The killifish visual system as an in vivo model to study brain aging and rejuvenation

Abstract

Worldwide, people are getting older, and this prolonged lifespan unfortunately also results in an increased prevalence of age-related neurodegenerative diseases, contributing to a diminished life quality of elderly. Age-associated neuropathies typically include diseases leading to dementia (Alzheimer’s and Parkinson’s disease), as well as eye diseases such as glaucoma and age-related macular degeneration. Despite many research attempts aiming to unravel aging processes and their involvement in neurodegeneration and functional decline, achieving healthy brain aging remains a challenge. The African turquoise killifish (Nothobranchius furzeri) is the shortest-lived reported vertebrate that can be bred in captivity and displays many of the aging hallmarks that have been described for human aging, which makes it a very promising biogerontology model. As vision decline is an important hallmark of aging as well as a manifestation of many neurodegenerative diseases, we performed a comprehensive characterization of this fish’s aging visual system. Our work reveals several aging hallmarks in the killifish retina and brain that eventually result in a diminished visual performance. Moreover, we found evidence for the occurrence of neurodegenerative events in the old killifish retina. Altogether, we introduce the visual system of the fast-aging killifish as a valuable model to understand the cellular and molecular mechanisms underlying aging in the vertebrate central nervous system. These findings put forward the killifish for target validation as well as drug discovery for rejuvenating or neuroprotective therapies ensuring healthy aging.

Some Aspects of Development and Histological Structure of the Visual System of Nothobranchius Guentheri

“…From the group of annual killifish, similar development times are observed in Aphyosemion gardneri [44]. The formation of the visual system of N. guentheri proceeds in parallel with the formation of the fish brain and, by the time of the onset of III diapause, it is fully functional (phototaxis) [39]. This is typical for most annual fish [24,44].…”

“…The study of the development of the visual system in other members of the genus Nothobranchius shows that differentiation of retina cells does not stop after hatching and continues throughout the life of the fish [38,39]. The emergence of new cells in the fish retina occurs from the proliferation of multipotent progenitor cells located in the CMZ [40,41] and from dividing Müller glial cells [41].…”

The age factor in optic nerve regeneration: Intrinsic and extrinsic barriers hinder successful recovery in the short‐living killifish

“…In the optic tectum of uninjured fish, cell bodies of quiescent radial glia are positioned right below the neuronal layer of the PGZ and adjacent to the tectal ventricle. Their individual cytoplasmic processes (fibers) project upwards, protrude in the superficial tectal layers, and terminate as end feet on the pia surface (Lindsey et al, 2019 ; Than‐Trong & Bally‐Cuif, 2015 ; Vanhunsel et al, 2021 ). Similarly, our findings show that in uninjured young female killifish, vimentin staining of diffuse glial end feet was clearly present in the SGC, SFGS, and SO layers of the optic tectum, and to a lesser extent in the radial fibers.…”

“…Given that, just like in young adult fish, only ~50% of the RGCs regenerated an axon, this shows that also a certain level of plasticity still exists in these middle‐aged fish. Of note, as killifish body length increases with about 32% between 6 weeks and 12 weeks of age (Vanhunsel et al, 2021 ), one could assume that the delay in tectal reinnervation might (in part) be attributable to axons having to overcome longer distances. However, also when studying axonal outgrowth initiation, during which the retrograde biocytin tracer was always placed at the same distance from the ONC site, a retardation was observed, which somewhat counters this alternative explanation.…”

Killifish switch towards mammalian-like regeneration upon aging

“…We postulate that age-associated changes within neurons and their glial environment –already manifesting before damage occurs– negatively affect the regeneration potential of the killifish CNS, which then leads to a mammalian-like regenerative response upon injury. Indeed, recent findings from our team revealed the presence of several aging hallmarks particularly in the old killifish visual system [ 7 ], which could underlie the flawed optic nerve regeneration that is observed in aged killifish. With increasing age, we revealed reduced expression levels of growth-associated genes in retinal neurons, thereby affecting the intrinsic ability of RGCs to regrow their axons.…”