Senolytic Treatment Improves Neurogenesis in Aged Killifish

Killifish exhibit proficient regeneration, but lose regenerative capacity with advancing age. Some of this loss is due to the growing presence of lingering senescent cells, as the balance between the pace of creation of senescent cells and timely immune-mediated clearance of senescent cells is disrupted by the mechanisms of aging. Senolytic drugs that can force senescent cells into apoptosis represent a way to greatly reduce the impact of senescent cells on tissue function in later life. Researchers here show that the production of new neurons is inhibited by senescent cells in aged killifish, and is improved following senolytic treatment, leading to greater regeneration after brain injury.

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.