2025, Vol. 49
文章信息
- 张泽斌, 姜楠, 唐永政, 王春德, 卢霞. 2025.
- ZHANG Zebin, JIANG Nan, TANG Yongzheng, WANG Chunde, LU Xia. 2025.
- Argopecten属海湾扇贝和紫扇贝的寿命调控机制
- Regulatory mechanism of lifespan of bay scallops and peruvian scallops of Argopecten
- 海洋科学, 49(3): 116-125
- Marine Sciences, 49(3): 116-125.
- http://dx.doi.org/10.11759/hykx20241030002
-
文章历史
- 收稿日期：2024-10-30
- 修回日期：2025-01-06
2. 中国科学院烟台海岸带研究所, 山东 烟台 264003
2. Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China
衰老的分子机制研究一直以来都是国际生命科学的热点和前沿。在酵母(Saccharomyces cerevisiae)、果蝇(Drosophila melanogaster)、线虫(Caenorhabditis elegans)和小鼠(Mus musculus)等模式生物的研究中发现影响衰老的因素包括遗传和环境因素, 并且生物寿命的演化主要来源于遗传因素的改变, 即基因突变的积累[1]。基因调控与能量代谢失衡以及彼此之间的相互作用是导致衰老发生与发展的核心原因。IIS/FoxO通路是第一个被发现的营养感应途径, 也是首个动物寿命调节信号通路[2, 3]。在线虫寿命周期的研究中, 科学家发现不同形式营养限制介导的长寿均由IIS/FoxO信号通路积极调控, 而该通路下游转录因子Daf-16则是寿命长短的决定因素[4, 5]。在寿命调控中, Ras/MAPK信号级联在IIS通路中同样重要[6, 7], 其核心成员MEK1也广泛参与多种衰老和寿命途径的调节[8, 9]。营养限制和维持基因组稳定性作为两个重要的抗衰老干预措施, 同时也是研究衰老以及年龄相关疾病背后机制的重要策略, 其能有效抑制生物体内损伤的累积, 从而减缓衰老速度, 延长寿命[10]。目前, 关于寿命调控基因的研究多在陆生模式生物中进行, 主要通过诱变或基因敲除等方法获得突变体, 在延长寿命的同时往往会损害其健康性能, 比如生长、运动和繁殖等性能[11–13]。因此, 在进化中的基因突变自然延长寿命且保持健康的生物将是理想的研究模型。
海洋是生命的起源, 不同物种间寿命迥异, 尤其以海洋双壳贝类最为典型, 不同种间寿命周期跨度1~ 400 a[14]。此外, 海洋双壳贝类还具有结构简单、代谢调节快速、参与适应性调控的途径较短等特点[15, 16]。因此, 有研究者提出海洋双壳贝类非常适合作为研究衰老与寿命调控机制的新模式生物[17]。Argopecten属的紫扇贝(Argopecten purpuratus)和海湾扇贝(Argopecten irradians)由共同祖先分化而来, 在适应各自环境的进化过程中, 发生了不同的遗传变异, 可能导致二者的代谢差异和生存策略的不同, 使其具有截然不同的寿命周期。海湾扇贝的寿命小于2 a, 而紫扇贝的寿命长达7~10 a, 是接近可忽略衰老的类型[18–21]。其种间杂交一代中部分个体的寿命明显延长, 介于双亲之间, 并且随着年龄的增长, 个体的体质量往往会呈现增加的趋势(未发表)。早在2007年, ESTABROOKS等[22]就通过比较紫扇贝与海湾扇贝的端粒酶活性, 发现紫扇贝体内端粒酶含量更高, 推测这一差异可能源于进化中的遗传变异。因此, 寿命周期显著不同的两种Argopecten属扇贝为探讨环境和遗传因素对自然种群衰老及寿命的影响提供了理想材料[17, 23, 24]。
