Radiation Control Technologies, Inc., Loudonville, New York.
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Am J Physiol Cell Physiol. 2020 Jul 1;319(1):C45-C63. doi: 10.1152/ajpcell.00089.2020. Epub 2020 May 6.
Numerous age-dependent alterations at the molecular, cellular, tissue and organ systems levels underlie the pathophysiology of aging. Herein, the focus is upon the secreted protein thrombospondin-1 (TSP1) as a promoter of aging and age-related diseases. TSP1 has several physiological functions in youth, including promoting neural synapse formation, mediating responses to ischemic and genotoxic stress, minimizing hemorrhage, limiting angiogenesis, and supporting wound healing. These acute functions of TSP1 generally require only transient expression of the protein. However, accumulating basic and clinical data reinforce the view that chronic diseases of aging are associated with accumulation of TSP1 in the extracellular matrix, which is a significant maladaptive contributor to the aging process. Identification of the relevant cell types that chronically produce and respond to TSP1 and the molecular mechanisms that mediate the resulting maladaptive responses could direct the development of therapeutic agents to delay or revert age-associated maladies.
许多与年龄相关的分子、细胞、组织和器官系统水平的改变是衰老病理生理学的基础。本文重点介绍了作为衰老和与年龄相关疾病促进因子的分泌蛋白血栓反应蛋白-1（TSP1）。TSP1 在年轻时具有多种生理功能，包括促进神经突触形成、介导对缺血和遗传毒性应激的反应、最大限度地减少出血、限制血管生成和支持伤口愈合。TSP1 的这些急性功能通常只需要蛋白质的短暂表达。然而，越来越多的基础和临床数据强化了这样一种观点，即衰老相关的慢性疾病与细胞外基质中 TSP1 的积累有关，这是衰老过程中一种显著的适应不良的贡献因素。鉴定出持续产生和响应 TSP1 的相关细胞类型，以及介导这种适应性不良反应的分子机制，可能会指导开发治疗药物来延缓或逆转与年龄相关的疾病。
