Wang Wen-Ying, Bin Xin, Xu Yanxuan, Chen Si, Zhou Shuyi, Chen Shaowan, Cao Yingjie, Qiu Kunliang, Ng Tsz Kin
Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou 515041, China.
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Int J Mol Sci. 2025 Jun 6;26(12):5436. doi: 10.3390/ijms26125436.
Older age is a risk factor for glaucoma, in which progressive retinal ganglion cell (RGC) loss leads to visual field defects and irreversible visual impairment and even blindness. We recently identified the involvement of cellular senescence in RGC cell death post-optic nerve injury. Here we further aimed to delineate the profile of RGC survival in mice with aging, a physiological process with increasing cellular senescence. The numbers of senescent cells in the ganglion cell layer (GCL) significantly and progressively increased starting at 8 months of age. Yet, significant reduction of ganglion cell complex layer thickness began in the 10-month-old mice, and significant reduction in the number of RGCs began in the 12-month-old mice as compared to the 2-month-old mice. Meanwhile, pyroptosis and ferroptosis markers as well as cellular senescence-related cell cycle arrest proteins p15, p16, p21, and p53 were significantly and progressively increased in GCL. In contrast, there were no significant changes in dendritic field, complexity, and branches with increasing ages. Comparing between the 2- and 16-month-old mouse retinas, the differentially expressed genes were involved in the pathways of neurodegeneration, innate immunity, and mitochondrial ATP synthesis. In summary, this study revealed the gradual increase in senescent cells as well as pyroptosis and ferroptosis with progressive RGC reduction in mice with aging. Cellular senescence and the related cell death pathways are potential targets for age-related RGC reduction.
年龄增长是青光眼的一个风险因素，在青光眼中，视网膜神经节细胞（RGC）的渐进性丧失会导致视野缺损以及不可逆的视力损害甚至失明。我们最近发现细胞衰老参与了视神经损伤后RGC的细胞死亡。在此，我们进一步旨在描绘衰老小鼠中RGC存活的情况，衰老是一个细胞衰老不断增加的生理过程。从8月龄开始，神经节细胞层（GCL）中衰老细胞的数量显著且逐渐增加。然而，与2月龄小鼠相比，神经节细胞复合体层厚度在10月龄小鼠中开始显著降低，RGC数量在12月龄小鼠中开始显著减少。同时，GCL中焦亡和铁死亡标志物以及与细胞衰老相关的细胞周期阻滞蛋白p15、p16、p21和p53显著且逐渐增加。相比之下，随着年龄增长，树突野、复杂性和分支没有显著变化。比较2月龄和16月龄小鼠的视网膜，差异表达基因涉及神经退行性变、先天免疫和线粒体ATP合成途径。总之，本研究揭示了衰老小鼠中衰老细胞以及焦亡和铁死亡随着RGC逐渐减少而逐渐增加。细胞衰老和相关的细胞死亡途径是与年龄相关的RGC减少的潜在靶点。
