Enhancing Lysosomal Activation Restores Neural Stem Cell Function During Aging

Abstract

Adult neurogenesis supports cognitive and sensory functions in mammals and is significantly reduced with age. Quiescent neural stem cells are the source of new neurons in the adult brain and emerging evidence suggests that the failure of these cells to activate and re-enter the cell cycle is largely responsible for reduced neurogenesis in old animals. However, the molecular mechanisms supporting quiescence and activation in the adult and aged brain remain undefined. Recent work published by Leeman et al. in Science uncovers a novel role for lysosomes in supporting neural stem cell activation, and reveals that loss of lysosome function during aging contributes to reduced neural stem cell activity. Using a combination of transcriptomics and functional analysis, the authors show that quiescent and activated neural stem cells employ different branches of proteostasis networks, with quiescent stem cells particularly dependent on the lysosome-autophagy system. Excitingly, stimulation of lysosomal activity in the aged quiescent population significantly enhanced their ability to activate and increased the frequency of activated neural stem and progenitor cells within the neural stem cell niche. This work for the first time identifies lysosomal dysfunction as a cause of reduced neurogenesis during aging, and shows that enhancing lysosomal function is sufficient to restore healthy stem cell activity in the aged brain.