Molecular Mechanisms of Exercise-Mediated Protection in the Aging Retina

Abstract

The retina is the complex, multilayered structure that is the essence of our vision. It converts light into neural signals and transmits them to the brain for visual perception. As we age, the systems responsible for maintaining the health and integrity of the retina, including those governing oxidative stress, inflammation, and cellular repair, begin to decline. This physiological aging process increases susceptibility to retinal degenerative diseases, including retinal degenerations, such as age-related macular degeneration (AMD), which is the leading cause of vision loss in developed nations. Understanding the molecular changes that drive retinal aging, and degeneration is therefore critical for identifying early therapeutic targets and preventative strategies. This thesis aimed to investigate the molecular landscape of the aging retina and the potential for physical exercise to act as a non-invasive, systemic intervention to slow or prevent retinal degeneration. A multi-omics approach, including transcriptomics, proteomics, and small RNA sequencing, was employed in both physiologically aged and young mouse models. Across three distinct but interconnected experimental arms, this work examined the complex gene-protein regulatory networks involved in retinal aging, the impact of exercise on the healthy retina and the impact of exercise on the aged, degenerating retina. The first results chapter focused on identifying how microRNAs (miRNAs), important post-transcriptional gene regulators, contribute to retinal aging. Aged retinas displayed functional decline and heightened inflammation, with miRNA sequencing revealing significant dysregulation in key regulators of immune and inflammatory pathways, which was further reflected at the gene and protein levels. Integrated analysis highlighted specific miRNAs, such as miR-17 and miR-93, as potential modulators of aging-related inflammation via regulation of the Stat3 signalling pathway. The second results chapter explored the molecular landscape of voluntary exercise in the healthy retina and also following acute stress. Mice subjected to four weeks of voluntary wheel running did not exhibit significant changes in retinal gene or protein expression under healthy conditions. However, when exposed to photo-oxidative damage (PD), exercised animals demonstrated a more robust molecular and functional response compared to sedentary controls. Proteomic analysis post-damage revealed two distinct gene-protein networks: a downregulated cluster linked to phototransduction and a strongly upregulated inflammatory module. The final results chapter extended these findings by examining how exercise influences molecular aging in the retina. In aged mice subjected to a 28-day voluntary exercise regimen, retinal function remained unchanged. Transcriptomic and proteomic analyses uncovered pronounced age-related dysregulation in inflammatory and immune signalling pathways, independent of exercise. While exercise itself did not significantly modulate retinal gene or protein expression in aged mice, it demonstrated the ability to attenuate levels of inflammation and preserve retinal health, suggesting its protective effects occur independent of large-scale molecular reprogramming. In conclusion, this thesis provides new insight into the molecular mechanisms of the aging retina and highlights the nuanced role of physical exercise as a protective intervention. While exercise does not substantially remodel the retinal transcriptome or proteome under normal conditions, it may exert its benefits through more subtle regulatory processes, such as modulation of inflammatory mediator activity, maintenance of cellular homeostasis, or preservation of antioxidant capacity. Collectively, these findings advance our understanding of retinal aging and point toward novel strategies, for preventing or delaying vision loss. Show more