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

小分子伴侣HSP25在长寿和健康老龄化中的作用

• 批准号: 9411307
• 负责人: Karl A Rodriguez
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9411307
• 关键词: Age; Aging; Alpha Cell; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Animals; Apoptosis; Autophagocytosis; Biological Process; Body Size; Brain; Caenorhabditis elegans; Cataract; Cell Death; Cell physiology; Cells; Cellular Stress Response; Cellular Structures; Complex; Critical Pathways; Data; Degradation Pathway; Disease; Drosophila genus; Elderly; Exhibits; Exposure to; Functional disorder; Gait abnormality; Genetic; Genetic Techniques; Health; Health Benefit; Heart; Heat Stress Disorders; Heat shock proteins; Homeostasis; Human; Huntington Disease; In Vitro; Inflammatory; Inflammatory Response; Kidney; Knock-out; Knockout Mice; Knowledge; Leg; Life; Link; Liver; Location; Longevity; Maintenance; Mammalian Cell; Measures; Mediating; Modeling; Mole Rats; Molecular; Molecular Chaperones; Mus; Muscle; Muscle function; Muscular Atrophy; Neurons; Organism; Orthologous Gene; Oxidative Stress; Parkinson Disease; Pathology; Pathway interactions; Play; Population; Principal Investigator; Proteins; Quality Control; Quality of life; Regulation; Research; Resistance; Review Literature; Rodent; Role; Signal Transduction; Spleen; Stimulus; Stress; System; Testing; Testis; Time; Tissues; Transgenic Mice; Work; age related; base; biological adaptation to stress; career development; cytotoxic; environmental stressor; extracellular; follow-up; genetic manipulation; healthy aging; heat-shock factor 1; improved; in vivo; mortality; multicatalytic endopeptidase complex; new therapeutic target; novel; overexpression; oxidative damage; preference; prevent; protein aggregation; protein degradation; protein transport; proteostasis; public health relevance; quadriceps muscle; response; sarcopenia; skills; stress protein; stressor; transcription factor; walking speed

 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.

 描述（由申请人提供）：蛋白质稳态是健康衰老的组成部分。在大多数后生动物中，蛋白质质量在衰老过程中下降，导致受损或自聚集细胞毒性蛋白的积累，与几种年龄相关疾病（例如，阿尔茨海默病、帕金森病）和病理学（例如，肌肉减少症、白内障）。老鼠大小的裸鼹鼠[NMR]的寿命比基于身体大小的预期长约5倍，尽管在很小的时候就检测到高水平的氧化损伤，但在其漫长的生命中大部分时间都保持良好的健康状况。与其他长寿动物模型一样，无论是体内还是体外 研究表明，NMR对广泛的环境应激源具有抵抗力。总的来说，这些发现表明NMR具有保持蛋白质质量的有效机制。我们以前的研究表明，这部分归因于蛋白酶体形式和亚细胞位置的改变。然而，蛋白酶体相关的分子伴侣活性的变化，有助于运输受损蛋白进入蛋白酶体也可能在这种下降中发挥作用。在这里，我们研究了关键的蛋白酶体相关的分子伴侣[HSPs]和热休克因子1 [HSF1]转录因子在脑，心脏，肝脏，脾脏，肾脏， 睾丸和小鼠的四头肌腿部肌肉以及NMR。在所有检查的组织中，与小鼠相比，HSP 25在NMR中均显示出更高水平的蛋白质。因此，我们测定了7只年龄从4岁到32岁的啮齿动物肝脏和肌肉中的HSP 25蛋白含量。这一比较结果表明，与长寿的显着相关性表明，热休克蛋白25可能发挥关键作用，在长寿动物的蛋白质稳态与年龄相关的维护。文献综述表明，HSP 25参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凋亡。因此，我们测试的总体假设，即热休克蛋白25介导的蛋白质的贩运到不同的蛋白质降解途径的基础上的“压力状态”的细胞，以保持体内平衡，这种行动是一个不可分割的组成部分，负责增加寿命和健康寿命的长寿物种。