Decoding Dental Stem Cell Aging: Mechanisms, Therapeutic Strategies, and Beyond

Dental stem cell (DSC) aging involves genomic instability, mitochondrial dysfunction, telomere attrition, and epigenetic alterations, leading to impaired proliferation, reduced differentiation potential, and pro‐inflammatory secretory activity. These processes drive cellular senescence and compromise regenerative and immunomodulatory functions, thereby limiting therapeutic efficacy. Defining the molecular basis of DSC aging not only clarifies the mechanisms underlying their decline but also informs strategies for rejuvenation, quality control, and patient stratification, which are essential for advancing their clinical translation in tissue repair and disease treatment. Abstract Dental stem cells (DSCs) hold immense potential in regenerative medicine due to their unique properties, including superior proliferative and differentiation capacities, robust immunomodulatory functions, and resilience to aging. However, the aging process profoundly impairs their functionality, diminishing their regenerative potential and limiting their clinical utility. This review provides a systematic examination of the mechanisms underlying DSC aging, focusing on disrupted signaling pathways, metabolic dysregulation, and epigenetic modifications, as well as the regulatory roles of non‐coding RNAs and critical proteins. It further investigates the key intrinsic and extrinsic factors driving this process, offering a comprehensive perspective on the interplay between cellular and systemic influences. Building on this foundation, the review explores innovative strategies to mitigate age‐related decline in DSCs, emphasizing approaches that target the extracellular matrix, mitochondrial dysfunction, and key molecular pathways. Finally, it addresses the challenges in translating these findings into clinical applications, such as inter‐individual variability and systemic influences, and advocates for multidisciplinary approaches to enhance therapeutic outcomes. Collectively, this review provides a critical framework for advancing the clinical translation of DSC‐based therapies, with broader implications for regenerative medicine in aging contexts. Dental stem cell (DSC) aging involves genomic instability, mitochondrial dysfunction, telomere attrition, and epigenetic alterations, leading to impaired proliferation, reduced differentiation potential, and pro-inflammatory secretory activity. These processes drive cellular senescence and compromise regenerative and immunomodulatory functions, thereby limiting therapeutic efficacy. Defining the molecular basis of DSC aging not only clarifies the mechanisms underlying their decline but also informs strategies for rejuvenation, quality control, and patient stratification, which are essential for advancing their clinical translation in tissue repair and disease treatment. Abstract Dental stem cells (DSCs) hold immense potential in regenerative medicine due to their unique properties, including superior proliferative and differentiation capacities, robust immunomodulatory functions, and resilience to aging. However, the aging process profoundly impairs their functionality, diminishing their regenerative potential and limiting their clinical utility. This review provides a systematic examination of the mechanisms underlying DSC aging, focusing on disrupted signaling pathways, metabolic dysregulation, and epigenetic modifications, as well as the regulatory roles of non-coding RNAs and critical proteins. It further investigates the key intrinsic and extrinsic factors driving this process, offering a comprehensive perspective on the interplay between cellular and systemic influences. Building on this foundation, the review explores innovative strategies to mitigate age-related decline in DSCs, emphasizing approaches that target the extracellular matrix, mitochondrial dysfunction, and key molecular pathways. Finally, it addresses the challenges in translating these findings into clinical applications, such as inter-individual variability and systemic influences, and advocates for multidisciplinary approaches to enhance therapeutic outcomes. Collectively, this review provides a critical framework for advancing the clinical translation of DSC-based therapies, with broader implications for regenerative medicine in aging contexts. Advanced Science, Volume 12, Issue 44, November 27, 2025.