Deconstruction of Human Age-Related Cataract Capsules Defines Aging

Age-related cataracts (ARC), a disease associated with aging, is the leading cause of blindness worldwide. To better understand the heterogeneous pathogenesis of ARC and identify potential therapeutic targets, we generate a comprehensive atlas of age-related cataracts at a single-cell resolution, encompassing three disease states-mild cataract group (Mild), severe cortical cataract group (Severe_C), and severe nuclear cataract group (Severe_N)-with a total of 230 838 lens epithelial cells (LECs) derived from the lens capsules of 554 patients. We find that ARC involves seven distinct lens capsule cell types, with notable differences in cellular composition and functional states across disease severities. Unexpectedly, we discover that neuronal axon-like structures ingrowth into the lens is associated with cataractogenesis and its progression. All three disease groups show significant enrichment of the neurotrophic SLIT-ROBO signaling pathway. Cluster 0 exhibits high expression of the neurotrophic factor NRG1, which forms a stable ligand-receptor axis with the ERBB3 receptor on sympathetic neurons. These findings not only reveal the heterogeneity of ARC at the levels of cellular composition and signaling pathways but also suggest that neuro-lens interactions may play a critical role in cataract development. This provides a new perspective for understanding the pathogenesis of age-related cataracts.