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.