Mechanisms of enhanced quiescence in neural stem cell aging

Abstract

The maintenance of neural stem cell function is vital to ensure neurogenesis throughout adulthood. During aging, there is a significant reduction in adult neurogenesis that correlates with a decline in cognitive function. Although recent studies have revealed novel extrinsic and intrinsic mechanisms that regulate the adult neural stem cell (NSC) pool and lineage progression, the precise molecular mechanisms that drive dysregulation of adult neurogenesis in the context of aging are only beginning to emerge. Recent studies have shed light on mechanisms that regulate the earliest step of adult neurogenesis, the activation of quiescent NSCs. Interestingly, the ability of NSCs to enter the cell cycle in the aged brain significantly declines suggesting a deepend state of quiescence. Given the likely contribution of adult neurogenesis to supporting cognitive function in humans, enhancing neurogenesis may be a strategy to combat age-related cognitive decline. This review highlights the mechanisms that regulate the NSC pool throughout adulthood and discusses how dysregulation of these processes may contribute to the decline in neurogenesis and cognitive function throughout aging.

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age

“…Consistent with the known decrease in neurogenesis with age (Audesse & Webb, 2020;Corenblum et al, 2016;Daynac et al, 2016), we observed that NSPCs isolated from aged mice had a reduced proliferation rate compared to young (Figure S1A,B). To elucidate the age-associated chromatin changes in NSC quiescence and activation, we compared the young ATAC-seq and RNA-seq profiles to datasets collected in parallel from aged NSPCs isolated from 20-24 month-old mice.…”

“…NSC quiescence is a tightly regulated state characterized by a transcriptional program enriched for lipid metabolism, glycolysis, and specific cell signaling pathways. This transcriptional program is dramatically altered as NSCs activate, upregulating genes involved in oxidative metabolism, cell proliferation, and protein translation (Audesse & Webb, 2020;Llorens-Bobadilla et al, 2015;Morizur et al, 2018;Shin et al, 2015). Moreover, with NSC activation, aggregates of damaged proteins and molecular cargo that accumulate in qNSCs are cleared.…”

Adult Hippocampal Neurogenesis in Aging and Alzheimer's Disease

“…In addition, a highly integrated network of signals is required to maintain healthy lifelong neurogenesis and alterations to these signaling pathways during aging have been linked to the decline in neurogenesis (e.g., BMP, Notch, Wnt, EGF, and IGF). A number of age-associated intrinsic cellular changes impact neurogenesis in aged animals, including transcriptional, metabolic, proteostatic, and epigenetic changes (for an in depth review see Audesse and Webb, 2020 ). For example, a major age-associated feature of NSCs is the deterioration of protein quality control, including autophagy-lysosome function, chaperone activity, and overall aggregate processing.…”

FOXO3 regulates a common genomic program in aging and glioblastoma stem cells

“…For example, there was a strong enrichment for processes associated with neuronal fate commitment and differentiation, such as axon guidance, synapse maturation, and neuronal migration ( Figures 1A and S1B ). Moreover, features of the quiescent state such as high fatty acid beta-oxidation, autophagic flux, cell cycle restraint, and transcriptional repression 70 were upregulated in the FOXO3 high tumor samples ( Figure 1A and S1C ). Overall, FOXO3 high tumors tended to have elevated FOXO3 protein levels as well ( Figure S1D ), further supporting distinct quiescence-like hallmarks of FOXO3 high GBMs.…”