Background: Cardiovascular disease (CVD) is the predominant cause of mortality, with aging being a significant risk factor. Nucleotides (NTs), essential for numerous biological functions, are particularly vital under conditions like aging, starvation, and nutrient deficiency. Although the antiaging benefits of exogenous NTs have been recognized in various systems, their cardiac-specific effects are not well understood. This study, therefore, investigated the impact of exogenous NTs on cardiac aging and delved into the potential mechanisms. Methods: Senescence-accelerated mouse prone-8 (SAMP8) mice were utilized, randomly assigned to one of three groups: a control group (Control), a low-dose NTs group (NTs_L), and a high-dose NTs group (NTs_H). Meanwhile, senescence-accelerated mouse resistant 1 (SAMR1) mice were set up as the SAMR1 group. Following a 9-month intervention, cardiac tissues were subjected to analysis. Results: The results showed that NTs improved the morphological structure of the cardiac tissue, enhanced the antioxidant capacity, and mitigated inflammation. Metabolomics analysis revealed that the high-dose NT intervention improved cardiac tissue energy metabolism, potentially through activating the AMPK pathway, enhanced mitochondrial biogenesis, and increased TFAM protein expression. Conclusions: Together, these results indicate that exogenous NTs exert beneficial effects on the cardiac tissues of SAMP8 mice, potentially mitigating the cardiac aging process.

Nucleotides—fundamental cellular building blocks—are an underappreciated dietary component, especially in aging when metabolic resilience wanes.