Oral stem cell aging: From mechanisms to therapeutic rejuvenation

Oral stem cells (OSCs) represent a group of mesenchymal stromal/stem cell-like populations localized within dental and craniofacial tissues, where they play vital roles in maintaining tissue integrity and supporting regeneration. Although OSCs possess robust self-renewal capacity and multilineage differentiation potential, they progressively develop senescent phenotypes in response to organismal aging, prolonged in vitro culture, and adverse microenvironmental stimuli. The senescent state of OSCs is characterized by diminished proliferation and differentiation, genomic instability, mitochondrial impairment, and the establishment of a senescence(definition)-associated secretory phenotype. Mechanistically, OSC senescence arises from a series of interacting processes, including DNA damage, metabolic imbalance, epigenetic reprogramming, and persistent inflammatory signaling. These alterations drive stem cell functional decline and compromise the surrounding regenerative niche. Consequently, OSC aging is closely associated with multiple craniofacial disorders, including periodontal tissue breakdown, defective dentin-pulp regeneration, alveolar bone resorption, and delayed mucosal healing. To reverse these age-related changes, various rejuvenation approaches have been explored, including epigenetic modulation, metabolic intervention, senescence-targeting therapies, extracellular vesicle-mediated strategies, and biomaterial-based niche engineering. Nonetheless, translational challenges remain, particularly in cellular heterogeneity, donor-related variability, and age-dependent functional changes in extracellular vesicles (EVs). Future efforts are expected to focus on developing targeted and clinically translatable strategies to rejuvenate OSCs and enhance regenerative outcomes.