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细胞衰老与年龄相关性黄斑变性

Cellular senescence in the pathogenesis of age-related macular degeneration

来源期刊： 眼科学报 | 2024年7月 第39卷 第7期： 332-344 发布时间：2024-07-28 收稿时间：2024/9/20 16:54:22 阅读量：975
作者：
刘威,
龚莉莉,
关键词：
衰老细胞衰老年龄相关性黄斑变性衰老相关分泌表型
aging cellular senescence age-related macular degeneration senescence-associated secretory phenotype
DOI：
10.12419/24071505
收稿时间：
2024-06-07 
修订日期：
2024-06-30 
接收日期：
2024-07-18 
年龄相关性黄斑变性(age-related macular degeneration, AMD)是导致老年人失明的主要原因之一，其特征为光感受器的死亡和视网膜色素上皮细胞的变性。该病的发病机制复杂，涉及遗传、环境和代谢等多种因素。细胞衰老是AMD的重要危险因素，表现为细胞在经历有限次数的分裂后进入永久性细胞周期停滞状态。随着年龄增长，衰老细胞的数量增加，并与多种年龄相关的慢性疾病密切相关。细胞衰老的潜在机制包括氧化应激、DNA损伤、线粒体功能障碍、自噬/线粒体自噬缺陷以及表观遗传改变等。在AMD中，色素上皮细胞、血管内皮细胞、Bruch膜、感光细胞和小胶质细胞等不同类型的细胞均表现出衰老及其相关变化。细胞衰老在AMD的发病机制中起着关键作用，涉及多种视网膜细胞类型和血管系统的退化。通过深入研究这些机制，期望能开发出更有效的治疗方法，以帮助患者恢复和保护视力。本文回顾了细胞衰老的生物学机制及其在AMD中的作用，深入探讨了不同细胞衰老引发AMD发病的具体机制，旨在为AMD的发病机制和治疗研究提供新思路。
Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly, characterized by the degeneration of retinal pigment epithelial cells and the death of photoreceptors. The pathogenesis of AMD is complex, involving a multitude of factors, including genetic, environmental, and metabolic influences. Cellular senescence serves as a significant risk factor for AMD, where cells enter a permanent state of cell cycle arrest after a limited number of divisions. As age increases, the accumulation of senescent cells is closely associated with various age-related chronic diseases. Key mechanisms underlying cellular senescence include oxidative stress, DNA damage, mitochondrial dysfunction, defects in autophagy and mitophagy, and epigenetic alterations. In the context of AMD, various cell types-including pigment epithelial cells, vascular endothelial cells, cells of Bruch's membrane, photoreceptors, and microglia-exhibit signs of senescence and related changes. Cellular senescence plays a pivotal role in the pathogenesis of AMD, contributing to the degeneration of different retinal cell types and supporting vascular systems. By thoroughly investigating these mechanisms, there is hope for the development of more effective therapies aimed at restoring and protecting vision in affected patients. This article reviews the biological mechanisms of cellular senescence and its role in AMD, exploring how different cell types contribute to the disease's onset, with the goal of providing new insights into the pathogenesis and treatment of AMD.

文章亮点

1. 关键发现

• 细胞衰老在年龄相关性黄斑变性 (age-related macular degeneration, AMD) 的发生、发展中起着重要作用，涉及多种视网膜细胞和血管系统的退化，包括色素上皮细胞、感光细胞、小胶质细胞和血管内皮细胞等。视网膜中关键细胞的衰老和丢失会改变视网膜的结构和功能，从而加速 AMD 的发展。本文总结了 AMD 中不同细胞衰老的分子机制及其与疾病进展的关系。

2. 已知与发现

• 细胞衰老在AMD的进展中起着关键作用，表现为细胞在应激后进入不可逆的停滞状态，失去增殖能力。其分子机制复杂，伴随着促炎细胞因子和趋化因子的分泌，长期可导致慢性炎症，损伤正常细胞，并促进AMD等退行性疾病的发展。靶向衰老细胞对治疗AMD具有重要意义。

