Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol, BS8 1TD, UK.
School of Cellular and Molecular Medicine, University of Bristol, Bristol, BS8 1TD, UK.
J Neuroinflammation. 2021 Jan 22;18(1):32. doi: 10.1186/s12974-021-02088-0.
Age-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed "chronic" senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.
年龄相关性黄斑变性（AMD）是神经视网膜中央黄斑区和支持视网膜色素上皮的退行性疾病，是老年人视力丧失的最常见原因。尽管取得了进展，但缺乏预防进行性退化的治疗方法。除了先天免疫途径基因与 AMD 易感性的关联外，环境应激和细胞衰老诱导的代谢功能和炎症反应等途径的改变也与 AMD 的病理生理学有关。细胞衰老是一种对有丝分裂和无丝分裂细胞中有害刺激的适应性细胞过程，由肿瘤抑制蛋白激活，并通过炎症分泌组进行。除了在胚胎发生和组织再生中的生理作用外，细胞衰老随着年龄的增长而增加，并导致多种与年龄相关的慢性疾病。衰老细胞的积累伴随着免疫介导的消除机制受损，导致衰老细胞的频率增加，称为“慢性”衰老。衰老相关的衰老细胞表现出异常代谢、活性氧生成增加和衰老相关分泌表型增强，培育出有利于邻近细胞的促炎环境。各种视网膜和脉络膜组织细胞（包括视网膜色素上皮细胞、小胶质细胞、神经元和内皮细胞）的衰老变化，以及固有和适应性细胞的全身免疫衰老，已成为 AMD 发病和发展的重要因素。衰老治疗策略的范围不断扩大，如衰老细胞清除剂、衰老模拟物、细胞周期调节和恢复细胞内稳态，这些策略针对组织和全身水平，有可能治疗一系列与年龄相关的疾病，包括 AMD。
