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-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.

Mesenchymal stem cells (MSCs) hold substantial promise for treating aging and age-related diseases due to their regenerative and immunomodulatory properties. However, clinical applications remain limited by the poor survival and short retention of transplanted cells within the hostile aged microenvironment. Emerging genetic-engineering approaches, including viral vector-mediated genetic modification and genome-editing technologies such as clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) systems, offer powerful strategies to enhance MSC resilience, functionality, and reparative capacity. Recent advances, such as the development of senescence-resistant mesenchymal progenitor cells (SRCs), demonstrate that precise modification of key longevity pathways can produce MSCs with superior stress resistance, reduced senescence, and improved regenerative performance in both rodent and non-human primate models. These findings highlight the potential of genetically enhanced MSCs as next-generation cellular therapeutics for precision interventions in aging. Nevertheless, challenges related to long-term safety, immunogenicity, off-target effects, and large-scale manufacturing must be addressed before clinical translation.

While genomic instability is a hallmark of aging, and unrepaired or mutagenic double-strand breaks (DSBs) are established drivers, recent evidence suggests that even accurately repaired DSBs contribute to aging. Here, we focus on an intriguing study by Bantele et al. published in Science, which demonstrates that Cas9-induced DSB repair can induce persistent, heritable alterations in higher-order chromatin structure and function, termed "chromatin fatigue". These alterations, characterized by changes in chromatin topology and gene expression, persist long after DNA sequence restoration and are inherited through cell divisions. Crucially, they impair transcriptional responsiveness to physiological stimuli. This finding provides a novel mechanism for DNA damage-driven aging independent of mutations, potentially explaining age-related epigenetic dysfunction. The commentary also highlights key unresolved questions regarding the permanence, locus-specificity, and physiological impact of chromatin fatigue, and explores its interaction with age-related DNA repair decline. This striking molecular phenomenon challenges the notion that faithful repair ensures full functional restoration and opens avenues for future research into interventions against aging and other age-related diseases, such as cancer.

Genomic instability (GI), characterized by the progressive failure of mechanisms that maintain genome integrity, serves as a fundamental link between aging and cancer at the molecular level. It not only drives the aging process but also promotes tumorigenesis through multiple pathways: on one hand, GI can induce cellular senescence and create a pro-inflammatory and tissue remodeling microenvironment via the senescence-associated secretory phenotype; on the other hand, GI can bypass senescence, directly facilitating tumor progression through mechanisms such as aneuploidy, the expansion of pre-malignant clones, and chronic inflammation mediated by DNA damage-associated molecular patterns. The decline in physiological functions accompanying aging and the increased risk of cancer are closely associated with the accumulation of GI, while aging itself may exert anti-cancer effects through irreversible cell cycle arrest in specific contexts. Therefore, a thorough investigation of GI’s dual role in aging and cancer can help reveal the shared biological basis of both processes and provide new strategies for the precise prevention and treatment of age-related tumors.

Aging tissues accumulate DNA damage, while genome instability is a defining feature of cancer. Despite this shared foundation, DNA damage is still largely viewed as a transient lesion that is either faithfully repaired or converted into a mutation. New evidence challenges this binary view, indicating that DNA double-strand breaks (DSBs), even when accurately repaired at the sequence level, can leave durable and heritable alterations in chromatin organization and gene regulation. Accordingly, DSB repair restores DNA integrity but does not necessarily re-establish the original regulatory architecture. The biological consequences of such post-repair regulatory memory remain largely underappreciated, progressively contributing to age-associated tissue dysfunction while simultaneously creating permissive states for malignant transformation and therapy resistance. In this commentary, we argue that reframing DNA damage as a source of heritable regulatory change, rather than solely as a mutational event, reshapes our understanding of aging trajectories and cancer risk.