3. 意义与改变

• 细胞衰老是AMD发生的重要环节，延缓细胞衰老或清除衰老细胞，改善细胞衰老相关微环境在治疗AMD方面具有巨大潜力。

       随着人口老龄化增加，衰老相关疾病研究的重要性日益显现。目前年龄相关性黄斑变性(age-relatedmaculardegeneration, AMD)在全球范围内影响约1.96亿人口，至2040年影响范围预计达到约2.88亿人[1]。AMD是导致老年人不可逆盲的主要原因，其主要影响区域为视网膜的黄斑区，即视网膜中央负责精细视觉的部分[1]。AMD的发病机制复杂，涉及遗传、环境和代谢等多种因素[2-3]，在临床上可分为干性AMD和湿性AMD[1-3]。细胞衰老(cellular senescence)是指细胞在经历有限次分裂后进入的一种永久性停滞状态。尽管细胞衰老在肿瘤的发展中起到抑制作用，但其在组织和器官中的积累却通常导致多种年龄相关性疾病[4-6]。越来越多的研究表明，细胞衰老在AMD的发生、发展中起到重要的作用[7-10]。例如，在高氧诱导的小鼠新生血管模型中，衰老的内皮细胞显著增加。而清除这些衰老细胞可有效抑制病理性新生血管的形成[11]。本文旨在回顾细胞衰老的生物学机制及其在AMD中的作用，详细总结细胞衰老在AMD发病中改变的具体机制。

1 年龄相关性黄斑变性概述

       AMD是一种累及视网膜感光细胞、视网膜色素上皮(retinal pigment epithelium, RPE)、Bruch膜(Bruch's membrane)和脉络膜的退行性致盲眼病(图1)。虽然AMD最显著的病理变化发生在黄斑区域，但是其周边区视网膜功能也可能受到影响[1-3]。AMD的主要眼底特征是RPE层或RPE和Bruch膜之间的玻璃膜疣(Drusen)的沉积[12-13]。Drusen是一种富含补体蛋白、胆固醇、载脂蛋白、糖类等的黄白色细胞外沉积物。Drusen的大量积聚阻碍视网膜和脉络膜之间营养物质和代谢产物交换，导致感光细胞和RPE的逐渐退化，最终引起中心视力丧失[14-16]。
       RPE细胞的衰老和功能障碍是AMD的重要病理机制[17-19]。RPE细胞对维持视网膜的健康和功能起关键作用，其衰老导致感光细胞的退化和死亡[19]。而代谢废物的积累、炎症和免疫反应以及氧化应激的增加，是导致Drusen在RPE和Bruch膜沉积的重要原因[12, 20- 21]。通常通过Drusen的大小来对AMD的发展阶段进行分类：中等大小的Drusen被分类为早期AMD，大型Drusen被分类为中期AMD[22-25]。如果Drusen面积大且伴有色素变化，则发展为晚期AMD的风险最高[22-25]。晚期AMD表现为地图样萎缩(geographic atrophy, GA)和/或新生血管AMD[1-2]。GA以感光细胞、RPE和脉络毛细血管的融合性萎缩为特征，通常伴有盲点[26-28]。GA区域随着时间的推移而扩大，最终导致中央视野丧失[27]。在AMD的任何阶段，新生血管都可能侵入外视网膜、视网膜下空间或RPE下空间，从而导致新生血管AMD(湿性AMD)的出现。一旦这些新生血管发生泄漏或破裂，就会导致液体的积聚和(或)出血，从而进一步出现视力扭曲和恶化[1-3]等表现。
图1 正常视网膜和衰老或AMD的视网膜结构对比
Figure 1 comparison of normal retinal structure and retinal structure in aging or AMD
(A)正常视网膜结构分为10层，从外到内分为脉络膜血管(choroidal vessels)、Bruch膜(Bruch's membrane)、视网膜色素上皮 (retina pigment epithelium, RPE)、外节段(outer segment, OS)、外核层(outer nuclear layer, ONL)，外丛状层(outer plexiform layer, OPL)、内核层(inner nuclear layer, INL)、内丛状层(inner plexiform layer, IPL)、神经结细胞层(ganglion cell layer, GCL)、神经纤维层(nerve fiber layer, NFL)；(B)衰老或AMD患者的视网膜结构示意图，特征：a.视网膜下新生血管和drusen的沉积，b.衰老断裂的Bruch膜，c.衰老的视杆细胞出现丢失，d.衰老的RPE细胞发生迁移及色素丢失，e.衰老或活化的小胶质细胞迁移到ONL和RPE层，各种细胞的衰老伴随着SASP的分泌不断影响邻近细胞；(C)为各种细胞类型及分泌物的指示图；本图由Figdraw绘制。
(A) The normal retinal structure is divided into 10 layers from outer to inner: choroidal vessels, Bruch's membrane, Retina pigment epithelium (RPE), outer segment (OS), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer (INL), inner plexiform layer (IPL), ganglion cell layer (GCL), nerve fiber layer (NFL). (B) Schematic diagram of the retinal structure in aging or AMD patients, featuring: a. subretinal neovascularization and drusen deposition; b. aged and broken Bruch's membrane; c. loss of aged rod cells; d. migration and pigment loss of aged RPE cells; e. migration of aged or activated microglia to the ONL and RPE layers. The senescence of various cells is accompanied by the secretion of SASP, continuously affecting nearby cells.(C) Indication diagram of various cell types and secretions. This figure is drawn by Figdraw.

