The Converging Roles of Nucleases and Helicases in Genome Maintenance and the Aging Process

The process of aging is fundamentally driven by genomic instability and the accumulation of DNA damage, which progressively impair cellular and tissue function. In order to counteract these challenges, cells rely on the DNA damage response (DDR), a multilayered signaling and repair network that preserves genomic integrity and sustains homeostasis. Within this framework, nucleases and helicases have pivotal and complementary roles by remodeling aberrant DNA structures, generating accessible repair intermediates, and determining whether a cell achieves faithful repair, undergoes apoptosis, or enters senescence. Defects in these enzymes are exemplified in human progeroid syndromes, where inherited mutations lead to premature aging phenotypes. This phenomenon is also replicated in genetically engineered mouse models that exhibit tissue degeneration, stem cell exhaustion, and metabolic dysfunction. Beyond their canonical repair functions, helicases and nucleases also interface with the epigenome, as DNA damage-induced chromatin remodeling alters enzyme accessibility, disrupts transcriptional regulation, and drives progressive epigenetic drift and chronic inflammatory signaling. Moreover, their dysfunction accelerates the exhaustion of adult stem cell populations, such as hematopoietic, neural, and mesenchymal stem cells. As a result, tissue regeneration is undermined, establishing a self-perpetuating cycle of senescence, impaired repair, and organismal aging. Current research is focused on developing therapeutic strategies that target the DDR-aging axis on several fronts: by directly modulating repair pathways, by regulating the downstream consequences of senescence, or by preventing DNA damage from accumulating upstream. Taken together, evidence from human disease, animal models, molecular studies, and pharmacological interventions demonstrates that nucleases and helicases are not only essential for genome maintenance but also decisive in shaping aging trajectories. This provides valuable knowledge into how molecular repair pathways influence organismal longevity and age-related diseases.