Rapamycin Attenuates Age-Related Changes in Marmoset Submandibular Gland: A Non-Human Primate Model of Human Oral...

The aging of salivary glands (SGs) leads to xerostomia, impaired oral defenses, and a compromised quality of life, yet the biology of human submandibular gland (SMG) aging remains poorly understood due to limited availability of human tissues and differences in anatomy and physiology between rodent and human SGs. The common marmoset (Callithrix jacchus) is a short-lived non-human primate (NHP) with SMG histology that closely resembles humans and has the potential to provide a translational model for investigating SG aging. In this study, we examined the age-associated structural and molecular alterations that occur in marmoset SMGs and evaluated whether chronic oral rapamycin treatment, a gerotherapeutic mTOR inhibitor, mitigates these age-related changes. Histological and immunofluorescence analyses revealed that there was a substantial decline in mucous and serous acinar units, expansion of ductal and collagen-rich stromal compartments, increased extracellular matrix remodeling, elevated dysregulation of lipid metabolism, and increased numbers of apoptotic and senescent cells in the SMG with aging. Rapamycin treatment was associated with partial preservation of acinar structure and a reduction in fibrosis, lipid accumulation, and number of apoptotic and senescent cells that resulted in an overall tissue phenotype that more closely resembled that of younger animals. These findings suggest that the aging marmoset SMG recapitulates key features of human SG aging and that rapamycin treatment was associated with an attenuation in the hallmarks of SG degeneration. The results suggest that the marmoset represents a valuable NHP model for studying SG aging biology and testing therapeutic strategies aimed at attenuating age-related structural degeneration associated with SG dysfunction.