NAD+-sirtuin-mitochondrial quality control in lens epithelial cells: a candidate modulatory network in crystalline lens aging.

Crystalline lens aging reflects parallel processes: intrinsic chemical modification of exceptionally long-lived fiber-cell proteins, deterioration of lens-wide redox and transport homeostasis, and declining maintenance in metabolically active cellular compartments. Lens epithelial cells (LECs) support antioxidant defense, ion and water balance, stress responses, and the quality of newly formed fibers. Current lens and LEC evidence shows age-associated reductions in mitochondrial oxygen consumption in primary human LECs obtained during cataract surgery; SIRT1-related signaling is linked to epithelial stress tolerance; PINK1/Parkin-dependent mitophagy and autophagy-lysosomal function protect LECs in lens-relevant stress models; and transport systems shape the mature fiber-cell environment. Together, these findings identify NAD+ homeostasis as a testable link among established maintenance components, although age-dependent NAD+ change in normal human LECs and a causal epithelial-to-tissue pathway remain unproven. Direct lens evidence strongly supports crystallin modification, aggregation, insolubilization, redox disruption, and age-related material change. We therefore propose three falsifiable levels of validation: age-stratified measurement of NAD+ homeostasis in ethically sourced human LECs; pathway-dependent testing of whether NAD+ restoration improves sirtuin-dependent mitochondrial quality control (MQC); and determination of whether verified LEC MQC rescue alters intact-lens homeostasis, crystallin damage, material properties, transparency, or optical quality. Presbyopia and age-related cataract are considered distinct outcomes with partially overlapping determinants. This evidence-stratified synthesis positions the LEC NAD+-sirtuin-MQC network as a candidate modulator of crystalline lens aging whose contribution can be supported, restricted, or rejected experimentally.