调控昼夜节律系统对延缓皮肤炎症性老化的新兴作用

昼夜节律系统与睡眠紧密关联，对同步生物体的日常行为活动和环境周期性的明暗变化至关重要，并从系统和细胞两种层面上运作^{[1, 2]}。位于下丘脑前部视交叉上核（SCN）的中央起搏器响应环境光的输入，通过神经和内分泌信号调节着系统的昼夜节律^{[3, 4]}。细胞水平上则是由几乎所有细胞中都存在的细胞自主的分子振荡器所控制，并形成一条以24 h为周期的转录翻译反馈环（TTFLs）（图1）^[5]。核心的TTFLs由两种活化因子[脑和肌肉芳香烃受体核转运样蛋白1基因（BMAL1）和昼夜节律运动输出周期故障基因（CLOCK）]和两种抑制因子[周期基因（PER）和隐花色素基因（CRY）]组成^{[6, 7]}。干扰其中任何一种基因都可能导致节律稳态的破坏^[8-10]。

近年来，通过靶向干扰模式生物中不同的时钟基因，研究者们逐渐将生物节律与衰老这一慢性疾病联系了起来^[11-13]。

早期就曾有研究报道，小鼠BMAL1的缺失导致了受损的节律行为，因而也出现了一些早衰表型以及寿命缩短的现象^[14]。CLOCK的活性也被证实在调控正常生理状态以及晶状体和皮肤的衰老中至关重要^[15]。大量研究表明，生物节律影响衰老的分子机制与多种因素有关，包括活性氧平衡、氧化应激反应、细胞和生物体代谢、DNA修复以及免疫系统和炎症反应等^{[6, 16]}。其中，炎症作为衰老的十二大标志性特征之一，已经被广泛报道受昼夜节律系统调控^{[17, 18]}。炎性衰老是身体免疫引起慢性炎症反应所产生的加速老化现象^{[19, 20]}。然而传递炎症信号的分子路径及其在自然衰老中的影响仍不十分清楚^[21-23]。值得一提的是，细胞衰老普遍伴随着衰老相关分泌表型（SASP）的表达，从而影响整个生物体的衰老进程（图2）^[24]。目前已知的调节SASP表达的因素有功能障碍的线粒体^[25]，持续的DNA损伤反应^[26]，核因子-κB（NF-κB）^[27] 和哺乳动物雷帕霉素靶蛋白（mTOR）^[28]。然而，这些因素介导的通路都不能清楚地解释昼夜节律系统、炎症反应和机体衰老之间相互作用的具体机制。

图1.  哺乳动物的分子时钟和三种TTFLs^[5]。

 
昼夜节律紊乱引发炎症性衰老

任何与昼夜节律周期的偏离都会导致寿命缩短约20%，且节律周期和生物体的健康状况互相影响^[29]。研究者们往往通过干扰节律基因表达来研究昼夜节律在衰老中的作用^[30]。例如与野生型小鼠100%的生存率相比，敲除BMAL1基因会导致其平均寿命缩短到8个月，并伴随多种衰老相关的生理表现^[31]。另外， CLOCK缺陷的小鼠平均寿命会下降10%，并且更易出现皮炎^[32]。PER3沉默的人源角质形成细胞也显示了上调的基质金属蛋白酶1（MMP-1）蛋白的分泌，影响皮肤衰老^[33]。据估计，约10%的哺乳动物基因处于昼夜节律转录控制之下^[34]。昼夜节律在睡眠、代谢及免疫等过程中均发挥着显著作用，这些行为过程与昼夜节律相互调节^[35]。同样的机制也存在于炎症性疾病中，生物钟紊乱可诱导或加重炎症反应，同时炎症反应也可引起生物钟紊乱^[36]。在节律基因突变模型中，组织中的促炎性细胞因子含量明显增加^[37]。临床研究也证明了PER1表达与诱导型一氧化氮合酶（iNOS）活性之间存在依赖关系^[38]。此外CLOCK的过表达也能激活NF-κB介导的炎症通路，导致大量促炎细胞因子释放^[39]。另外，CRY也已被证明是天然免疫和炎症反应的基本免疫调节成分^[40]。 

图2. 炎症和衰老的相互作用以及在分子、细胞和器官水平上的炎症衰老^[24]。

炎症相关通路与衰老的关系也正逐步深化，消除炎症可能是潜在的抗衰老策略^[17]。炎症相关信号传导通路，例如NF-κB、去乙酰化酶家族（SIRT）、mTOR和Toll样受体（TLR）等信号通路能通过多种途径调控炎症，最终影响衰老进程（图3）^[41-43]。NF-κB参与调控众多炎症因子基因表达，涉及组织应激和损伤、细胞分化和凋亡、机体防御反应等过程^{[24, 44]}。腺苷单磷酸活化蛋白激酶（AMPK）-SIRT通路的下调也会引发炎症性衰老^[45]。 激活AMPK也会导致细胞NAD+：NADH比例的上调并促进SIRT的表达，从而抑制NF-κB的活化。mTOR同样是较为公认的调节寿命的信号通路，参与调控细胞生长、分化、增殖、迁移和存活^[46]。氧化应激诱导的分子损伤也参与慢性炎症，通过环鸟苷酸-腺苷酸合成酶-干扰素基因刺激因子（cGAS-STING）通路对胞质染色质片段的固有免疫识别及其下游介质也在衰老进程中发挥潜在作用^{[47, 48]}。

