Integrative Mechanisms and Emerging Therapies for Lacrimal Gland Aging

To synthesize current evidence on structural, cellular, metabolic, and neuro-immune mechanisms of lacrimal gland (LG) aging in humans and animal models, and to map translational strategies for age-related aqueous-deficient dry eye (ADDE). Narrative synthesis of clinical tear-function studies; human histopathology/biobank data; and mechanistic experiments in mouse, rabbit, and non-human primates, with emphasis on single-cell and spatial omics, autonomic regulation, and immune remodeling. LG aging is characterized by acinar attrition, ductal-stromal fibrosis, mitochondrial fragmentation with lipofuscin accumulation; and diminished parasympathetic and sympathetic innervation. Convergent mechanisms-oxidative stress, mitochondrial insufficiency, cellular senescence, immunosenescence with low-grade inflammation, and disrupted cholinergic/catecholaminergic signaling-jointly depress tear volume and alter composition. Cross-species comparisons reveal conserved pathways alongside species-specific susceptibilities that inform model selection. Therapeutic avenues under investigation include anti-inflammatory and metabolic modulators, senolytics, hormone/secretagogue approaches, and regenerative platforms leveraging stem cells, lacrimal organoids, and bioengineered scaffolds. Emerging organoid and ex vivo secretion assays hold potential for mechanism-based screening and phenotyping that bridge preclinical and clinical endpoints. LG aging is a tractable, multifactorial driver of ADDE. Priorities for translation include standardizing functional readouts, aligning cross-species endpoints, and testing mechanism-selected cohorts in early-phase trials with objective measures of tear secretion and ocular-surface integrity. Integrating multi-omics with advanced models and regeneration-focused strategies offers a path from symptomatic relief to durable restoration of gland function.