本文对IIS信号通路核心基因在海湾扇贝与紫扇贝寿命调控中的潜在作用进行概述, 旨在为海洋双壳类动物以及其他陆生动物寿命决定机制提供一定的参考。本研究不仅丰富了对衰老与长寿机制的理论认知, 还为提高扇贝寿命及规格的育种技术提供理论支持和潜在的生物标记物。
1 IIS通路核心基因在长寿与衰老中的研究目前, 已发现多种途径参与动物衰老和寿命的调节, 包括胰岛素/胰岛素样生长因子信号通路(IIS通路)、mTOR信号通路、JNK通路和AMPK通路[25–27]。IIS通路是一种激素调节的细胞信号通路, 涵盖胰岛素及胰岛素样多肽、其相应的细胞表面跨膜受体、受体底物和下游效应因子, 在从酵母到无脊椎动物(线虫、果蝇)再到哺乳动物的进化过程中, 均相对保守[28]。在IIS通路中, 胰岛素样生长因子(Insulin Like Grawth Factor, IGF)系统是重要的调节点, 参与多种细胞过程的调控, 包括生长、自噬、衰老以及长寿等。IGF系统由配体(IGF)、受体(Insulin Like Growth Factor Receptor, IGFR)和IGF结合蛋白(Insulin Like Growth Factor Binding Protein, IGFBP)组成, 被认为是调控衰老过程和健康寿命的关键因素之一[29, 30]。环境应激, 如饥饿、氧化应激、紫外线辐射和热量限制, 都会引发IGF/IGF1R水平的协调变化, 从而诱导生理反应, 保护机体免受有害影响。比如长期营养限制能抑制IGF信号, 从而延缓生长和代谢, 进而促进健康长寿[31, 32]。当胰岛素或胰岛素样生长因子(IGF)与其细胞表面受体(IGF1R)结合时, 受体被激活并导致受体底物的磷酸化, 从而通过IIS通路的两个主要分支(PI3K/AKT途径和Ras/MAPK途径)启动信号传导(图 1)。
在PI3K/AKT途径中, 二聚体受体触发一系列的自动磷酸化, 生成的PIP3作为第二信使, 依次激活磷脂酰肌醇依赖蛋白激酶1(PDK1)和蛋白激酶B(AKT或PKB)。其中, 张力蛋白同源物(PTEN)负责对PI3K/AKT途径的负向调控。同时, 活化的AKT转移至细胞核, 在3个保守残基上磷酸化FoxO, 促使其从细胞核转移到细胞质, 从而抑制依赖FoxO的靶基因转录[33]。PTEN具有保护机体免受癌症侵害并促进抗衰老的作用。作为唯一可抑制PI3K/AKT途径活性的调控因子, 高表达的PTEN能提高FoxO的转录活性, 而FoxO在抗衰老和长寿中起着关键作用[34, 35]。作为长寿相关途径的下游效应因子, FoxO通过调控细胞代谢、DNA修复、抗氧化和蛋白质合成等多种过程, 对长寿产生积极影响[36, 37]。
Ras/MAPK途径主要由激酶级联组成, 依赖蛋白Grb2和鸟嘌呤核苷酸交换因子直接或通过对接蛋白与活化的IIS受体结合, 进而激活小GTP酶Ras。此过程引发丝氨酸/苏氨酸激酶Raf、MAPK激酶MEK1和MEK2逐步激活, 最终激活ERK1和ERK2[38, 39]。作为双特异性蛋白激酶家族的成员, MEK1的核心功能是促进ERK1/2在苏氨酸和酪氨酸上的磷酸化, 通过调节关键转录因子的磷酸化水平来控制多种生理功能, 在Ras/MAPK信号传导中发挥核心作用[40–42]。以MEK1为核心成员的3层蛋白激酶级联反应Raf/MEK1/ERK广泛参与mTOR和IIS等许多衰老和寿命途径的调控[43]。在果蝇中, 应用MEK1激酶抑制剂抑制Ras/MAPK途径可减少IIS信号并延长寿命[44]。此外, MEK1还可磷酸化FoxO的丝氨酸残基, 导致其泛素化并通过蛋白酶体降解, 进而影响寿命[45–48]。作为另一个衰老调控网络中的关键途径, 保守的mTOR通路已知与Ras/MAPK途径相互作用[43]。在小鼠的T细胞中, MEK1作为上游激活剂能够促进mTORC1激活, 与寿命延长呈负相关[49–51]。
