Abstract
Purpose :
Age and elevated intraocular pressure (IOP) are major risk factors for glaucoma. We aim to learn how aging contributes to loss of vision in response to stress caused by elevated IOP.
Methods :
3 and 18-month-old mice were treated with mild IOP (30mmHg). Phenotype and molecular changes in young and old retina upon IOP stress assessed included: RGC cell body survival by Brn3a immunostaining; Visual path in optic nerve neurofilament by NF68 staining; RGC function measured by pattern electroretinography (PERG); Transcriptomic and epigenomic analyses.
Results :
Both RGC counting statistics and PERG assays showed significant decreases in old retina upon 1hr of 30mmHg IOP elevation but barely changed in young ones. Optic nerve analysis showed dramatically reduced NF68 immunoreactivity in aged eye. RNA-Seq analysis with FDR<0.05 and two-fold expression change cutoff revealed 156 activated genes and none repressed upon stress in young retina. In old retina, there were more stress dysregulated genes including 257 up- and 24 down-regulated. And a large portion of the stress-activated genes showed higher fold changes in old versus young retina. Pre-ranked gene set enrichment analysis and heatmaps showed multiple curated aging related pathways such as inflammatory/immune response, senescence and p53 pathways. ATAC-Seq analysis revealed that chromatin accessibility changes played a necessary regulatory role in many susceptible genes against stress like Fgf2 and Bcl3.
Conclusions :
RGC/axonal loss and deterioration of vision correlated with age. Transcriptomic response to IOP stress revealed ontology enrichment in pathways associated with aging and senescence and showed higher vulnerability in old versus young retinae. Our data suggests that stress accelerates aging of the visual system. Current glaucoma treatment paradigm limits to lowering eye pressure. Elucidating pathways involved in accelerated aging may lead novel therapeutic targets for glaucoma treatment and prevention in the future.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.