Recent Advances in Our Understanding of Age-Related Macular Degeneration: Mitochondrial Dysfunction, Redox Signaling, and the Complement System

Abstract

Age-related macular degeneration (AMD) is a prevalent degenerative disorder of the central retina, which holds global significance as the fourth leading cause of blindness. The condition is characterized by a multifaceted pathophysiology that involves aging, oxidative stress, inflammation, vascular dysfunction, and complement activation. The complex interplay of these factors contributes to the initiation and progression of AMD. Current treatments primarily address choroidal neovascularization (CNV) in neovascular AMD. However, the approval of novel drug therapies for the atrophic and more gradual variant, known as geographic atrophy (GA), has recently occurred. In light of the substantial impact of AMD on affected individuals' quality of life and the strain it places on healthcare systems, there is a pressing need for innovative medications. This paper aims to provide an updated and comprehensive overview of advancements in our understanding of the etiopathogenesis of AMD. Special attention will be given to the influence of aging and altered redox status on mitochondrial dynamics, cell death pathways, and the intricate interplay between oxidative stress and the complement system, specifically in the context of GA. Additionally, this review will shed light on newly approved therapies and explore emerging alternative treatment strategies in the field. The objective is to contribute to the ongoing dialogue surrounding AMD, offering insights into the latest developments that may pave the way for more effective management and intervention approaches.

Aging in Ocular Blood Vessels: Molecular Insights and the Role of Oxidative Stress

“…Oxidative stress, a pivotal pathogenic stimulus in neovascular AMD and geographic atrophy, is induced by hypoxia and chemical mediators, leading to increased VEGF production and playing a role in choroidal neovascularization [64,65]. The Nrf2 antioxidant pathway emerges as a crucial homeostatic mechanism against oxidative stress, with studies highlighting its significance in the RPE antioxidant response [47].…”

“…As research and science progress, significant strides have been made in treating common eye conditions associated with aging. For example, anti-vascular endothelial growth factor (anti-VEGF) drugs have revolutionized the treatment of AMD [65,176]. The continuous discovery of aging-related molecular mechanisms provides numerous potential targets and research directions for the treatment of age-related eye diseases.…”

The Complement System as a Therapeutic Target in Retinal Disease

“…Geographic atrophy (GA) is an irreversible, advanced form of dry AMD [ 31 , 153 ]. Unlike neovascular AMD, which is characterized by irregular neovascularization and fluid leakage, GA is characterized by atrophy of outer retinal tissue, RPE, and choriocapillaris, leading to progressive vision loss [ 154 , 155 , 156 ].…”

Diabetic Retinopathy: New Treatment Approaches Targeting Redox and Immune Mechanisms

“…Over recent decades, the advancements in research have substantially deepened our understanding of numerous eye diseases. Notably, significant progress has been achieved in elucidating the molecular pathomechanisms underlying debilitating ocular disorders [122][123][124][125]. Regarding DR, these breakthroughs transcend the mere comprehension of its molecular mechanisms, extending to the identification of novel therapeutic, diagnostic, and preventive strategies that have transitioned into clinical trials.…”