2 衰老与细胞衰老

       衰老(aging)是一个复杂的生命进程，几乎存在于所有生命体中，标志着多种细胞和组织功能的逐渐丧失和退化[29]。衰老会导致多种年龄相关性疾病，如动脉粥样硬化、心力衰竭、阿尔茨海默病、AMD、老年性白内障、骨质疏松和糖尿病等[6, 29]。细胞衰老是指细胞在面对各种应激刺激后进入的一种不可逆的细胞周期停滞状态，进入这一状态的细胞往往会失去增殖能力[4]。这一过程可作为防御机制，阻止受损细胞的继续分裂，从而避免细胞进一步发生癌变[4, 6]。尽管衰老和细胞衰老是两个独立的过程，但它们之间仍存在着密切的联系。在衰老过程中，细胞衰老的累积会导致组织功能的逐渐下降，并增加患退行性疾病的风险[30-32]。例如，RPE的衰老会导致AMD的发生、发展[33-35]。机体内存在多种生物学机制可促进细胞衰老，如炎症反应、氧化应激和DNA损伤等。
       细胞衰老被认为是直接驱动衰老进程的关键因素之一[29]。细胞衰老这一现象最早由伦德纳•海佛利克和保罗•莫尔黑德于1961年在体外进行描述[36]，其被认为是一种为应对多种应急刺激因素而发生的自身保护机制，具有抑制肿瘤和组织修复的功能[6]。然而，过度衰老会导致机体出现慢性炎症和组织功能衰退等现象，这与年龄相关性疾病密切相关[4]。细胞衰老可分为两种类型：1)复制性衰老，这是一种由端粒缩短所引起的衰老状态。当端粒长度缩短到临界值时，细胞即进入该衰老状态；2)应激诱导的早衰，该种衰老状态往往由各种应激因素(如氧化应激、DNA损伤、致癌基因激活等)引起，而不依赖于端粒长度的变化[6]。
       端粒是染色体末端的一段重复的DNA序列，具有保护染色体完整性的作用。伴随着细胞的逐次分裂，端粒也会逐次缩短[37-39]。当端粒长度缩短到临界值时，细胞内会激活DNA损伤反应，进而通过共济失调毛细血管扩张突变基因(ataxia telangiectasia-mutated gene, ATM)和共济失调毛细血管扩张突变基因Rad3相关激酶(ataxia telangiectasia and Rad3-related, ATR)途径激活P53蛋白[40]。P53是一种重要的肿瘤抑制因子，它通过诱导细胞周期抑制因子P21的表达，使细胞停留在G1期，从而引发细胞衰老[40-42]。DNA损伤还会激活P16通路，通过抑制细胞周期蛋白依赖激酶，阻止细胞周期的进行[32, 43]。在细胞衰老过程中，组蛋白修饰(如去乙酰化、甲基化)和DNA甲基化状态发生变化，进而导致基因表达的重编程[44-47]。例如，抑制组蛋白去乙酰化酶会导致组蛋白乙酰化水平升高，使染色质结构松散，影响基因表达，从而促进细胞衰老[48-49]。此外，蛋白质的错误折叠和聚集也是细胞衰老的重要标志之一[50]。细胞内的蛋白质质量控制系统(如分子伴侣、蛋白酶体)在衰老过程中功能下降，导致错误折叠的蛋白质积累[50]。这些错误折叠的蛋白质会形成异常的蛋白质聚集体，损伤细胞内其他成分，进而诱导细胞衰老[50]。在衰老的细胞中，线粒体功能障碍，产生活性氧(reactive oxygen species, ROS)，会诱导细胞进入衰老状态。此外，线粒体的损伤还会引发细胞内钙离子失衡和代谢紊乱，进一步促进细胞衰老[51-53]。
       衰老相关分泌表型(senescence-associated secretory phenotype, SASP)是衰老的另一种特异性表型，是衰老细胞分泌大量的促炎细胞因子、趋化因子、生长调节剂和基质金属蛋白酶等的统称[54-56]。SASP在一定程度上可以清除受损细胞，具有保护的作用，但长期来看，SASP会引发慢性炎症，损伤周围正常细胞，进一步促进衰老和相关疾病的发展[54-56]。清除衰老细胞或抑制SASP已成为治疗衰老相关疾病的重要方法[38, 57]。在细胞衰老过程中，SA-β-gal的表达和活性显著增加是检测细胞衰老的经典标志物[58]。此外，由衰老相关诱导因素引起的SASP分泌或周期蛋白抑制因子P16、P21的增加等也是判断细胞衰老的重要指标[4, 6]。

