Aging Stem Cells and Somatic Mosaicism as a Precursor to Malignant Transformation

Adult stem cell aging and malignant transformation are inextricably linked through a complex interplay of intrinsic cellular dysfunction and extrinsic microenvironmental remodeling. Together, these factors generate a positive feedback loop that drives quiescent, tightly regulated stem cells toward dysregulated, mutation-enriched states characterized by a loss of lineage fidelity. This review synthesizes literature detailing how age-associated alterations, including epigenetic drift, genomic instability, telomere dynamics, and metabolic rewiring, converge with extracellular matrix remodeling, paracrine shifts, and inflammaging to foster permissive tissue niches. Furthermore, we discuss the mechanisms and consequences of somatic mosaicism, notably clonal hematopoiesis, in relation to malignant risk. Finally, we highlight current and potential clinical interception strategies designed to mitigate clonal expansion, optimize risk assessment, and disrupt oncogenesis across diverse human tissues.