Urate‐Related Genetic Risk Modulates the Anti‐Aging Effects of Exogenous Nucleotides: Multi‐Omics Evidence From Older Adults

Nucleotides-essential substrates for DNA repair, energy metabolism, and redox regulation-are emerging as nutritional modulators of biological aging. Yet, individual responses to exogenous nucleotide (NTs) supplementation remain poorly understood. Given that urate metabolism governs systemic oxidative balance, this study investigated whether genetic variability in urate regulation modifies the anti-aging effects of NTs. In this secondary analysis of the TALENTs randomized controlled trial (121 adults aged 60-70 years; 19-week intervention; NCT05243108), participants were stratified by urate polygenic risk score (UA-PRS) to evaluate genotype-dependent responses in DNA methylation age (DNAmAge) and leukocyte telomere length (LTL). A significant UA-PRS × intervention interaction was observed for ΔDNAmAge (p = 0.0114) and ΔLTL (p = 0.0271). NTs supplementation reduced DNAmAge in the High-PRS group (β = -5.10, p = 0.00013) and preserved telomere length in the Low-PRS group (β = 0.31, p = 0.0043). Multi-omics analyzes revealed that NTs modulated glucose-transport and pentose phosphate pathways in High-PRS individuals, while enhancing immune regulation and reducing GDF15 and IL-1β levels in Low-PRS individuals. These findings suggest that genetic variation in urate metabolism determines whether NTs are preferentially utilized for redox and epigenetic maintenance or for immune and inflammatory regulation, supporting a precision-nutrition model for delaying biological aging.