Lens aging and disease: Molecular mechanisms, functional consequences, and pharmacological implications
Abstract
Age-related cataract (ARC) remains the leading cause of blindness worldwide, reflecting the progressive failure of lifelong mechanisms that preserve the transparency and refractive precision of the ocular lens. The lens is uniquely vulnerable to aging because its core fiber cells, crystallin proteins, and lipids persist for decades without turnover, relying on stable protein solubility, redox homeostasis, membrane integrity, and tightly coordinated epithelial renewal. With age, gradual biochemical and biomechanical shifts, including crystallin oxidation and truncation, deamidation and racemization, glycation, formation of disulfide and non-disulfide crosslinks, membrane remodeling, and stiffening of the lens nucleus, erode the structural and optical properties required for clear vision. Decline in glutathione (GSH) synthesis and redox-repair enzymes amplifies oxidative damage, while emerging evidence identifies ferroptosis, rather than apoptosis, as a dominant regulated cell-death pathway compromising lens epithelial cell survival in aging. In parallel, genome-wide association studies and exome sequencing have revealed a complex polygenic architecture for ARC, highlighting modifier genes that influence cytoskeletal resilience, protein stability, ion transport, and systemic metabolic signaling. Environmental exposures, including ultraviolet radiation, smoking, heat stress, and air pollution, interact with these genetic and biochemical pathways to accelerate opacity formation.…
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