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Abstract:

Purpose: As adult mammals lack the capacity to regenerate lost or damaged neurons, age-related deterioration of the central nervous system (CNS) seriously constrains life quality of a growing number of elderly. Despite intensive research, induction of neuronal and axonal regeneration and subsequent functional recovery remains a challenge, especially in an aging environment. In contrast to mammals, adult zebrafish have a high neurogenic and regenerative capacity. As they were recently identified to age gradually, they form an ideal model to study the effects of aging on regeneration potential. We focus on the zebrafish retinotectal system, a powerful model to study neurogenesis, neuronal survival and axonal regrowth after damage. Methods: The overall effects of aging on retinal and optic nerve morphology in zebrafish were evaluated using immunohistological methods (IHC) for detection of neurogenesis, apoptosis, synaptic integrity and inflammation. Aged zebrafish were subjected to optic nerve crush (ONC) and axonal regeneration was followed using biocytin tracing and GAP43 immunostainings within the retinotectal system. Underlying processes were analysed via IHC and Western blotting. Results: Detailed morphometric and IHC analyses of the aged zebrafish eye confirmed the occurrence of age-related retinal atrophy and demonstrated an increased number and altered distribution of microglia/macrophages, indicative for a clear manifestation of ‘inflammaging’. These hallmarks of aging are accompanied by a reduction in the endogenous neurogenic capacity of the ciliary marginal zone and importantly, by a significant delay in axonal regeneration after optic nerve crush, resulting in a diminished reinnervation of the tectum in 2-year-old zebrafish. Preliminary data suggest that altered morphological and functional changes of senescent microglia, Müller glia and reactive astrocytes could underlie this diminished regeneration capacity in the aged zebrafish. Conclusions: The zebrafish, already the focus of a myriad of comparative studies investigating retinal regeneration, was recently also put forward as an ideal aging model. Indeed, our results indicate several hallmarks of aging in the aged zebrafish retinotectal system, which seem to influence regeneration capacities. These studies will allow us to elucidate underlying mechanisms and pathways, and might unveil new targets for the development of novel regenerative strategies in the senescent mammalian CNS.