Enhancing DNA Repair Prolongs Lifespan and Improves Healthspan in Mice

Impairments in DNA repair mechanisms undermine genomic integrity, accelerating the aging process and elevating the risk of age-related diseases in both murine models and humans. Despite the recognized link between DNA repair and aging, empirical evidence supporting the lifespan and healthspan extension through enhanced DNA repair is lacking. This knowledge gap is attributed to the complex interplay of numerous DNA repair genes involved in maintaining genomic stability, making it challenging to pinpoint specific pathways and factors that could be targeted for lifespan and healthspan improvements. In this study, we generated a knock-in mouse model overexpressing XRCC4 and DNA LIG4, key components of the non-homologous end joining (NHEJ) pathway, the predominant mechanism for repairing DNA double-strand breaks. Our findings reveal that augmenting NHEJ is a viable anti-aging strategy in mammals, as evidenced by extended lifespan and improved healthspan in both wild type mice and LmnaG609G/+ progeroid mice. Additionally, enhanced NHEJ activity improves cardiac, motor, and cognitive functions, as well as bone quality in aged mice. Transcriptomic and epigenetic analysis across different organs indicates significant downregulation in inflammatory responses and upregulation of pathways associated with maintaining organ homeostasis and function, further supporting the role of DNA repair in modulating aging and age-related diseases. Our data underscore the potential of targeting DNA repair pathways as a strategy to counteract aging and its associated health decline.