The Molecular Basis of Ocular Aging: Mechanisms, Pathologies, and Emerging Therapeutics

Age-related eye diseases (AREDs)-including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy-are leading causes of permanent blindness. Current treatments manage clinical manifestations but do not halt the molecular processes that drive disease progression. This limitation has shifted attention toward "geroscience," a strategy that targets the fundamental biology of aging rather than treating each disease in isolation. Four key hallmarks of aging-mitochondrial dysfunction, loss of proteostasis, cellular senescence, and epigenetic drift-are widely implicated in AREDs. We review evidence that these hallmarks do not act independently; instead, they form an interactive, self-reinforcing network. The way this network engages differs from tissue to tissue. In the high-energy environment of the retinal pigment epithelium, mitochondrial dysfunction dominates and drives AMD. In the mechanically stressed trabecular meshwork (TM), senescence and epigenetic drift take precedence, leading to glaucoma. In the neurovascular unit, chronic hyperglycemia routes the same network into a metabolic-epigenetic amplification loop that sustains diabetic retinopathy. The same aging mechanisms, routed through distinct tissue contexts, thus produce divergent clinical phenotypes. We also evaluate emerging therapies, including senolytics, mitochondria-targeted agents, and partial epigenetic reprogramming, and identify key intervention nodes such as NLRP3, p62, and NAD⁺ metabolism. Dismantling these pathological feedback loops offers a path beyond symptom management toward combination strategies that restore tissue resilience.