图3. 联系衰老的慢性炎症信号通路^[42]。

昼夜节律紊乱致皮肤炎症性衰老的应对策略
. 抗蓝光辐射
近几十年来，电子设备和其他人造光源的使用日益增多，改变了蓝光（400-500 nm）的照射模式（图4a）^[49]。蓝光对皮肤的直接影响主要体现在其与发色团的相互作用，发色团的活化会导致活性氧（ROS）和活性氮（RNS）的过量产生以及色素沉着，造成线粒体损伤，影响细胞增殖及活性，激活细胞内丝裂原活化蛋白激酶（MAPK）信号通路，增加促炎信号传导和胶原代谢紊乱等（图4b）^[50-52]。除了直接影响皮肤，蓝光还能通过扰乱正常的昼夜节律对人体和夜间的皮肤修复过程产生负面影响，如蓝光会降低皮肤细胞中BMAL1和PER1等的转录水平等^[53-56]。这些因素最终都导致了蓝光直接或间接作用于皮肤的光老化。

图4. 蓝光对皮肤的生物学效应^[51]。 (a) 不同波长光对皮肤的照射模式。(b) 蓝光对皮肤的影响及相关信号

为了对抗蓝光对皮肤的直接和间接影响，目前的两种策略，一是通过一些活性成分吸收、散射或反射蓝光，二是使用某些抗氧化剂来避免由ROS和RNS产生的皮肤损伤。多年来，无机材料如二氧化钛、氧化锌、氧化铈、氧化铁、钙钠硼硅酸盐等一直被用于第一道防线中的蓝光保护，甚至用于治疗光敏性皮肤病患者^[57-60]。植物提取物也可凭借抗氧化活性用作防护蓝光成分。越橘（Vaccinium vitis-idaea）提取物因富含抗氧化成分可以作为一种自由基清除剂，预防皮肤光老化及皱纹产生^[61]。印度人参（Withania somnifera）根提取物可以靶向成纤维细胞并促进真皮蛋白的合成，对抗人工可见光（AVL）的有害影响^[62]。其他热门植物原料，如大米和米胚芽提取物^[63]、可可种子^[64]和姜花（Hedychium coronarium）根提取物^[65]也显示出抗蓝光特性。某些藻类提取物，如巴西栅藻（Scenedesmus rubescens）提取物、褐藻（Zonaria tournefortii）提取物，可以屏蔽蓝光并保护皮肤免受氧化应激的影响，预防蓝光老化^{[60, 66, 67]}。此外，假单胞菌（Pseudoalteromonas）发酵提取物也可以保护皮肤免受蓝光的伤害，并降低MMP1水平^[68]。类胡萝卜素如胡萝卜素、叶黄素、玉米黄质和番茄红素也是一类出色的植物源抗氧化剂和蓝光保护剂，可以从胡萝卜根提取物和种子油以及酸浆（Physalis alkekengi）萼提取物万寿菊油树脂中提取，防止皮肤的蓝光老化^[69-73]。

. 抗节律紊乱
昼夜节律系统对外界信号高度敏感，某些分子调节剂可通过反馈机制直接靶向或作用到昼夜节律系统。目前，研究者主要通过分子化合物库大规模筛选具有靶向调控昼夜节律功能的分子调节剂^{[74, 75]}。除此之外许多护肤原料也被开发用作皮肤节律调节。例如，三肽-32（Ser-Thr-Pro-NH2），被证实能够激活角质形成细胞中CLOCK and PER1的表达^[76]。猴面包树（Adansonia digitata）提取物可以通过促进miR-146a的表达来上调PER1表达，促进皮肤细胞的I型胶原生成和DNA修复^[77]。由向日葵（Helianthus Annuus）籽油、乙基阿魏酸酯、迷迭香（Rosmarinus Officinalis）叶提取物和生育酚组成的抗氧化原料被认为可以保持皮肤的自然生物节律，加强皮肤屏障^[78]。另外从山茱萸（Lindera strychnifolia）中获得的富含寡聚α-葡聚糖的原料可以恢复CLOCK的表达，并有潜力用于皮肤抗衰^[79]。一种包含多肽、黄酮和迷迭香叶提取物的组合物也被证明可以重新同步OPN5和PER2的生成，并在蓝光压力下增加褪黑素的生成[80]。穿心莲叶提取物还被用作老化皮肤细胞昼夜节律的调节剂，促进皮肤活化^[81]。通过分子生物学开发的水解酵母蛋白表现出增加角质形成细胞表达CLOCK、BMAL1和PER1的能力^{[82, 83]}。九肽-1被认为可以增强JARID1A的表达，从而激活细胞中的CLOCK和BMAL1表达，上调PER和CRY，唤醒衰老细胞的新陈代谢^{[84, 85]}。由从酵母（Saccharomyces cerevisiae）的细胞质和线粒体成分中提取的糖蛋白混合物以及谷氨酸、缬氨酸和苏氨酸三种氨基酸构成的组合物被发现可以从昼夜节律角度改善紫外线压力下的昼夜节律失衡^{[86, 87]}。