3 AMD中衰老相关改变和细胞衰老

       细胞衰老在AMD发生的各个阶段都扮演重要角色。在早期AMD的Drusen附近，可检测到激活并释放炎症因子的小胶质细胞。这些炎症因子形成以Drusen为中心的炎症微环境，进而可引起RPE和血管内皮细胞的衰老，对血-视网膜屏障完整性产生影响[59-60]。在AMD晚期，干性AMD可进展为湿性AMD。衰老的小胶质细胞和内皮细胞互作加剧了炎症反应、氧化应激，进而促进病理性新生血管的形成和渗漏[61]。以下讨论细胞衰老在AMD中的具体作用和机制。

3.1 SASP与AMD

       年龄是导致AMD发生的最强危险因素。研究表明，在衰老的小鼠RPE中存在衰老的细胞[3]，视网膜中视杆/锥细胞、小胶质细胞、米勒细胞、RPE细胞的衰老等均被证明与AMD发生有关[62-64]。在小鼠的视网膜氧化损伤模型(如碘酸钠和光损伤诱导的小鼠视网膜损伤模型)中，小鼠视网膜SASP产生增加，出现DNA损伤、免疫细胞浸润和炎症增强等与衰老相关的表型[65-67]。在早衰的OXYS大鼠模型中，视网膜表现出类似于AMD的病理变化如炎症、凋亡、DNA损伤和氧化应激等特征[68]。这些研究表明细胞衰老与AMD的发生、发展密切相关[10]。氧化或代谢应激可能导致视网膜细胞损伤，包括各种神经元和RPE细胞，进而引起免疫系统的适应性反应(如热休克蛋白的上调和自噬通路的激活等)，以修复损伤和维持稳态[2, 18-19]。随着损伤的持续刺激，应激细胞可能经历衰老或细胞死亡。衰老细胞可分泌促炎细胞因子和趋化因子，如白介素-6(interleukin 6, IL-6)、白介素-8(interleukin 8, IL-8)、肿瘤坏死因子-α(tumor necrosis factor alpha, TNFα)、白介素-1α(interleukin 1 alpha, IL-1α)、白介素-1β(interleukin 1 bata, IL-1β)、单核细胞趋化蛋白-1(monocyte chemotactic protein 1, MCP-1)、单核细胞趋化蛋白-2(monocyte chemotactic protein 2, MCP-2)、趋化因子C-X3-C-基元配体1(chemokine c-x3-c-motif ligand 1, CX3CL1)和粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony stimulating factor, GM-CSF)[6, 32]。这些研究表明，SASP在促进AMD或视网膜退行性改变的进程中起到重要作用。因此，靶向SASP的治疗能有效抑制相关疾病的发生。

