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 fastingglucose polygenic risk score (FBG-PRS)-modifies the effect of exogenous nucleotides (NTs) on IR. A significant PRS×intervention interaction was observed for change 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 (log2FC = -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.