Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche

• DOI: 10.1016/j.stemcr.2021.12.010
• Publication Date: 2022-01-20T15:37:16Z
• Authors: Michael P. Fatt; Lina M. Tran; Gisella Vetere; Mekayla A. Storer; Jaclin V. Simonetta; Freda D. Miller; Paul W. Frankland; David R. Kaplan
• Keywords: Male; Aging; Sulfonamides; 0303 health sciences; Aniline Compounds; Neurogenesis; Hippocampus; Article; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Neural Stem Cells; Dentate Gyrus; Animals; Female; Stem Cell Niche; Cellular Senescence; Cell Proliferation; Spatial Memory

Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on CNS neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an aging-dependent accumulation of senescent cells, largely senescent NPCs, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug ABT-263 (Navitoclax) caused a rapid increase in NPC proliferation and neurogenesis. Genetic ablation of senescent cells similarly activated hippocampal NPCs. This acute burst of neurogenesis had long-term effects in middle-aged mice. One month post-ABT-263, adult-born hippocampal neuron numbers increased and hippocampus-dependent spatial memory was enhanced. These data support a model where senescent niche cells negatively influence neighboring non-senescent NPCs during aging, and ablation of these senescent cells partially restores neurogenesis and hippocampus-dependent cognition.