Cellular Senescence Contributes to the Dysfunction of Tight Junctions in Submandibular Glands of Aging Mice

ABSTRACT The current mechanism by which aging reduces salivary secretion is unknown. This study investigates the mechanism of aging‐related submandibular (SMG) dysfunction and evaluates the therapeutic potential of dental pulp stem cell‐derived exosomes (DPSC‐exos). We found that the stimulated salivary flow rate was significantly reduced in naturally aging and D‐galactose‐induced aging mice (D‐gal mice) compared to control mice. Acinar atrophy and periductal fibrosis in SMGs and parotid glands (PGs) were observed in naturally aging and D‐gal mice, whereas sublingual glands (SLGs) had no notable alterations. We observed the accumulation of senescent cells in the SMGs, along with a decrease in claudin‐3 (Cldn‐3) expression and alterations in the distribution of Cldn1 and Cldn3. Additionally, after D‐gal‐induced senescence of SMG‐C6 cells, there was a decrease in paracellular pathway permeability, reduced expression of Cldn3 and occludin, and changes in the distribution of Cldn1, 3, 4, and 7. Furthermore, injecting DPSC‐exos into the SMGs of D‐gal mice improved stimulated salivary flow rate, reduced acinar atrophy, and decreased SA‐β‐gal activity. Our study identified that increased senescence of SMGs in aging mice can cause a decrease in salivary secretion by disrupting the expression and distribution of tight junction molecules, and injection of DPSC‐exos ameliorates SMG secretory dysfunction. These findings may provide new clues to novel therapeutic targets for aging‐related dysfunction of SMGs.