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Abstract: Stem cells can exist in either active or quiescent states. In the aging hippocampus, adult neural stem cells (aNSCs) shift into a quiescent state, contributing to age-related reductions in hippocampal neurogenesis. Here, we focused on the subventricular zone (SVZ) stem cell niche of the adult forebrain, asking to what extent quiescence-associated changes in aNSCs are initiated between early and middle-age. Immunohistochemical and label retention experiments revealed that the overall output of the SVZ stem cell system was already highly decreased in middle-aged mice (12-months-old) compared with young adult mice (2-month-old), as measured by reduced marker expression for multiple neural precursor sub-populations and diminished addition of SVZ-derived neuroblasts to the olfactory bulbs (OBs). These changes were associated with significant cytological aberrations within the SVZ niche, including an overall atrophy of the SVZ and accumulation of large lipid droplets within ependymal cells, which are key support cells of the SVZ niche. Importantly, the reduced output of the middle-aged SVZ stem cell system correlated with quiescence-associated changes in middle-aged aNSCs. Specifically, while tissue culture experiments showed that young adult and middle-aged forebrains possessed equal numbers of neurosphere-forming aNSCs, the middle-aged neurospheres exhibited differences in their in vitro properties, and middle-aged aNSCs in vivo divided less frequently. These findings demonstrate that aNSCs begin undergoing quiescence-associated changes between early and mid-adulthood in the mouse SVZ, and serve as a useful framework for further studies aimed at defining the early events involved in aging-associated quiescence of aNSCs. [ABSTRACT FROM AUTHOR]