The role of the small molecular chaperone HSP25 in longevity and healthy aging

 描述(由申请人提供)：蛋白质平衡是健康衰老不可或缺的组成部分。在大多数后生动物中，蛋白质质量在老化过程中下降，导致受损或自我聚集的细胞毒性蛋白的积累，与几种与年龄相关的疾病(例如阿尔茨海默病、帕金森病)和病理(例如石棉减少症、白内障)有关。根据身体大小，老鼠大小的裸色鼹鼠[NMRS]的寿命比预期长约5倍，尽管在很小的时候就检测到高水平的氧化损伤，但它们在长寿的大部分时间里都保持着良好的健康。像其他长寿动物模型一样，在体内和体外都是如此 研究表明，NMR对广泛的环境应激源具有抵抗力。总而言之，这些发现表明，NMRS拥有维持蛋白质质量的有效机制。我们之前的研究表明，这部分归因于蛋白酶体形式和亚细胞位置的改变。然而，与蛋白酶体相关的分子伴侣活性的变化也可能在这种下降中起到作用。在这里，我们研究了脑、心、肝、脾、肾中关键的蛋白酶体相关分子伴侣[HSPs]和热休克因子1[HSF1]转录因子， 睾丸，以及小鼠和NMRS的股四头肌腿肌。在所有被检测的组织中，HSP25在NMRS中都显示出比小鼠更高的蛋白质水平。因此，我们测量了7只年龄从4岁到32岁的啮齿动物肝脏和肌肉中HSP25蛋白的含量。这一比较结果与寿命显著相关，表明HSP25可能在长寿动物中与年龄相关的蛋白质稳态的维持中发挥关键作用。文献综述表明，HSP25参与了许多细胞系统或反应，包括热应激、蛋白酶体活性、自噬、炎症反应和细胞结构稳定，所有这些都是为了防止细胞内的凋亡。因此，我们测试了总体假设，即HSP25根据细胞的“应激状态”介导蛋白质运输到不同的蛋白质降解途径，以维持动态平衡，这一作用是延长长寿物种寿命和健康寿命的不可或缺的组成部分。

 DESCRIPTION (provided by applicant): Proteostasis is an integral component of healthy aging. In most metazoans, protein quality declines during aging, resulting in accrual of damaged or self-aggregating cytotoxic proteins, linked to several age-associated diseases (e.g., Alzheimer's Disease, Parkinson's Disease) and pathology (e.g., sarcopenia, cataracts). The mouse-sized naked mole-rat [NMRs] lives ~5 times longer than expected based on body size, and despite detected high levels of oxidative damage even at a young age, maintain good health for most of their long lives. Like other long-lived animal models, both in vivo and in vitro studies reveal that NMRs are resistant to a broad spectrum of environmental stressors. Collectively these findings suggest that NMRs possess efficient mechanisms to maintain protein quality. Our research has previously shown that this is attributed in part to altered proteasome forms and subcellular location. However, changes in proteasome-related molecular chaperone activity that assists in the transport of damaged proteins into the proteasome may also play a role in this decline. Here we examine key proteasome-related molecular chaperones [HSPs] and the heat-shock factor 1 [HSF1] transcription factor in the brain, heart, liver, spleen, kidney, testes, and quadriceps leg muscle in mice and NMRs. HSP25 both showed higher levels of protein in NMRs compared to mice in all the tissues examined. Hence we measured HSP25 protein content in seven rodents with ages ranging from four to 32 years in both liver and muscle. This comparison resulted in a significant correlation with longevity suggesting that HSP25 may play a key role in age-related maintenance of protein homeostasis in long-lived animals. A review of the literature suggested that HSP25 was involved in a number of cellular systems or responses including heat stress, proteasome activity, autophagy, inflammatory response, and cell structure stabilization all to prevent apoptosis in the cell. Thus, we test the overall hypothesis that HSP25 mediates the trafficking of proteins to different protein degradative pathways based upon the "stress-state" of the cell to maintain homeostasis, and this action is an integral component responsible for increasing longevity and healthspan in long-lived species.