Murine models of neovascular AMD revisited: Mechanistic pathways, immune-metabolic crosstalk, and the impact of aging and sex.

Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in older adults. Neovascular AMD (nAMD) is characterized by choroidal neovascularization (CNV), vascular leakage, and fibrotic remodeling. Although anti-vascular endothelial growth factor (VEGF) therapy has improved visual outcomes for some patients, emerging findings highlight growing concerns regarding treatment resistance, persistent disease activity, and progression to subretinal fibrosis, which remain major challenges. Growing evidence indicates that nAMD arises from the interplay among metabolic dysfunction, oxidative stress, chronic inflammation, hypoxia signaling, and extracellular matrix remodeling within the outer retina. Disruption of mitochondrial function, lipid handling in the retinal pigment epithelium, complement activation, inflammasome signaling, macrophage immune-metabolic reprogramming, and hypoxia-driven VEGF expression collectively shape angiogenesis and lesion progression. Murine models, including laser-induced CNV, two-stage laser-induced fibrosis, and spontaneous or genetic systems such as JR5558, VLDLR-deficient, and CYP27A1-deficient mice, have provided essential mechanistic insights into these pathways. Aging and biological sex influence metabolism, mitochondrial efficiency, immune responses, hypoxia responsiveness, and wound-healing capacity. However, many widely used experimental models rely on young adult animals and often use a single sex without accounting for sex- or age-based differences, leaving these critical factors understudied and inadequately integrated into preclinical design. This review integrates current mechanistic understanding with a critical evaluation of murine nAMD models and emphasizes the importance of incorporating biological age and sex into experimental systems to improve mechanistic interpretation and translational relevance.