2 Argopecten属扇贝中IIS通路核心基因的结构变异与表达模式在后生动物类群中, 不同物种间寿命周期存在着极大差异, 如线虫与人类由共同祖先urbilaterian分化而来, 但二者的寿命周期相差了2 000多倍。与物种间的巨大差异相比, 物种内寿命的变异较为有限, 这表明寿命周期的多样性主要取决于特定的遗传因素[52, 53]。对几种处于不同进化地位的陆生模式生物(酵母、线虫、果蝇、小鼠等)的研究结果表明, 基因的确可以影响生物的衰老及寿命, 这种寿命的演化来源于基因突变的逐渐积累。
WANG等[54]在海湾扇贝(A. irradians)和紫扇贝(A. purpuratus)中分别鉴定出唯一的IGF及其受体, 并分别命名为IGF2和IGF1R。研究发现, IGF2和IGF1R功能结构域中的氨基酸变异, 似乎是导致这两种扇贝间配体—受体结合能力及信号传导差异的关键, 从而使海湾扇贝呈现短寿命表型, 这与先前关于IGF2和IGF1R在其他物种中的研究结果相吻合[55–58]。PTEN蛋白PTPc_dsPC功能结构域内的核心序列“HCxxGxxR”对其催化和磷酸化活性至关重要[59, 60]。海湾扇贝与紫扇贝的PTEN蛋白在该核心基序邻近位点的突变可能导致两种扇贝磷酸酶活性的差异[61]。对海湾扇贝和紫扇贝中的FoxO基因研究发现, 多个氨基酸位点存在变异, 特别是在Akt磷酸化位点附近存在的两个氨基酸变异, 可能影响FoxO蛋白的磷酸化水平[62]。此外, 海湾扇贝FoxO蛋白第76位的特异性潜在磷酸化位点Thr位于功能结构域内, 推测其可能会影响DNA结合结构域的磷酸化, 从而抑制FoxO的转录活性[62]。YUAN等[63]克隆并分析了海湾扇贝和紫扇贝MEK1序列的差异, 发现在保守结构域S-TKc中以及ATP结合位点上下游的SNP可能导致其活性不同。
同缢蛏(Sinonovacula constricta)研究结果一致[64], 海湾扇贝和紫扇贝IIS通路中的5个核心基因(IGF2、IGF1R、PTEN、FoxO和MEK1)在不同发育阶段不同组织中均有表达, 表明这些基因均不是组织特异性基因, 推测两种扇贝可能通过差异性表达IIS通路核心基因以调控生长发育与寿命。其中, 海湾扇贝和紫扇贝外套膜和性腺中的IGF2和IGF1R表达量随龄期增加呈现上升趋势, 而FoxO和PTEN表达量随龄期增加呈下降趋势, 因此WANG等[54]推测外套膜和性腺是扇贝衰老的代表性组织。抑制MEK1可以上调超氧化物歧化酶(Superoxide Dismutase, SOD)的活性[65], 而MEK1在海湾扇贝所有组织中的表达随着衰老显著上调, 可能通过影响抗氧化水平促进组织衰老。
3 Argopecten属扇贝中IIS通路核心基因对饮食限制和电离辐射的响应机制研究表明, 参与调控衰老的基因通常是经典信号通路的重要组成部分, 这些信号通路将衰老速率与环境因素和生理状态有机地联系起来, 这可能是生物进化过程中多样性的基础[66]。饮食限制和电离辐射常用于检测基因在响应环境压力下的适应性表现。其中, 饮食限制作为不同物种延长寿命的最有效的非遗传手段[67, 68], 能够下调IIS通路的活性[69]。有学者提出, 双壳贝类生活环境中季节性的营养不足可通过降低代谢率与生长以延缓衰老, 从而延长寿命, 这一机制与模式生物饮食限制相似[70]。与饮食限制作用相反, 电离辐射可以直接诱导DNA损伤或者通过增加活性氧(Reactive Oxygen Species, ROS)的生成间接促进基因表观修饰和DNA损伤, 从而加速机体老化。电离辐射的长期影响还包括与年龄相关的ROS水平上升、细胞凋亡增加、组织纤维化和炎症反应等, 这些都可能引发机体衰老并缩短寿命[71–74]。此外, 先前的研究表明, 营养限制能够激活FoxO途径, 上调抗氧化酶、DNA修复和自噬等抗衰老基因的表达, 增强细胞的抗衰老能力[46, 47, 75], PTEN通过维持基因组稳定性发挥延长寿命的作用[76–78], 而MEK1则通过降低ERK1/2的磷酸化水平和活性来延缓衰老[79, 80]。
