Semaglutide Alleviates Age-Related Dry Eye Disease By Restoring Lacrimal Gland Structure And Function

The prevalence of age-related dry eye disease (DED) is increasing with global aging, and progressive lacrimal gland (LG) dysfunction represents a central pathogenic mechanism with limited targeted therapeutic options. Semaglutide (Sema), a glucagon-like peptide-1 receptor agonist widely used for metabolic diseases, has recently been shown to exert anti-aging effects in multiple tissues. However, its role in LG aging and age-related DED remains undefined. This study aimed to investigate the therapeutic effects and underlying mechanisms of Sema in age-related DED.

A naturally aged mouse model was used to evaluate age-related LG dysfunction and DED phenotypes, with long-term semaglutide administration as an interventional strategy.

Aged mice were treated with semaglutide for two months, followed by comprehensive evaluation of ocular surface integrity, tear secretion, and LG histopathology. High-throughput single-cell RNA sequencing was performed to characterize LG cellular composition and transcriptional programs. Cellular senescence was assessed using SenMayo-based scoring, senescence-associated β-galactosidase staining, p21 expression, and SASP-related markers. In vivo and in vitro assays were used to validate cell-type–specific molecular and functional changes.

Long-term semaglutide treatment alleviated DED phenotypes, improved tear secretion, and preserved LG structure in aged mice. Single-cell analysis showed that aging was associated with acinar cell loss, expansion of fibroblast and immune populations, and activation of stress- and inflammation-related programs, which were broadly attenuated by semaglutide. SenMayo profiling revealed widespread senescent cell accumulation across epithelial, stromal, and immune compartments, which was markedly reduced by semaglutide. Mechanistically, semaglutide alleviated oxidative stress in acinar cells, suppressed pro-fibrotic programs in fibroblasts, and dampened inflammatory and chemotactic activation in macrophages.

Semaglutide mitigates age-related LG dysfunction and DED through coordinated attenuation of senescence-associated pathological programs across multiple cellular compartments. These findings support cellular senescence as a pharmacologically tractable mechanism in age-related DED and highlight semaglutide as a potential therapeutic strategy for aging-related ocular surface disease.