Aging impairs the essential contributions of non-glial progenitors to neurorepair in the dorsal telencephalon of the Killifish <i>N. furzeri</i>

Summary The aging central nervous system (CNS) of mammals displays progressive limited regenerative abilities. Recovery after loss of neurons is extremely restricted in the aged brain. Many research models fall short in recapitulating mammalian aging hallmarks or have an impractically long lifespan. We established a traumatic brain injury model in the African turquoise killifish ( Nothobranchius furzeri ), a regeneration-competent vertebrate model that evolved to naturally age extremely fast. Stab-wound injury of the aged killifish dorsal telencephalon unveils an impaired and incomplete regeneration response when compared to young individuals. Remarkably, killifish brain regeneration is mainly supported by atypical non-glial progenitors, yet their proliferation capacity appears declined with age. We identified a high inflammatory response and glial scarring to also underlie the hampered generation of new neurons in aged fish. These primary results will pave the way for further research to unravel the factor age in relation to neurorepair, and to improve therapeutic strategies to restore the injured and/or diseased aged mammalian CNS. Highlights Aging impairs neurorepair in the killifish pallium at multiple stages of the regeneration process Atypical non-glial progenitors support the production of new neurons in the naive and injured dorsal pallium The impaired regeneration capacity of aged killifish is characterized by a reduced reactive proliferation of these progenitors followed by a decreased generation of newborn neurons that in addition, fail to reach the injury site Excessive inflammation and glial scarring surface as potential brakes on brain repair in the aged killifish pallium