Aging of the Retina: Molecular and Metabolic Turbulences and Potential Interventions

Abstract

Multifaceted and divergent manifestations across tissues and cell types have curtailed advances in deciphering the cellular events that accompany advanced age and contribute to morbidities and mortalities. Increase in human lifespan during the past century has heightened awareness of the need to prevent age-associated frailty of neuronal and sensory systems to allow a healthy and productive life. In this review, we discuss molecular and physiological attributes of aging of the retina, with a goal of understanding age-related impairment of visual function. We highlight the epigenome-metabolism nexus and proteostasis as key contributors to retinal aging and discuss lifestyle changes as potential modulators of retinal function. Finally, we deliberate promising intervention strategies for promoting healthy aging of the retina for improved vision.

Keywords: age-related macular degeneration; diet; environment; epigenome; metabolism; mitochondria; vision health.

Figure 1

Signatures of aging in the retina. A schematic of molecular and cellular signatures of retinal aging is shown. Stem cell exhaustion and post-transcriptional regulation have been observed in other organisms but not yet established as signatures of retinal aging.

Figure 2

Functional and structural changes in the aging retina. (a) Visual impairment is prevalent in the elderly. Molecular alterations accumulated over time trigger cellular responses that together determine the structural and functional retinal aging phenotype. (b) Representation of retinal vertical sections showing characteristic morphological features of the young adult retina (left) and anatomical modifications in the aged retina (right).

Figure 3

Differential methylation at gene bodies of long genes. Re-analysis of published (Corso-Diaz et al. 2020) differentially methylated regions (DMRs) identified in purified mouse rod photoreceptors at 24 months old compared to at 3 months old is shown. (a) Gene length expressed in base pairs (bp) and exon number of all genes and genes containing DMRs that are hyper- or hypo-methylated with age. ***indicates p < 2 × 10⁻¹⁶; ns indicates not significant. (b) Genome browser view of DMRs at genes involved in aging and longevity (Foxp1, Immp2l, and Igf1r) and cellular communication (Col18a1, Trpm1, and Pcdh15). The red vertical line on the chromosome pictogram indicates the location of the loci presented below. The location of DMRs on or in the vicinity of associated genes is shown by a green vertical line. Signal levels for open chromatin (ATAC-seq), histone modifications associated with active (H3K27ac) and repressed (H3K27me3) regions, and CpG methylation are shown for the three-month time point across the respective genes and their surroundings. The bottom panel represents a zoomed-in view of DMRs (green box) showing methylation levels of each CpG for rods from the 3-month-old (blue), 12-month-old (green), 18-month-old (purple), and 24-month-old (red) retina.

Figure 4

The epigenome–metabolism nexus in retinal aging. Among the signatures of retinal aging, epigenome–metabolism crosstalk is now emerging as a key determinant of age-related molecular and functional changes. Traditionally, genomic and epigenomic alterations have been considered primary drivers of aging. However, aging-related metabolic dysregulation and the possibility of epigenome moderation through metabolites are suggestive of a previously unappreciated molecular nexus. Asterisks indicate advanced glycation end product–modified biomolecules.

Figure 5

Principles of retinal aging and potential strategies to alleviate its impact. (a) Aging of the retina is influenced by genetic, environmental, and stochastic events. (b) The retina is subjected to constant environmental stressors, including UV and blue light, and lifestyle variables, such as diet and smoking, that contribute to loss of functional and cellular integrity with age. (c) Age-dependent shifts in retinal integrity. Genetic variants, comorbidities, and environmental risk factors can exacerbate retinal aging, whereas specific cellular and molecular alterations can be ameliorated by pharmaceutical compounds or modifications in lifestyle. These interventions could prevent or delay functional decline and emergence of disease.