Transient transcriptomic rejuvenation during intestinal and liver regeneration in mice

Aging and regeneration are fundamental biological processes, but the relationship between them is poorly understood. During intestinal regeneration, adult epithelial cells reactivate developmental programs that support repair. To investigate if this plasticity alters tissue biological age, we developed and validated intestinal tissue and epithelium-specific transcriptomic aging clocks. Across various regeneration models, epithelial states were predicted by these clocks to be younger than controls. Their expression changes were also negatively associated with intestinal aging signatures. The resulting younger state was characterized by YAP-associated regeneration and reduced mature enterocyte identity. In a separate irradiation model, the predicted epithelial age first increased, then fell at the peak of regeneration and later increased again during recovery. The pace of this response differed with host age. In a chemotherapy-induced injury model, epithelium in young animals also entered this younger state earlier and then returned to its preinjury state during recovery. Old epithelium responded later, but also reversibly transitioned through a rejuvenated state. Further spatial transcriptomic analyses linked lower epithelial age with regeneration in selected injured and tumor-associated regions. In addition, liver regeneration after partial hepatectomy in old animals also led to a decreased transcriptomic age, accompanied by pathway changes negatively associated with aging signatures. Overall, these findings suggest that mammalian regeneration is associated with a transient reduction in biological age, whose timing and persistence depend on tissue, host age and the course of repair.