Stress induced aging in mouse eye

Abstract

Aging, a universal process that affects all cells in an organism, is a major risk factor for a group of neuropathies called glaucoma, where elevated intraocular pressure is one of the known stresses affecting the tissue. Our understanding of molecular impact of aging on response to stress in retina is very limited; therefore, we developed a new mouse model to approach this question experimentally. Here we show that susceptibility to response to stress increases with age and is primed on chromatin level.We demonstrate that ocular hypertension activates a stress response that is similar to natural aging and involves activation of inflammation and senescence. We show that multiple instances of pressure elevation cause aging of young retina as measured on transcriptional and DNA methylation level and are accompanied by local histone modification changes. Our data show that repeated stress accelerates appearance of aging features in tissues and suggest chromatin modifications as the key molecular components of aging. Lastly, our work further emphasizes the importance of early diagnosis and prevention as well as age-specific management of age-related diseases, including glaucoma.

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

“…Younger killifish have higher adherence of the RPE to the neural retina than old killifish, and RPE contamination may therefore be higher in the dataset for the young age group. Gene ontology (GO) term analysis of our up-regulated gene dataset revealed pathway enrichments related to oxidative stress (GO:0051775, GO:0034599, GO:0006979), metabolism (GO:0042572, GO:0031325), and inflammation (GO:0090025, GO:0043368); these findings coincide with those of the aged murine retinal transcriptome for pathways correlated to oxidative stress and inflammatory responses (Xu et al, 2022), which had age-related changes in similar categories. A detailed list containing the GO categories of all up-and down-regulated biological processes (BP) and molecular functions (MF) of the aged killifish is included in Table S2.…”

“…We next compared our dataset to published mouse ageing retinal transcriptomes (3-month-old versus 18-month-old (Xu et al, 2022)) to investigate the transcriptional similarities between killifish and mammalian retinal ageing. Genes with increased expression during killifish retinal ageing showed a similar trend to their mouse orthologs (Figure 1D).…”

Restoring AIBP expression in the retina provides neuroprotection in glaucoma

“…PERG analysis. PERG recordings were performed by Celeris ERG platform equipped with pattern ERG stimulators (Diagnosys LLC) (49). Following anesthesia and eye dilation pattern, ERG stimulators were placed on corneal surface.…”

The Role of Epigenetics in Accelerated Aging: A Reconsideration of Later-Life Visual Loss After Early Optic Neuropathy

“…In younger mice, the induced DNA patterns mimicked that found in naturally aged older mice (i.e., those not exposed to ocular hypertension). 19 More recently, another group demonstrated accelerated DNA aging in humans undergoing major surgery, or having severe COVID-19, or even being pregnant. Remarkably, the accelerated DNA in these 3 scenarios returned to a normal pattern after the period of stress, 15 which suggests the existence of some fundamental and dynamic organization of epigenetic factors that can be reversibly modified by injury or stress.…”