Abstract: Molecular mechanisms of aging specific to each stem cell (SC) are being elucidated. However, the common molecular basis for senescence in various SCs remains largely unexplored. Here, we have shown that the dysregulation of DNA damage response (DDR) modulated by lymphoid enhancer-binding factor 1 (Lef1) and DDR-microRNAs (DDR-miRs) is the common molecular basis for aging in SCs. We identified Lef1as the most repressed transcription factor with aging in common between mesenchymal stem/stromal cells (MSCs) and hematopoietic stem/progenitor cells. Like the expression profiles of aged MSCs, Lef1 knockdown reduced broad microRNAs and loss of induction of DDR-miRs in young MSCs. DDR capacity was also diminished in aged SCs in vivo. Moreover, Lef1 deficiency in intestinal stem cells induced precocious dysregulation of DDR and inflammation and senescence in the remote brain. This study demonstrates that the Lef1/DDR-miR axis is the common molecular basis underlying SC aging.