López-Luppo Mariana, Catita Joana, Ramos David, Navarro Marc, Carretero Ana, Mendes-Jorge Luísa, Muñoz-Cánoves Pura, Rodriguez-Baeza Alfonso, Nacher Victor, Ruberte Jesus
Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain 2Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain 3Interdisciplinary Centre of Research in Animal Health, Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal.
Invest Ophthalmol Vis Sci. 2017 Jun 1;58(7):2832-2842. doi: 10.1167/iovs.16-20312.
Microaneurysms are present in healthy old-age human retinas. However, to date, no age-related pathogenic mechanism has been implicated in their formation. Here, cellular senescence, a hallmark of aging and several age-related diseases, has been analyzed in the old-age human retina and in the retina of a progeric mouse.
Retinas were obtained from 17 nondiabetic donors and from mice deficient in Bmi1. Cellular senescence was analyzed by immunohistochemistry, senescent-associated β-galactosidase activity assay, Sudan black B staining, conventional transmission electron microscopy, and immunoelectronmicroscopy.
Neurons, but not neuroglia, and blood vessels undergo cellular senescence in the old-age human retina. The canonical senescence markers p16, p53, and p21 were up-regulated and coexisted with apoptosis in old-age human microaneurysms. Senescent endothelial cells were discontinuously covered by fibronectin, and p16 colocalized with the β1 subunit of fibronectin receptor α5β1 integrin under the endothelial cellular membrane, suggesting anoikis as a mechanism involved in endothelial cell apoptosis. In a progeric mouse model deficient in Bmi1, where p21 was overexpressed, the retinal blood vessels displayed an aging phenotype characterized by enlarged caveolae and lipofuscin accumulation. Although mouse retina is not prone to develop microaneurysms, Bmi1-deficient mice presented abundant retinal microaneurysms.
Together, these results uncover cellular senescence as a player during the formation of microaneurysms in old-age human retinas.
微动脉瘤存在于健康老年人的视网膜中。然而，迄今为止，尚未发现与年龄相关的致病机制参与其形成。在这里，我们对老年人视网膜和早衰小鼠的视网膜进行了分析，细胞衰老作为衰老和几种与年龄相关疾病的标志。
从17名非糖尿病供体和Bmi1基因缺陷小鼠中获取视网膜。通过免疫组织化学、衰老相关β-半乳糖苷酶活性测定、苏丹黑B染色、传统透射电子显微镜和免疫电子显微镜分析细胞衰老情况。
在老年人视网膜中，神经元而非神经胶质细胞和血管会发生细胞衰老。典型的衰老标志物p16、p53和p21在老年人微动脉瘤中上调并与细胞凋亡共存。衰老的内皮细胞被纤连蛋白间断覆盖，且p16在内皮细胞膜下与纤连蛋白受体α5β1整合素的β1亚基共定位，提示失巢凋亡是内皮细胞凋亡的一种机制。在p21过度表达的早衰小鼠模型Bmi1基因缺陷小鼠中，视网膜血管呈现出以小窝扩大和脂褐素积累为特征的衰老表型。尽管小鼠视网膜不易形成微动脉瘤，但Bmi1基因缺陷小鼠出现了大量视网膜微动脉瘤。
总之，这些结果揭示了细胞衰老在老年人视网膜微动脉瘤形成过程中发挥了作用。
