Aging Disrupts Spatiotemporal Regulation of Germline Stem Cells and Niche Integrity

A major factor driving stem cell decline is stem cell niche aging, but its molecular mechanism remains elusive. We use the Caenorhabditis elegans distal tip cell (DTC), the mesenchymal niche that employs Notch signaling to regulate germline stem cells (GSCs), as an in vivo niche aging model and delineate the molecular details of the DTC/niche aging process. Here, we demonstrate that a drastic decrease in C. elegans germline fecundity, which begins even in early adulthood, is mainly due to an age-induced disruption in spatial regulation of Notch-dependent transcription in the germline combined with a moderate reduction in Notch transcription at both tissue and cellular levels. Consequently, the Notch-responsive GSC pool shifts from the distal end of the gonad to a more proximal region, disrupting the distal-to-proximal germline polarity. We find that this GSC pool shift is due to a dislocation of the DTC/niche nucleus, which is associated with age-induced changes in the structure and morphology of the DTC/niche. Our findings reveal a critical link between physiological changes in the aging niche, their consequences in stem cell regulation, and germline tissue functions.