Once young and carefree, the passing years creep up on us all and bring so many responsibilities and places to be that we don’t know whether we are coming or going! A busy new study shows that the chromatin accessibility and gene expression alterations that occur during aging impact neural stem cells (NSCs) in much the same way, leading these pro-regenerative cells to “lose their way” and lose their proper function.
Teeter-tottering researchers led by Anne Brunet (Stanford University, California) understood that NSC-containing neurogenic niches suffered from a decline in normal function during the aging process; however, they didn’t quite have a handle on the mechanism underlying this deterioration. In their forever-shifting recent study, the always-active authors evaluated whether changes to the epigenome during normal aging in model mice affect the comings-and-goings of quiescent and activated NSCs from their niche, inhibiting their normal in vivo function.
Let’s hear more about the epigenetic coming and goings in this new NSC-based study from Yeo, Zhou, and Colleagues:
- Analysis of genome-wide chromatin accessibility using ATAC-seq during normal mouse agingrevealed decreases in chromatin accessibility at the regulatory regions of niche cell adhesion/cell migration-associated genes in quiescent NSCs but increases in chromatin accessibility at the same genes in activated (proliferative) NSCs
- These chromatin and gene expression profiles prompt quiescent NSCs to become less adhesive to their niche, and activated NSCs become more adhesive during aging
- Age-related alterations to activated NSCs decrease their migration in vitro and reduce their niche mobilization potential in vivo, which reduces their potential to migrate from the niche and support neurogenesis to repair damage in the brain
- Visualization of the mechanical forces exerted by activated NSCs in their niche using Förster resonance energy transfer (FRET)-based molecular tension sensors showed that aging increases force-producing adhesions in activated NSCs
- Inhibiting the focal adhesion-associated Rho and Rho-associated protein kinase (ROCK) reduces adhesions, decreases force production, and restores migration in old activated NSCs in vitro
- Interestingly, the injection of ROCK inhibitor into the vicinity of the neurogenic niche in old mice brains significantly boosts neurogenesis
Overall, these epigenetic comings-and-goings help to demonstrate that restoring the migratory potential NSCs could improve neurogenesis in the aged brain. This exciting and ever-moving study also suggests that ROCK inhibition represents an exciting therapeutic means of rescuing age-dependent neural defects in the ever-expanding aged population.
For more details on how chromatin accessibility helped show why aging NSCs don’t know if they are coming or going, see Nature Aging, July 2023.