The impact of aging on the regenerative potential of the zebrafish

Since 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 of the diseased mammalian CNS remains a challenge, especially in an aging environment. In contrast to mammals, zebrafish have a high neurogenic and regenerative capacity. However, they also age gradually and thus form an ideal model to study the effects of aging on regeneration. We focus on the zebrafish retinotectal system, a powerful system to study neurogenesis, neuronal survival and axonal regrowth after damage. Detailed morphometric and immunohistochemical analyses of the aged zebrafish retina confirmed the occurrence of age-related retinal atrophy and revealed 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, more 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. A detailed characterization of the aged zebrafish retinotectal system and its regeneration potential, 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.status: publishe