Abstract
Purpose :
The aging population is rapidly increasing in the world and various pathological conditions are associated with aging, for example, the ocular surface becomes more vulnerable to external stimuli, potentially leading to corneal opacity and angiogenesis, resulting in blindness. Dry eye disease (DED) is a common age-related ocular surface pathology. It is unknown whether cellular senescence (a state of permanent cell cycle arrest) influences the ocular surface microenvironment during DED. We, therefore, investigated the presence of senescent cells in young versus old mice before and after exposure to desiccating stress due to lacrimal gland excision (LGE), and we determined the potential role of senescent cells.
Methods :
We used our p16-3MR transgenic mice model, which allows the visualization and elimination of senescent cells that express the cell cycle inhibitor and tumor suppressor p16Ink4a. Ocular surface, including cornea and conjunctiva, was analyzed using imaging and quantitative reverse transcription in young (4 months) and old mice (24 months). LGE, which triggers dry eye conditions at the ocular surface, was performed, and ocular surface changes were assessed by measuring the expression of p16Ink4a, matrix metalloproteinase 9 (Mmp9), and vascular endothelial growth factor (Vegf). To eliminate senescent cells, topical ganciclovir treatment, which enables the elimination of p16-expressing senescent cells through the herpes simplex virus thymidine kinase, was applied to p16-3MR transgenic mice.
Results :
Old mice displayed more punctate epithelial damage in the cornea and a significant decrease in goblet cell density in the conjunctiva compared to young mice. In addition, p16Ink4a mRNA levels showed an age-related increase in both the cornea and the conjunctiva. LGE caused punctate corneal damage, accompanied by lower tear secretion. Even though the cornea remained clear in young mice, LGE in old mice caused corneal opacity with severe angiogenesis and an increase in p16Ink4a, Mmp9, and Vegf expression. Topical ganciclovir applied to LGE-treated eyes of old mice reduced angiogenesis and corneal epithelial hyperproliferation and downregulated p16Ink4a, Mmp9, and Vegf.
Conclusions :
We conclude that selective elimination of senescent cells is a potential approach for the treatment of ocular diseases, such as DED, that are associated with aging.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.