Cellular senescence in posterior segment neovascular diseases: A proposed feed-forward amplification model.
Source: PubMed, NCBI / U.S. National Library of Medicine
Neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy (PDR) continue to be significant contributors to permanent visual impairment. Although anti-vascular endothelial growth factor (anti-VEGF) therapy has substantially improved disease management, recurrent neovascularization, persistent leakage, incomplete treatment response, subretinal fibrosis in nAMD, and fibrovascular membrane formation or tractional complications in PDR indicate that disease progression involves mechanisms beyond VEGF signaling alone. Cellular senescence-a stress-induced condition marked by persistent cell-cycle arrest, altered stress responses, and context-dependent senescence-associated secretory phenotype (SASP) activity-has been identified as a potential pathogenic amplifier in posterior-segment neovascular diseases. Chronic oxidative stress, hyperglycemia, hypoxia, metabolic dysfunction, and inflammation in the retina and choroid may induce senescence-associated or senescence-like remodeling in retinal pigment epithelial cells, Müller glia, endothelial cells, and pericytes. Nonetheless, conclusive evidence of bona fide cellular senescence in human ocular tissues remains scarce and varies markedly across cell types and disease contexts. This review integrates direct experimental evidence, marker-based observations, and inferred mechanistic insights to delineate a proposed, evidence-based senescence-associated feed-forward amplification model. In this model,
Abstract
Neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy (PDR) continue to be significant contributors to permanent visual impairment. Although anti-vascular endothelial growth factor (anti-VEGF) therapy has substantially improved disease management, recurrent neovascularization, persistent leakage, incomplete treatment response, subretinal fibrosis in nAMD, and fibrovascular membrane formation or tractional complications in PDR indicate that disease progression involves mechanisms beyond VEGF signaling alone. Cellular senescence-a stress-induced condition marked by persistent cell-cycle arrest, altered stress responses, and context-dependent senescence-associated secretory phenotype (SASP) activity-has been identified as a potential pathogenic amplifier in posterior-segment neovascular diseases. Chronic oxidative stress, hyperglycemia, hypoxia, metabolic dysfunction, and inflammation in the retina and choroid may induce senescence-associated or senescence-like remodeling in retinal pigment epithelial cells, Müller glia, endothelial cells, and pericytes. Nonetheless, conclusive evidence of bona fide cellular senescence in human ocular tissues remains scarce and varies markedly across cell types and disease contexts. This review integrates direct experimental evidence, marker-based observations, and inferred mechanistic insights to delineate a proposed, evidence-based senescence-associated feed-forward amplification model. In this model, chronic pathological stress may initiate or reinforce senescence-related programs, whereas SASP factors, extracellular vesicles, and immune microenvironment remodeling may further amplify angiogenic, inflammatory, vascular, and fibrotic dysfunction. Importantly, this model should be interpreted as a hypothesis-generating, non-exclusive framework rather than a fully established causal pathway. We also compare disease-specific features of nAMD and PDR, discuss methodological challenges in defining retinal senescence, and evaluate the translational potential and safety concerns of senolytics and SASP-modulating strategies as adjuncts to anti-VEGF therapy. Rather than presenting cellular senescence as a fully established causal driver, this review frames senescence-associated remodeling as a context-dependent, evidence-stratified amplifying component within this proposed feed-forward framework.