现象，而成像技术可以最直观了解细胞衰老的发生和进展过程。目前，用于检测衰老细胞的主要成像技术是体内探针（细胞衰老的一般生物标志物）的实时跟踪[153]。此外，还有将成像结果与基因表达数据相结合的方式，也叫ST分析法，可以更加深入了解到细胞衰老的时空变化，目前，已应用成熟的ST分析技术有：下一代测序技术(NGS)、现场测序技术（ISS）和现场基于杂交的测序技术（ISH）[154]。 算法： 将多组学数据结合机器学习算法，可以通过对丰富的数据资源的开发，识别出潜在的生物标志物和干预目标，从而为衰老生物学的发展提供新见解[155] 时光派点评 在各领域研究学者的共同努力下，我们现在已经进入了一个最好的老龄化研究时代，众多预防、延缓甚至在某些情况下逆转衰老迹象的方式均得到有力证实。虽然本世纪能否通过生物医药技术实现人类寿命的延长仍是一个悬而未决的问题，但派派和众多学者们坚信，预防衰老、延缓人类健康寿命终必会在不久的将来真正实现。 愿世人“年老而不衰,智尽而不乱”。 由于篇幅所限，无法传达更多精彩内容，我们特将研究全文翻译，以飨大众。 扫码添加助理 —— TIMEPIE —— 参考文献 [1]C López-Otín, Blasco, M. 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