3.2 自噬与AMD

       AMD的进展最初特征表现为RPE的萎缩性改变，以及溶酶体脂褐素和细胞外硬膜沉积的形成。巨自噬/自噬在AMD病理中的作用正在稳步显现[69]。自噬功能障碍与细胞表型向衰老细胞的转移有关，并且会导致组织稳态的丧失。自噬在AMD的不同发展阶段表现出不同的特点[69]。在AMD早期，自噬流较为活跃，有助于清除细胞废物和减轻氧化应激[69-71]。然而，在AMD晚期，自噬流显著减少，溶酶体酶活性降低，导致细胞内废物的堆积以及进一步的细胞损伤[69, 71]。在AMD的发病过程中，自噬和泛素-蛋白酶体系统作用于代谢废物或细胞碎片的清除[72]。自噬发生时首先形成自噬小体，自噬小体包裹受损的细胞器及蛋白质，再通过与溶酶体融合的方式将其降解。这一过程在维持RPE细胞的稳态中尤为重要[71-74]。研究表明，自噬相关基因5(autophagy-related gene 5, ATG5)和自噬相关基因7(autophagy-related gene 7, ATG7)的缺失与小鼠RPE细胞中出现的AMD样表型有关，包括RPE增厚、肥大、萎缩、色素异常或氧化蛋白质的积累等表型特征[71,74- 75]。选择性自噬是指通过特定受体蛋白识别和降解特定的细胞成分[74-75]。关键分子包括雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)、自噬相关基因、UNC-51 样激酶 1 (UNC - 51 - like kinase, ULK1)、微管相关蛋白1轻链3(microtubule-associated protein 1 light chain 3, MAP1LC3)和螯合体1(sequestosome 1, SQSTM1)，这些分子共同调控自噬小体的形成和成熟。在AMD中，选择性自噬障碍如自噬小体的形成或成熟障碍，导致细胞内废物堆积，进而加速疾病的发生[69]。自噬相关分子SQSTM1在连接自噬和泛素 - 蛋白酶体系统(ubiquitin-proteasome system, UPS)系统中起到桥梁的作用，其失调可能导致炎症和AMD的发展[76-77]。
       综上所述，自噬在AMD发病中起到重要作用，从代谢废物的清除、抗氧化应激到调控炎症反应及细胞衰老，自噬发生过程中的任何一个环境受损均会加剧AMD的发生和发展。

3.3 Bruch膜的衰老

       Bruch膜是位于脉络膜毛细血管层与RPE之间的一层薄薄的膜状结构。在AMD的发生过程中Bruch膜经历了明显的与衰老相关的变化，如脂蛋白样、富含胆固醇的载脂蛋白(Apolipoprotein, Apo)以及含B100的脂蛋白的积累[59-60]。Bruch膜的结构也可能会发生变化，如出现断裂或不规则的区域，这些变化会影响RPE细胞和脉络膜之间的连接[1- 2, 60]。在湿性AMD中，Bruch膜的改变可能导致异常的血管从脉络膜长入视网膜(称为脉络膜新生血管)，这些新生血管出现渗漏，进而导致视网膜受损及视力丧失[1, 60]。

