The Use of Nutritional Interventions to Enhance Genomic Stability in Mice and Delay Aging.

<b>Background/Objectives:</b> Metabolism is fundamental to all living organisms. It comprises a highly complex network of fine-tuned chemical reactions that sustain life but also generate by-products that damage cellular biomolecules, including DNA, thereby contributing to aging and disease. As metabolism can be largely modified by dietary alterations, it has the potential to positively or negatively affect health and disease. Interestingly, many aging-associated illnesses known to be influenced by diet also show a causal relation with DNA damage. As DNA keeps all instructions for life, and DNA lesions, if unrepaired, interfere with vital processes such as DNA replication and transcription, DNA damage may be an important mediator of the impact of nutrition on health and aging. <b>Methods:</b> Here, we discuss the genome-protective effects of various oral interventions in mice, aiming to elucidate which nutritional alterations lower DNA damage and promote overall health. <b>Results:</b> Our analysis covers a wide range of interventions with reported positive impacts on genomic stability, including modified diets (e.g., dietary restriction, probiotics, micronutrients, fatty acids, and hormones), NAD+ precursors (e.g., nicotinamide riboside), plant derivatives, and synthetic drugs. Among these, caloric and dietary restriction emerge as the most potent, generic modulators of DNA damage and repair processes, enhancing aspects of repair efficiency through metabolic recalibration and improved cellular resilience. Other interventions, like NAD+ precursors, activate partly similar pathways without necessitating reduced food intake. <b>Conclusions:</b> While many interventions show promise, their effects are often less pronounced or are process-specific compared to caloric or dietary restriction. Additionally, many substances lack comprehensive exploration of their genome-protective effects in mice, with often only a small number of studies examining their impact on genome stability. Moreover, the heterogeneity between studies limits direct comparison. However, the observed overlap in mechanistic effects between treatments lends credibility to their potential efficacy. Ultimately, a deeper understanding of these mechanisms could pave the way for translating these findings into, e.g., combination treatments to promote healthy aging in humans.