Stress induced accelerated aging in mouse eye [RNA-seq]

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 program activated by stress caused by ocular hypertension is similar to natural aging and involves activation of inflammation and senescence. Finally, we show that multiple instances of pressure elevation cause accelerated aging of young retina as measured on transcriptional and epigenetic level and is accompanied by changes in chromatin modifications. Our data suggests that molecular mechanism of aging is regulated at the level of epigenetic activation and repression and, therefore, might be modifiable. Lastly, this work further emphasizes the importance of early diagnosis and prevention as well as age-specific management of age-related eye-diseases, including glaucoma. Overall design: To investigate whether the molecular changes in the aging retina can explain the observed functional decline of the visual system we performed a whole retina mRNA sequencing on retinas isolated from both 3-month and 18-month-old mice. 3-month-old bulk retinas (N=2) was set as control group to 18-month-old bulk retinas (N=2) in the natural aging related differential expression analysis in wildtype mouse. To capture age-dependent transcriptional changes in the retinas upon unilateral IOP elevation, RNA-seq analysis was performed on bulk retinas collected 2 days after 1 hour of constant 30mmHg IOP treatment from 3-month-old and 18-month-old wildtype C57BL/6J mice when retina ganglion cell loss is not yet observed. For mice at each age (3 month or 18 month), unilateral untreated retinas (N=2) were set as control group to unilateral IOP (constant 30mmHg IOP for 1 hour) treated retina (N=2) in the intraocular pressure elevation related differential expression analysis in wildtype mouse. To investigated whether repeated mild IOP elevation in young animal can affect the expression levels of genes involved in the response to IOP stress, 3-month-old mice were treated with unilateral constant 30mmHg IOP elevation for 1 hour biweekly, four times in total. The contralateral eye served as a control to the recurring stress treated eye (N=2). Two days after the final IOP insult, retinas were collected and bulk RNA-seq was performed.