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

Jun 9, 2026Aging cell

Genetic Risk for Urate Changes How Added Nucleotides May Affect Aging in Older Adults

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

A significant interaction between urate polygenic risk score and nucleotide supplementation was found for changes in DNA methylation age and leukocyte telomere length.

Nucleotide supplementation reduced DNA methylation age in individuals with a high urate polygenic risk score.
In participants with a low urate polygenic risk score, nucleotide supplementation preserved leukocyte telomere length.
Genetic variability in urate metabolism may influence the body's response to nucleotide supplementation.
Nucleotides appear to modulate glucose transport and specific metabolic pathways in high-risk individuals.
In low-risk individuals, nucleotide supplementation may enhance immune regulation and lower levels of certain inflammatory markers.

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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.