Genetic risk modifies the effect of exogenous nucleotides on insulin resistance in older adults: insights from multi-omics analyses

Abstract

Nucleotides—fundamental cellular building blocks—are an underappreciated dietary component, especially in aging when metabolic resilience wanes. Whether genetic background determines who benefits from NTs has been unknown. Insulin resistance (IR) underlies age-related metabolic disorders, yet responses to nutritional interventions are heterogeneous. In this secondary analysis of the TALENTs randomized controlled trial (121 adults aged 60–70 years; 19-week intervention; NCT05243108), we tested whether genetic background—quantified by a fasting-glucose polygenic risk score (FBG-PRS)—modifies the effect of exogenous nucleotides (NTs) on IR. A significant PRS × intervention interaction was observed with changes in HOMA-IR (p = 0.0115). Participants with high FBG-PRS exhibited improvements with NTs, including reduced HOMA-IR and visceral adiposity and increased limb muscle mass, whereas low FBG-PRS participants showed minimal benefit. Multi-omics supported a coherent mechanism: transcriptomics identified 39 differentially expressed genes with PPP4R2 most strongly downregulated (log 2FC = −2.00; p_adj = 2.81 × 10⁻¹³), and metabolomics revealed decreased cyclic AMP with enrichment of energy-metabolism pathways. These findings indicate that NTs improve insulin sensitivity primarily in genetically susceptible older adults and suggest NTs as a candidate precision-nutrition strategy for improving insulin sensitivity in aging.