在饮食限制下, 海湾扇贝和紫扇贝的IIS/FoxO通路信号分子IGF2、信号感应靶点IGF1R以及Ras/MAPK途径的核心分子MEK1的基因表达水平显著下调, 而IIS/FoxO通路的下游效应分子FoxO基因和肿瘤抑制因子PTEN的相对表达水平则显著上调[54, 61–63]。此外, 压力应答因子FoxO蛋白的磷酸化水平下降, 核内定位增加, 体内β-Gal活性显著降低。这些结果表明, IIS营养感应通路在海湾扇贝和紫扇贝中参与了饮食限制介导的寿命调控, 且营养条件改变了下游效应分子FoxO的亚细胞定位和磷酸化水平。但与紫扇贝相比, 海湾扇贝对饮食限制的响应速度更快、幅度更大。推测这一差异的主要原因在于, 海湾扇贝生活在气候波动较大、温度高、食物充沛的环境中, 能量代谢调节速度快, 且对营养需求更高; 而紫扇贝的生存环境则常年气候平稳、温度较低, 已进化出抵抗恶劣环境的保护机制, 抗逆性强且代谢速率慢, 从而对饮食限制不敏感。
急性电离辐射后, 海湾扇贝和紫扇贝机体均启动了应急机制, 出现反馈抑制现象, 诱导IGF2和IGF1R的分泌, 进而激活Akt存活信号。然而, 紫扇贝的存活率显著高于海湾扇贝, 暗示海湾扇贝和紫扇贝对电离辐射的响应存在差异。紫扇贝中DNA损伤修复相关基因FoxO、PTEN和GADD45表达水平显著上调, 而海湾扇贝中这些基因的表达水平显著下调, 尽管其自噬相关基因ULK2和ATG8表达量显著增加。这表明在电离辐射过程中, 紫扇贝具备更强的抗损伤和修复能力, 可能通过激活DNA损伤修复机制以维持基因组稳定性并延缓衰老, 而海湾扇贝则可能由于损伤修复机制较弱而启动细胞自噬性死亡。
综上所述, IIS通路参与了扇贝对饮食限制和电离辐射的响应。但由于海湾扇贝和紫扇贝中在进化过程中发生的遗传变异, 导致二者在营养感应、DNA损伤修复、抗氧化和基因组稳定性等方面均存在差异。
4 Argopecten属扇贝中IIS通路在扇贝寿命决定的调控网络目前, 科研人员已鉴定出200多个与衰老相关的基因, 涵盖包括胰岛素、氧化、免疫等多个信号通路。这些基因和通路并非单独作用于衰老, 而是彼此之间紧密关联, 共同构成一个复杂的调控网络。在IIS通路中, IGF1R作为主要的启动器之一, 负责介导生长因子信号传递; PTEN则作为PI3K/AKT途径唯一的负调控因子, 调节FoxO的活性; FoxO作为整合多条信号途径的关键下游调节因子, 在衰老调控中起核心作用; 此外, MEK1在Ras/MAPK信号传导途径中充当重要的中枢角色, 广泛参与mTOR和IIS等许多衰老和寿命途径的调控[43]。β-GAL是广泛使用的细胞衰老生物标志物[81], 而活性氧的生成主要源于线粒体和内质网的电子传递系统, 其也被发现促进衰老[82]。抗氧化系统, 尤其是SOD和CAT, 在将活性氧控制在低水平方面发挥着重要作用[83]。作为长寿控制的关键角色, FoxO通过转录活性氧解毒基因(包括Mn-SOD和CAT)保护细胞免受氧化应激[84–87]。先前研究表明, 缺失FoxO的表达会显著增加体内自由基水平, 并缩短秀丽隐杆线虫和果蝇的寿命[36, 88]。此外, MEK1的表达可以被营养限制抑制, 从而上调抗氧化基因和DNA修复基因的表达[89], 同时抑制mTOR途径的活性[49, 90]。
