Abstract
Purpose :
Age is one of the most relevant clinical traits for predicting disease risk, including age-related eye diseases. Despite advances in understanding of age-related changes in the neuroretina, there is a need to delineate the molecular events underlying the aging process in the retinal pigmented epithelium (RPE). In age-related macular degeneration (AMD), where RPE plays a key role, age is the single most reproducible risk factor for developing the disease; however, the molecular role of aging of RPE has not been routinely considered in pre-clinical studies. The goal of this project is to understand molecular differences in the aging processes of the retina and RPE, as well as uncover the specific resilience to stress of both tissues.
Methods :
Retinas and RPE were isolated from 3- to 18-months-old animals and analyzed at the transcriptional (RNAseq) and epigenetic (DNA methylation) levels. Epigenetic clocks for the retina and RPE were developed. To analyze the differences in resilience to stress between tissues, selected conditions were used: 1) 5 weeks of a high-fat diet versus a normal diet; 2) 4 weeks of exposure to 50 ppm of benzene for 6 hours/day; 3) repetitive intraocular elevation up to 30 mmHg for 1 hour; 4) specific mice strain with mutations accelerating aging, followed by measurement of epigenetic age.
Results :
Comparison of deregulated transcriptional pathways in aging retinal pigmented epithelium (RPE) and retina showed substantial differences between the tissues. Furthermore, specific epigenetic clocks for the retina and RPE revealed that: i) both tissues age significantly slower than other tissues in the body (e.g., 10x slower than the brain), however, ii) the retina ages slower than the RPE; iii) the RPE epigenetic clock shows differences in the rate of aging between females and males, while the retina clock does not. iv) The RPE and retina respond differently to tested stress conditions. Using DNA methylation based EWAS analysis, complementary pathways affected in the process of aging of both tissues were uncovered.
Conclusions :
Our work underscores the role of accumulated epigenetic changes in aging, their relation to tissue function, and their contribution to age-related eye diseases. Our results suggest that understanding molecular aging in the retina and RPE is crucial for designing tissue-specific therapies to prevent or slow down AMD and other eye diseases.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.