The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging

Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurode-generative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activ-ity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.

Automated summary

Aging leads to a decline in neural stem cells, neurogenesis, and cognitive function. Recent evidence shows disrupted adult neurogenesis in the hippocampus of patients with neurodegenerative disorders. Single-cell RNA sequencing reveals that mitochondrial protein folding stress is prominent in activated neural stem cells/neural progenitors in the neurogenic niche, and it increases with aging, leading to dysregulated cell cycle and mitochondrial activity. This stress compromises neural stem cell maintenance and reduces neurogenesis, resulting in neural hyperactivity and impaired cognitive function. Reducing mitochondrial protein folding stress improves neurogenesis and cognitive function in old mice, suggesting a potential approach to alleviate aging-associated cognitive decline.