Researchers at the University of California, Irvine (UCI) developed a mouse model of ocular hypertension to gain molecular insights into the role of age-related stress in glaucoma. They found that aging increases retinal susceptibility to stress, and that chromatin alterations play an important role in the stress-induced aging of the eye.1
“Using a new mouse model to study the molecular mechanisms of retinal aging, we showed that repetitive stress in the retina due to IOP elevation induces molecular changes that are similar to what happens in the aging eye,” said Dorota Skowronska-Krawczyk, PhD, at UCI’s Center for Translational Vision Research. She added, “Understanding the molecular mechanisms of stress-induced aging of the eye can help us develop drugs to prevent or treat the causes of glaucoma and other age-related eye neuropathies, rather than simply managing the symptoms.”
STRESS-INDUCED RETINAL AGING. Fluorescence imaging shows significant loss of RGCs (red staining with anti-RBPMS antibody) and aging-like changes in transcriptome and epigenome after repeated mild elevation of IOP. Adapted from Fig. 4 in Santhiago M et al. Ophthalmol Science. 2023;3:100256.
Study rationale. The researchers set out to investigate the mechanisms that promote senescence and cell death in retinal ganglion cells (RGCs), as a way of developing new strategies for preventing or treating vision loss in patients with glaucoma, Dr. Skowronska-Krawczyk said. “Based on our previous studies, we hypothesized that stress due to elevated IOP may accelerate aging in glaucomatous retinas.”
Impact of elevated IOP. The study’s results support the researchers’ hypothesis. The ocular hypertension–induced stress responses were “driven by senescence and age-related inflammation” (also referred to as inflammaging), Dr. Skowronska-Krawcyzk said. Compared with young retinas, aged mouse retinas were more sensitive to IOP elevation and IOP-associated stress.
The researchers also found that elevated IOP promotes age-related epigenetic remodeling, with young murine retinas showing changes typically detected in older retinas. “Our findings suggest that even mild elevation in IOP in young retinas can accelerate the accumulation of alterations in DNA methylation and histone modification, contributing to eye aging,” Dr. Skowronska-Krawczyk said. These stress-induced epigenetic modifications can result in significant alterations in gene expression, which can ultimately lead to senescence and RGC death, she said.
Next steps. The researchers believe that the molecular mechanisms of stress-induced aging in mice are very similar to what happens in the human eye, Dr. Skowronska-Krawzyk said.
Next, the team is planning to perform similar assessments in primates in collaboration with researchers at the University of Alabama at Birmingham School of Medicine. Whether these molecular alterations can be reversed using senolytic or anti-inflammatory drugs to prevent or treat glaucoma remains to be addressed.
—Christos Evangelou, PhD
1 Xu Q et al. Aging Cell. 2022;21(12):e13737.
Relevant financial disclosures: Dr. Skowronska-Krawczyk—None.
For full disclosures and the disclosure key, see below.
Full Financial Disclosures
Dr. Chaudhary Bayer: C,L,S; Boehringer Ingelheim: C; Novartis: C,S; Roche: L,S.
Dr. Santhiago Alcon: C; Ziemer: C.
Dr. Skowronska-Krawczyk Visgenx: C.
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