改善睡眠的原料或营养成分也为昼夜节律调控打开了新思路。目前，广泛报道的活性睡眠原料可以大致分为以下几类：激素类、氨基酸及其衍生物，植物提取物，传统中药成分，益生元以及牛奶蛋白类^[88-92]。通过将普罗旺斯的薰衣草油溶性天然提取物或澳大利亚茶树油与三庚酸甘油酯组合，两种组合物都被开发用于通过吸入嗅觉化合物来改善睡眠质量，减少皮肤老化^[93]。一种基于植物培养基从乳酸乳杆菌（Lactococcus lactis）中提取而来的后生元活性物被证明可以在蓝光过度暴露后重新同步皮肤细胞中CLOCK和CRY1的节律表达^[94]。藏红花酸也被开发为一种活性抗衰老皮肤保护剂，可以在深夜和蓝光压力下恢复褪黑素的平衡，激活皮肤抗氧化级联^[95]。

. 抗节律调控的炎症通路
生物钟基因在生物节律与氧化应激和炎症的相互作用中扮演着重要的角色。因此受昼夜节律调节的炎症通路阻断剂也可用于延缓衰老过程。近期一项动物实验发现，生物钟基因PER2与炎症诱导的疾病相关，PER2缺陷或可通过受激活调节正常T细胞表达和分泌因子（RANTES）等趋化因子导致衰老相关表型^[96]。另外CLOCK的甲基化水平较低被证明和IL-8炎症因子水平较高相关^[97]。睡眠节律紊乱还可通过激活NF-κB导致IL-6升高，同时海马组织中PER2表达显著降低，而阻断NF-κB活性可以逆转降低的PER2蛋白水平^[98]。生物钟基因的表达改变还能够通过TLR4/NF-κB信号通路参与衰老相关疾病的发展，其中TLR4可以激活NF-κB促进炎症细胞因子的产生。睡眠剥夺的小鼠昼夜节律紊乱，引起促炎细胞因子上调，这一过程可以被CRY1的过表达逆转，抑制NF-κB的活性^[99-101]。另外巨噬细胞中Akt信号的下游靶标细胞外信号调节激酶（ERK）、Akt和MAPK激酶1（MEK1）的活性和表达也显现出一定的昼夜节律，且巨噬细胞中生物钟基因核受体亚家族1组D成员1（REV-ERBα）或Bmal1的缺失能够增强细胞因子的产生，并破坏Akt的节律性表达。睡眠节律紊乱造成的时钟节律基因BMAL1表达失调，还会导致MAPK/ERK信号通路被激活，ERK的磷酸化水平逐渐升高，进一步上调了炎症性因子IL-6和MMP3、MMP13等的表达水平^{[102, 103]}。在哺乳动物中，CRY除了可以参与调节生物钟外，还可以调节（cAMP-PKA）信号通路。有报道表明，CRY的过表达可抑制cAMP-PKA信号通路，减少炎症反应^[104-106]。

结论

昼夜节律影响着身体的正常生理活动，慢性炎症在昼夜节律与衰老之间的关联机制中起着关键作用。通过探讨昼夜节律与炎症的关系以及介导炎症和衰老的信号通路，本文旨在阐明由炎症介导的昼夜节律紊乱导致衰老的清晰途径或机制，并从皮肤衰老角度总结当前应对昼夜节律紊乱引起的炎症性老化的策略。由于蓝光能通过直接的氧化应激效应和间接的节律失衡效应诱导炎症性皮肤老化，研究人员开发了多种根本性的解决方案来对抗蓝光诱导的老化。另外为了应对多种外部因素导致的皮肤外周时钟紊乱，除了一些临床或临床前的药物成分，更多的护肤原料也正被逐步开发出来。最后我们还清晰地介绍了目前报道的受昼夜节律影响的几条炎症通路。通过研究昼夜节律、炎症通路和衰老之间的相互作用，分子药物阻断剂或靶向炎症通路的某些成分都有望用于衰老治疗中，例如靶向TLR4/NF-κB、PI3K/Akt、MAPK/ERK等信号通路。我们也希望这篇综述在未来能够不止在皮肤学，也能在其他领域的机体的抗衰老研究中做出贡献。

作者：张秋玲1、崔俊毅¹、张钰莹¹、余斌¹、陈浩¹、张廷志³、颜少慰¹、    
                   Maurice A.M. van Steensel ²
                   1 熬夜肌实验室系统工程（上海）有限公司、
                   2新加坡南洋理工大学李光前医学院、
                   3水羊化妆品制造有限公司

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