Complementary fish models for brain ageing: insights from killifish and zebrafish

Abstract Ageing is the primary risk factor for neurodegenerative disease, yet experimental models often sacrifice natural age-related disease trajectories for genetically modified models. Teleost fish offer a useful complementary framework in this context. The African turquoise killifish (Nothobranchius furzeri) possesses a naturally compressed lifespan and develops age-associated phenotypes within months, including impaired proteostasis, reduced regenerative capacity, and disease-relevant neurodegenerative signatures. Zebrafish (Danio rerio), on the other hand, age over a longer timeframe, with lifespans that can extend up to ∼5 years under laboratory conditions, but provide exceptional experimental accessibility through well-established and standardised genetic, pharmacological, and behavioural tools for dissecting neural mechanisms in vivo. In the present review, we highlight how these two fish models can be used together to investigate mechanisms linking physiological brain ageing to neurodegenerative vulnerability. We focus on processes like proteostasis collapse, altered translational and nutrient-sensing pathways, and age-related decline in neurogenesis and tissue resilience. We argue that killifish are currently most informative for identifying naturally arising ageing trajectories and early degenerative signatures, whereas zebrafish are particularly suited to causal testing, pathway manipulation, and scalable disease modelling. Rather than treating these systems as alternatives, we propose that they should be considered as complementary vertebrate models. This comparative perspective also highlights how conserved biological processes shape brain ageing and determine vulnerability to age-related neurodegenerative disease.