An update on RPE cell senescence as a key contributor to age-related macular degeneration: support from current and experimental treatments

Abstract Background: Age-related macular degeneration (AMD) is a major cause of vision loss. Its prevalence has increased over the past decade. This increase is partly due to the scarcity of preventive and therapeutic interventions for this disorder, except when it is in its advanced neovascular form. Discovery of effective treatments for AMD is complicated by the multifactorial pathology of the disorder. Thus, it is difficult to determine which potential disease mechanism to target in order to achieve the greatest clinical benefit. Hypothesis: Over a decade ago, it was hypothesized that many of the pathologies observed in AMD stem from retinal pigment epithelial (RPE) cell senescence. This provided a potentially key mechanistic target. Supporting this hypothesis, many of the agents that were in development or clinical use for AMD at that time influenced RPE cell senescence, although they were not utilized for this specific effect. The present article re-evaluates this hypothesis by exploring the logical prediction that if RPE cell senescence is a key contributor to AMD, then inhibition of RPE cell senescence is important in the treatment of AMD. If this hypothesis holds true, the inhibition or reversal of RPE cell senescence or its effects should be a common characteristic of new treatments for AMD. Conclusions: Over the past decade, many agents have been investigated for the treatment of AMD. Although a few were designed to address cell senescence, the majority targeted other potential pathological mechanisms. In support of our original hypothesis, we now present evidence that many of the newer agents investigated for the treatment of AMD, even those that were not meant to reduce cell senescence or its effects, have this function as part of their activity profiles. Further experimental studies or clinical trials exploring the safety and efficacy of inhibiting RPE cell senescence or reversing its effects are needed to pave the way for improved AMD treatment. Keywords: age-related macular degeneration retinal pigment epithelium cell senescence VEGF vascular endothelial growth factor dry AMD exudative AMD wet macular degeneration geographic atrophy macular degeneration