NFATC1 dysfunction-triggered MSC senescence induces tooth aging amenable to senolytic therapy.

Organ-specific aging drivers extend our understanding of aging and offer therapeutic potential for combating age-related decline and rejuvenating organ function. Mature mammalian teeth possess unique characteristics, cell-free calcified parenchyma, isolated vasculature, specialized metabolic environment, limited turnover, and replenishment of repair-associated cell lineages, distinguishing them from other organs and leaving tooth aging mechanisms largely unexplored. Here, by analyzing clinical data from human tooth aging and developing genetic tools, comprising Cre-based pulse-chase tracing and ablation, gene manipulation combined with tracing, and fluorescent ubiquitination-based cell cycle indicator (FUCCI), we identify the first in vivo driver of tooth aging. We further demonstrate that this driver induces senescence in dental pulp mesenchymal stromal cells (MSCs), mechanistically explaining irreversible organ degeneration and regenerative disability during aging. Moreover, senolytic therapy effectively ameliorates phenotypic alterations of tooth aging caused by disfunction of this driver and restores dental repair capacity. Our findings elucidate mechanisms of tooth aging and provide promising strategies for tooth preservation during aging.