Regulation of the p19^Arf/p53 pathway by histone acetylation underlies neural stem cell behavior in senescence‐prone SAMP8 mice

Summary Brain aging is associated with increased neurodegeneration and reduced neurogenesis. B1/neural stem cells (B1‐ NSC s) of the mouse subependymal zone ( SEZ ) support the ongoing production of olfactory bulb interneurons, but their neurogenic potential is progressively reduced as mice age. Although age‐related changes in B1‐ NSC s may result from increased expression of tumor suppressor proteins, accumulation of DNA damage, metabolic alterations, and microenvironmental or systemic changes, the ultimate causes remain unclear. Senescence‐accelerated‐prone mice ( SAMP 8) relative to senescence‐accelerated‐resistant mice ( SAMR 1) exhibit signs of hastened senescence and can be used as a model for the study of aging. We have found that the B1‐ NSC compartment is transiently expanded in young SAMP 8 relative to SAMR 1 mice, resulting in disturbed cytoarchitecture of the SEZ , B1‐ NSC hyperproliferation, and higher yields of primary neurospheres. These unusual features are, however, accompanied by premature loss of B1‐ NSC s. Moreover, SAMP 8 neurospheres lack self‐renewal and enter p53‐dependent senescence after only two passages. Interestingly, in vitro senescence of SAMP 8 cells could be prevented by inhibition of histone acetyltransferases and mimicked in SAMR 1 cells by inhibition of histone deacetylases ( HDAC ). Our data indicate that expression of the tumor suppressor p19, but not of p16, is increased in SAMP 8 neurospheres, as well as in SAMR 1 neurospheres upon HDAC inhibition, and suggest that the SAMP 8 phenotype may, at least in part, be due to changes in chromatin status. Interestingly, acute HDAC inhibition in vivo resulted in changes in the SEZ of SAMR 1 mice that resembled those found in young SAMP 8 mice.