Diet- and sex-related responses in the aging retina identified by multi-omics approach

Abstract

Purpose : Advanced age is a major determinant of common eye diseases, including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy. In addition, environment and lifestyle factors, such as diet, contribute significantly to age-related vision impairment. Nutrients are vital for retinal metabolism, and dietary choices can impact homeostasis, especially at an advanced age. To add to the complexity, retinal diseases are reported to have sex-related trends, alluding to an intricate connection of diet and sex with aging. Epigenetic changes are recognized as drivers of biological aging, including in retinal photoreceptors. Age-related epigenetic modifications can affect gene regulatory changes that ultimately translate to adaptations in transcriptome as well as other molecular landscapes. We hypothesize that distinct gene regulatory networks (GRN) in the retina respond to dietary changes and that their identification can lead to lifestyle-strategies for mitigating age-related visual decline.

Methods : One year old male and female wildtype mice were fed specially designed diets for a period of six months. Treatments included Mediterranean and High Fat diets; as well as AREDS2 supplements or B-vitamins (B6, B9, and B12) supplemented control diets. After six-months, treated and control groups underwent electroretinogram analysis and their retinas assayed for transcriptome, DNA methylome, lipid and fatty acid profiles.

Results : We observed sex- and diet- specific body weight changes in male and female mice. Retinal epigenetic and gene expression analysis corroborated sex-related variances. Mediterranean and high fat diets led to greater changes in retinal gene expression, as compared to micronutrient supplemented diets. Additionally, we observed elevated levels of beneficial omega-3 polyunsaturated fatty acid in AREDS2 and vitamin treated groups. We are attempting to identify the relationship of diet-associated differentially methylated CpGs and pathway expression.

Conclusions : Our study shows sex as a key factor in determining dietary impact of retinal aging. We uncover adaptation of retinal molecular profiles to dietary inputs, indicating potential GRNs underlying these trends. Multi-omic integration can help characterize retinal GRNs responding to combined effects of aging and diet, and suggest lifestyle intervention strategies to slow down the impact of aging on visual dysfunction.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.