3.4 视网膜上皮细胞的衰老

     RPE是一种高度特化、独特的上皮细胞，它与顶端的光感受器以及基底侧的Bruch膜和毛绒膜相互作用[78]。因其保持光感受器健康的重要功能，RPE在视力的维持上至关重要。随着年龄的增长和环境应激的累积，RPE会出现功能失调甚至死亡的现象。RPE细胞的衰老是导致AMD的潜在因素之一，在AMD的病因中起着核心作用[18-19]。脂褐素在RPE中的积累被认为是AMD中RPE功能障碍和衰老的主要原因[73, 79]。衰老的RPE细胞功能失调导致视网膜和脉络膜之间的血－视网膜屏障(blood-retinal barrier, BRB)破坏[80-82]。
       在人类和恒河猴的眼睛中可以检测到衰老RPE细胞的年龄依赖性积累，在其表皮周围还表现出细胞形态改变和细胞密度降低的特征[82-83]。从人类衰老或AMD供体眼中分离出来的RPE细胞可以检测到与衰老相关的基因特征，如p16、p21和p53等基因的表达[18, 84-85]。AMD的RPE细胞测序分析结果显示，AMD患者RPE细胞中STING的表达明显增加[67]。这些研究都表明RPE的衰老与AMD密切相关。RPE细胞中的线粒体通过氧化磷酸化过程产生ATP，并伴随ROS的生成。随着年龄增长和环境压力的增加，线粒体损伤逐渐积累，导致其功能受损、ROS产生增加[86-88]。目前多项研究结果表明，AMD患者RPE中存在线粒体DNA(mtochondrial DNA, mtDNA)损伤，受损的mtDNA直接影响电子传递链(electrontransferchain, ETC)复合物，进而导致ATP的生成减少，RPE细胞的能量供应不足[89-94]。高脂饮食、吸烟以及暴露于高强度光线会进一步加剧RPE的氧化负担，细胞大分子的氧化损伤增加[83, 95-99]。RPE中还存在多种抗氧化机制来抵抗氧化损伤，如核呼吸因子2 (nuclear respiratoty factor 2, Nrf2)通路，该通路具有调控解毒和抗氧化酶的表达的作用[100]。在生理情况下，Nrf2与Kelch 样ECH关联蛋白1(kelch-like ECH-associated protein 1, Keap1)结合并存留在细胞质中，但在氧化应激发生时，Nrf2会释放并转移到细胞核中，从而促进保护基因的表达[100-102]。然而，在AMD的RPE细胞中，这些抗氧化系统的作用减弱，对氧化损伤的易感性增加。
       研究表明，在易患AMD的患者中，RPE的病理改变常发生在视杆/锥细胞死亡之前[4]。RPE的衰老会导致其功能和结构的改变，从而失去对光感受器细胞的营养支持作用，最终引起光感受器细胞的损伤或衰老。

3.5 光感受器细胞的衰老

       光感受器细胞对光信号的感受和传导至关重要。细胞衰老导致其功能下降，表现为视力模糊和视野丧失[10]。在人类视网膜中，感光细胞死亡是一个缓慢但明显的过程，会随着年龄的增长而持续进行[10]。在视网膜中，视杆细胞比视锥细胞更早发生死亡。约30%的视杆细胞出现丢失的现象时[1, 10]，视锥细胞还会继续以微妙的方式发生变化，直到衰老晚期[1]。环磷酸鸟苷-腺苷酸合成酶(cyclic guanosine monophosphate-adenosine monophosphate synthase, cGAS)-干扰素刺激因子(stimulator of interferon genes, STING)信号通路是与促炎因子分泌有关的重要DNA传感器，同时还与SASP密切相关[103-105]。我们近期的研究表明，在AMD患者中，cGAS和STING染色质开放程度增加[67]。在碘酸钠诱导的氧化损伤模型中，cGAS-STING信号通路被激活；在光损伤诱导的视网膜变性模型中，光感受器细胞DNA损伤泄露，进而诱导小胶质细胞中cGAS-STING信号的激活和SASP的分泌，如MCP1、抗黏液病毒1蛋白(the murine myxovirus resistance 1, Mx1)、TNF-α、IL-6、IL-8等[66-67]。通过抑制剂JQ1或dBET6抑制Brd4的作用也会间接抑制STING的激活，同时减少SASP的分泌，并保持视网膜结构和功能的完整性[66-67]。

