A short dasatinib and quercetin treatment is sufficient to reinstate potent adult neuroregenesis in the aged killifish

Abstract

The young African turquoise killifish has a high regenerative capacity, but loses it with advancing age, adopting several aspects of the limited form of mammalian regeneration. We deployed a proteomic strategy to identify pathways that underpin the loss of regenerative power caused by aging. Cellular senescence stood out as a potential brake on successful neurorepair. We applied the senolytic cocktail Dasatinib and Quercetin (D + Q) to test clearance of chronic senescent cells from the aged killifish central nervous system (CNS) as well as rebooting the neurogenic output. Our results show that the entire aged killifish telencephalon holds a very high senescent cell burden, including the parenchyma and the neurogenic niches, which could be diminished by a short-term, late-onset D + Q treatment. Reactive proliferation of non-glial progenitors increased substantially and lead to restorative neurogenesis after traumatic brain injury. Our results provide a cellular mechanism for age-related regeneration resilience and a proof-of-concept of a potential therapy to revive the neurogenic potential in an already aged or diseased CNS.

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

“…Overall, determining the impact of genetic or pharmacologic manipulation of age-associated senescence, oxidative stress, and/or inflammation signatures on retinal health and function may open avenues for novel targets amenable for therapeutic intervention. Pharmacological manipulation of senescence using senolytic drugs has recently been shown to remove senescent cells from the aged killifish telencephalon, thereby restoring the neurogenic potential of the aged killifish brain (Van houcke et al, 2023). Similar pharmacological approaches targeting the identified ageing processes might thus have the potential to rejuvenate the aged retina.…”

Age-related alterations in the behavioral response to a novel environment in the African turquoise killifish (Nothobranchius furzeri)

“…Previous research already revealed that killifish experience an age-related loss in the regenerative capacity of the brain, visual system, and fin ( Wendler et al, 2015 ; Van houcke et al, 2021 ; Vanhunsel et al, 2022 ). The age-related decline in regeneration potential allows researchers to exploit the killifish to study what hampers regeneration upon aging and to find interventions to boost the regeneration potential ( Van houcke et al, 2023 ). The killifish as a gerontology model can be used in the search for treatments for neurodegenerative diseases, that are characterized by symptoms like impaired movement, memory decline, spatial navigation impairments, anxiety, muscle weakness, etc.…”