WANG等[54]在抑制IIS/FoxO通路感应靶点IGF1R后, 发现下游效应因子PTEN和FoxO的表达量显著增加, 证实了在扇贝中IGF1R与FoxO和PTEN之间存在上下级联关系。此外, RNAi-IGF1R处理的海湾扇贝体内, 抗氧化酶SOD和过氧化氢酶(Catalase, CAT)的活性显著增强, 老化指标β-Gal活性显著下降, 表明抑制IGF1R表达可以缓解衰老扇贝体内的氧化应激压力, 从而发挥抗衰老作用。在紫扇贝中, PTEN的沉默导致FoxO表达量显著降低, 表明PTEN在扇贝中正向调控FoxO[61]。敲降FoxO和PTEN后, 扇贝体内的SOD和CAT等关键排毒基因的表达水平均下调, β-Gal活性显著下降, 显示出FoxO和PTEN在调控机体氧化应激能力中具有协同作用[61, 62]。使用RNAi技术敲低海湾扇贝中的MEK1后, 其下游靶基因ERK1/2表达显著下调, 导致FoxO转录水平显著提高, 而β-Gal活性显著低于对照组。同时, mTORC1、S6K1、4EBP1和自噬关键基因ULK1的表达显著下降, 这可能表明自噬在海湾扇贝中的作用相对较小。因此, YUAN等[63]推测MEK1通过Ras/MAPK途径上调mTOR途径活性, 并下调抗氧化和DNA损伤修复基因的表达, 以调节海湾扇贝的衰老过程。
总之, 目前的结果显示, 在海湾扇贝和紫扇贝中, IGF2可能通过与IGF1R结合从而启动IIS通路的信号传导。随后, MEK1可能通过激活下游的ERK1/2, 进一步影响mTORC1、ULK1等自噬相关基因以及SOD、CAT等抗氧化基因, 从而清除受损细胞成分、维持细胞稳态。同时, PTEN可能通过抑制PI3K/AKT通路间接激活FoxO, 使其进入细胞核后上调GADD45的表达, 进而提高抗氧化酶SOD、CAT的活力, 增强细胞在应激条件下的生存能力、促进基因组的修复和稳定性(图 2)。
 |
| 图 2 IIS通路核心基因在扇贝寿命决定中的潜在调控网络 Fig. 2 Potential regulatory network of IIS pathway core genes in lifespan determination of scallops 注: 红色字体表示正向调控寿命的基因, 绿色字体表示负向调控寿命的基因。箭头表示促进作用, 顿箭头表示抑制作用 |
因此, IIS通路核心基因在两种扇贝中发生特定变异, 进而可能影响其与抗氧化防御蛋白、DNA损伤修复相关蛋白和免疫与自噬相关蛋白的交互作用强弱, 从而导致寿命周期的差异。然而, 当前研究尚缺乏关键的分子间相互作用及功能验证实验, 这些方面的进一步研究将有助于验证上述假设并补充必要的证据。
5 结语衰老和寿命的演化机制一直是近年来研究的热点和难点, 许多衰老背后的分子机制在脊椎动物、无脊椎动物甚至植物模型中也是保守的[91, 92]。两种寿命迥异的Argopecten属扇贝在分子水平上展现出显著的差异, 其中IGF2、IGF1R、PTEN、FoxO和MEK1的结构变异可能导致不同的蛋白活性以及功能差异, 包括GF1R与IGF2的互作能力、FoxO的磷酸化水平、PTEN和MEK1的磷酸酶活性。目前的研究结果显示, 在面对环境压力时, 海湾扇贝和紫扇贝在IIS通路调控、抗氧化和DNA修复、代谢调节等方面的关键差异可能是导致两者寿命迥异的关键因素。因此, 探究海湾扇贝和紫扇贝间寿命差异的分子机制, 不仅有助于推动对海洋双壳贝类衰老演化的理解, 也为其他动物衰老和长寿机制研究提供新的见解。此外, 这一研究为培育长寿命、大规格扇贝提供了理论支持和潜在的生物标志物。
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