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

基本信息

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
项目类别：
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&apos 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

Age Aging Alpha Cell Alzheimer&apos 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

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项目摘要

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（由适用提供）：蛋白质症是健康衰老的组成部分。在大多数后代人中，蛋白质质量在衰老过程中会下降，导致损害或自我累积的细胞毒性蛋白质，与几种与年龄相关的疾病（例如，阿尔茨海默氏病，帕金森氏病）和病理学（例如，Sarcopenia，canaracts）相关。小鼠大小的裸小鼠鼠[NMR]的寿命比预期的约5倍，基于体型的预期，即使在年轻的时候也发现了高水平的氧化物损害，在长寿的大部分时间里，都保持身体健康。像其他长寿命的动物模型一样，体内和体外研究表明，NMR对广泛的环境压力源具有抗性。这些发现共同表明，NMR具有维持蛋白质质量的有效机制。我们的研究先前表明，这部分归因于蛋白酶体形式和亚细胞下位置的改变。然而，蛋白酶体相关的分子伴侣活性的变化有助于将受损蛋白传输到蛋白酶体中，也可能在这种下降中发挥作用。在这里，我们检查了与蛋白酶体相关的关键分子伴侣[HSP]和大脑，心脏，肝脏，sle骨，肾脏，肾脏中的热震因子1 [HSF1]转录因子睾丸和小鼠和NMR中的股四头肌腿部肌肉。与小鼠相比，在所检查的所有时序中，HSP25在NMR中均显示出更高的NMR蛋白质。因此，我们测量了七个年龄的七个啮齿动物中的Hsp25蛋白质含量在肝脏和肌肉中的4至32岁不等。这种比较导致与寿命有显着的相关性，表明HSP25可能在与年龄相关的长寿动物中蛋白质稳态的维持中起关键作用。对文献的综述表明，HSP25参与了许多细胞系统或包括热应激，蛋白酶体活动，自噬，炎症反应和细胞结构稳定的反应，以防止细胞中凋亡。因此，我们测试了HSP25的总体假设，即HSP25介导了基于细胞的“应激状态”来维持稳态的蛋白质降解途径的运输，以维持稳态，并且该作用是负责长寿物种寿命和健康范围的整体成分。