3.6 小胶质细胞的衰老或活化

       小胶质细胞在维持视网膜神经元功能和结构中起重要作用。在生理条件下具有免疫监视、营养和调控神经功能的作用；在病理条件下发生增殖、活化和迁移并引起炎症反应，导致邻近细胞的损伤[106-107]。小胶质细胞能动态检测神经环境，对最微小的神经损伤做出快速反应[106-107]，其活性和吞噬作用会随着年龄的增长而改变，这些细胞对损伤的反应也随着年龄的增长而改变[26, 108-109]。在生理条件下，视网膜中的小胶质细胞主要分布在GCL、IPL和OPL[26, 108, 110-111]。在病理条件(如光损伤，氧化应激或衰老等条件)下，视网膜中的小胶质细胞感知RPE、光感受器细胞损伤产生的代谢废物发生活化，从GCL、IPL或OPL迁移到ONL和RPE行使清除代谢废物的功能[67, 110-111]。
       活化的小胶质细胞通过Toll样受体4(toll-like receptor, TLR4)、白介素-1受体(interleukin-1 receptor, IL-1R)和STING等信号激活核因子-κB(nuclear factor kappa-B, NF-κB)促进炎症因子的表达[67, 112-115]。在炎症和应激反应中，p38 丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)和c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)信号通路会被激活，进而调控小胶质细胞的反应。实时成像研究结果表明，视网膜中的“静息态”小胶质细胞会出现衰老变化，表现为分支减少和动态行为减慢[116-117]。衰老的小胶质细胞对损伤的动态反应减弱。这些变化表明，衰老的小胶质细胞可能无法承载免疫监视功能，并且对损伤具有异常和更缓慢的反应[116-117]。
       在AMD的早期阶段，视网膜小胶质细胞迁移到视网膜下间隙会诱导RPE细胞发生重大变化，从而使小胶质细胞进一步积聚，增加视网膜外层的炎症，并为新生血管病变的形成创造有利环境[111-113]。此外，与年龄相关的小胶质细胞易位到视网膜下空间与细胞内脂褐素的积累有关，小胶质细胞通过摄取A2E(脂褐素的关键成分双维A酸)增加活化、降低趋化性以及失调补体的活化[118]。也有研究表明，在病理条件下，RPE触发小胶质细胞的促炎(M1)转变，同时 CXC 趋化因子受体 1(CX3C chemokine receptor1, CX3CR1)的表达减少[112, 119]。激活的小胶质细胞定位于ONL和RPE层，并调节中性粒细胞功能，触发它们的激活，从而诱导早期RPE变化。M1小胶质细胞还通过与小胶质细胞上的CD14相互作用诱导中性粒细胞黏附介质(整合素β1/α4)的表达[26]。此外，通过抑制小胶质细胞中的AKT丝氨酸/苏氨酸激酶2(AKT serine/threonine kinase 2, Akt2)，还能降低小胶质细胞诱导的中性粒细胞激活和中性粒细胞进一步损伤的RPE改变[26, 120]。在脉络膜新生血管(choroidal neovascularition, CNV)模型中，年轻的小胶质细胞在激光损伤后16 d从损伤部位扩散，而衰老的小胶质细胞在激光损伤时仍聚集在一起，扩散速度降低[121]。这些数据表明虽然小胶质细胞损伤反应在年轻的视网膜有提示和快速启动损伤的开始，但紧随其后的是一个快速下调损伤的程序，而在老年视网膜中损伤应答程序启动慢，其后续下调程序启动也变得缓慢[121-122]。这些失调的反应可能导致内稳态的紊乱和视网膜中神经炎症状态的持续活跃。
       综上所述，小胶质细胞的衰老和活化在AMD的疾病发展中发挥重要作用。因此，合理地调节小胶质细胞衰老表型的能力有望“恢复”视网膜的免疫环境，为预防与治疗年龄相关的视网膜疾病提供新思路。

