Is the retinal senescent due to neuronal disfunction or neuronal death?
Authors: Nadal‐Nicolas Francisco M. 
Published: December 2022

AbstractThe continuous decline in vision due to aging is a common and irreversible degenerative process that is a consequence of multiple cumulative factors. Genetic heritage, behaviour, nutrition, and environmental factors are tangled along the course of life making aging a heterogeneously complex process. This contributes to make the inherent effects of aging difficult to evaluate in vision, and more so, when its outcome is often masked by other chronic ocular pathologies.Thus, investigating small mammals (rodents) under controlled conditions (food, environmental light, and temperature), we characterized the functional and anatomical changes in the aged retina. Full field electroretinograms in aged rodents displayed retinal function reduced by ~50% of the averaged response observed in juvenile ones. However, we did not observe any corneal or lens opacification that could provide any functional deficit. Therefore, based on the literature, we investigated whether neuronal loss in any of the different retinal layers could explain the reduced functionality. First, we estimated neuronal loss by examining the retinal thickness in vivo by Optical Coherence Tomography. As reported for aged mice and rats, we also observed a significant retinal thinning (<20%) as measured by the total retinal thickness. However, this retinal thinning could not completely account for the ~50% reduction in retinal function.Consequently, we focused on the anatomical changes on aged retinas by quantifying two key neurons in the visual pathway: the photoreceptors, responsible for light capture, and the retinal ganglion cells (RGC), unique afferent neurons in the retina that project to the brain. First, Immunohistochemical analysis corroborated the retinal thinning; and second, quantitative analysis of Opsin and Brn3a (markers for photoreceptors and RGC respectively) demonstrated reduced densities in both cell populations as reported in other mammals. Interestingly, we found photoreceptor degeneration in the central retina of aged rodents. However, total quantification of RGCs in aged animals showed no significant differences compared to juvenile ones. By taking into account the growth of the retina over the lifetime of the rodents, the difference in retinal area provided an explanation to the observed retinal thinning and reduced RGC density across the retinal surface since volumetric analysis did not provide clear evidence of neuronal loss.Next, we assessed the glial state on aged brain and retina samples. In aged tissues, the microglial cells (Iba1) had ramified morphology, but quantitative analysis revealed a significant reduced dendritic arbor. Expression of GFAP in astrocytes and CD68, a lysosomal protein expressed on active phagocytic cells, showed a significant increase during healthy aging. Features that may contribute to a chronic parainflammation.Overall, these and previous data suggest that the reduced retinal function caused by aging may derive from neuronal disfunction, photoreceptor degeneration and imbalance of immune processes, including alterations in inflammation. Thus, the importance to better understanding of the aging processes become more crucial than ever before since our livespan is increasing over the years. Therefore, an early detection of these symptoms may help to identify healthier lifestyles to prevent vision loss, or to design new potential treatments to preserve or to restore vision.