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

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 ### Competing Interest Statement The authors have declared no competing interest. * AMC : age-matched control BBB : brain blood barrier BLBP : brain lipid-binding protein CNS : central nervous system dpi : days post injury GFAP : glial fibrillary acidic protein GS : glutamine synthetase hpi : hours post injury NGP : non-glial progenitor NPC : neuronal progenitor cell NSC : neuronal stem cell PCNA : proliferating cell nuclear antigen PVZ : periventricular zone RG : radial glia RMS : rostral migratory stream SGZ : subgranular zone SOX2 : SRY-box transcription factor 2 SVZ : subventicular zone TBI : traumatic brain injury TUNEL : terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling VZ : ventricular zone