3.7 血管内皮细胞的衰老

       血管内皮细胞(vascular endothelial cell, VEC)是一种高度动态的单层细胞，其完整性影响着血管生成[123]。视网膜内皮细胞具有维持视网膜内环境和营养供应的功能[124]。VEC衰老是一种结构和功能变化的病理生理过程，包括血管张力失调，内皮通透性增加，动脉僵硬度提高，血管生成和血管修复受损以及VEC线粒体生物生成减少等特征[125-127]。衰老的VEC具有高度活性、分泌性和促炎性，并且具有异常的形态表型[128]。而这些功能性的特征出现也往往伴随着AMD的形成，如视网膜血管渗漏和新生血管的形成，以及炎症细胞的入侵等。研究表明，VEC的衰老会导致NO生成减少，血管扩张功能受损，从而引起局部血流减少，最终影响视网膜脉络膜的营养供给，而在衰老的内皮细胞中血管内皮生长因子(vascular endothelial growth factor, VEGF)水平升高，进而诱导病理性新生血管生成，导致湿性AMD的发生[11,129-130]。衰老的VEC通过细胞间通讯网络影响周围细胞的行为，微环境中的细胞因子和趋化因子不仅影响内皮细胞自身的功能，还通过旁分泌的方式作用于RPE细胞、巨噬细胞和其他视网膜细胞，形成复杂的细胞间交互网络，共同参与AMD的病理进程。
       总而言之，VEC的衰老通过多种机制在AMD的发生和发展中发挥关键作用。深入理解内皮细胞衰老在AMD中的具体作用机制，有助于开发针对性的治疗策略，抑制AMD的发生、发展。

4 总结与展望

       综上所述，在AMD进展中，细胞衰老展现了重要作用。衰老的细胞在面对各种应激刺激后进入不可逆的细胞周期停滞状态，失去增殖能力。细胞衰老的分子机制非常复杂，涉及端粒缩短、DNA 损伤、表观遗传改变、线粒体功能障碍和自噬异常等多方面的变化。SASP也是细胞衰老的重要特征之一，SASP 会分泌大量的促炎细胞因子和趋化因子。长期来看，这些分泌物会引发慢性炎症，损伤周围正常细胞，促进 AMD 等退行性疾病的发展。在视网膜中，Bruch膜、RPE、光感受器细胞和内皮细胞的衰老和丢失，会引起视网膜结构和功能的改变，加速AMD疾病的发展(图2)。视网膜小胶质细胞作为一种免疫监测细胞在AMD的发生、发展中也扮演着重要的角色，其衰老和活化都能在一定程度上促进AMD疾病的发生(图2)。以上观点表明，细胞衰老是AMD发生的重要环节，延缓细胞衰老或清除衰老细胞，改善细胞衰老相关微环境在治疗AMD 方面具有巨大潜力。进一步深入研究细胞衰老在AMD中的发病机制以及靶向视网膜衰老细胞的药物或手段至关重要，这将为临床治疗AMD 提供新的理论依据和研究方向。
图2 AMD中细胞衰老和改变
Figure2 Cellular senescence and changes in AMD
图片总结了AMD发展中5种细胞的衰老表型，其中小胶质细胞表现为激活、炎性因子分泌、形态改变；Bruch膜表现为断裂、drusen的形成；RPE表现为萎缩、迁移、脂褐素沉积；血管内皮细胞表现为新生血管、炎症、屏障破坏；视杆细胞表现为退行、凋亡、功能障碍；本图由WPS Office绘制。
This figure summarizes the senescent phenotype of five cell types in the development of AMD: Microglia activation, inflammation, morphological changes; Bruch's membrane: rupture, drusen formation;RPE (Retinal Pigment Epithelium): atrophy, migration, lipofuscin formation;Vascular endothelial cells: angiogenesis, inflammation, barrier dysfunction;Rod: degeneration, apoptosis, dysfunction.

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1、广东省自然科学基金 (2024A1515010518)，广州市市校(院)企联合资助专题 (2023A03J0184)。
This work was supported by the Natural Science Foundation of Guangdong Province (2024A1515010518) and Guangzhou Municipal-University (Institute)-Enterprise Jointly Funded Projects (2023A03J0184).()
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一亿年进化出的晶状体有多重要？

How important is the lens evolved in 100 million years?

发布于: 2022-12-01
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