Hyperuricemia, characterized by abnormally high levels of serum uric acid (SUA), is a prevalent chronic metabolic disorder primarily resulting from dysregulated purine metabolism. While it is classically recognized as the primary cause of gout, emerging evidence suggests it plays a broader role in the pathogenesis of various age-related diseases, including cardiovascular disease and metabolic syndrome. However, the precise biological mechanisms linking hyperuricemia to these conditions, particularly its relationship with the fundamental process of biological aging, remain poorly understood and are subjects of ongoing debate.The primary aim of this study is to investigate the correlation between serum uric acid levels and biological aging using robust biomarkers. Specifically, this research seeks to determine whether elevated SUA is associated with Epigenetic Age Acceleration (EAA), which is defined as the discrepancy between an individual's biological age (as measured by DNA methylation patterns) and their chronological age. By utilizing data from the National Health and Nutrition Examination Survey (NHANES), this study aims to provide new epidemiological evidence on whether hyperuricemia acts as a potential risk factor for premature biological aging.

This study employed a cross-sectional design utilizing data from the NHANES cycles conducted between 1999 and 2002. The initial dataset contained records for 21,004 participants; however, strict inclusion criteria were applied to ensure data validity. The final analytical cohort consisted of 1,835 participants who had both epigenetic age estimates derived from DNA methylation data and available serum uric acid (SUA) measurements.To assess biological aging, the study utilized multiple established epigenetic clocks, including HorvathAge, HannumAge, PhenoAge, LinAge, SkinBloodAge, ZhangAge, VidalBraloAge, and WeidnerAge. The primary outcome measures were the Epigenetic Age Acceleration (EAA) residuals calculated from these clocks.Statistical analysis was performed using multivariable linear regression models to evaluate the association between continuous SUA levels and each EAA measure. These models were rigorously adjusted for a comprehensive set of potential confounders, including sociodemographic factors (e.g., age, sex, race), lifestyle variables (e.g., smoking, alcohol consumption), and relevant laboratory covariates to isolate the specific effect of uric acid.Furthermore, Restricted Cubic Spline (RCS) analysis was conducted. This method allowed the researchers to determine whether the association between SUA and EAA was linear or followed a more complex, non-linear pattern, providing deeper insight into how rising uric acid levels impact the aging trajectory.

A total of 1,835 participants were included, with a mean age of 65.8 years. After full adjustment for sociodemographic, lifestyle, and laboratory covariates, each 1 mg/dL increase in SUA was significantly associated with greater EAA across 7 epigenetic clocks: HorvathAge (β = 0.76, 95% CI: 0.48 to 1.04), HannumAge (β = 0.71, 95% CI: 0.41 to 1.00), PhenoAge (β = 0.87, 95% CI: 0.54 to 1.19), LinAge (β = 0.84, 95% CI: 0.47 to 1.20), SkinBloodAge (β = 0.57, 95% CI: 0.28 to 0.86), ZhangAge (β = 0.24, 95% CI: 0.13 to 0.36), and VidalBraloAge (β = 0.34, 95% CI: 0.13 to 0.54), all P < 0.001.WeidnerAge was not significantly associated with SUA (β = 0.10, 95% CI: −0.23 to 0.42, P = 0.560). RCS analyses demonstrated predominantly linear associations between SUA and most EAA measures, suggesting that epigenetic age acceleration increases linearly with rising uric acid levels.

This study provides compelling evidence that elevated serum uric acid levels are independently correlated with epigenetic age acceleration. These findings suggest that hyperuricemia may be a significant contributing factor to premature biological aging. This offers a plausible biological explanation for the well-documented clinical association between high uric acid levels and a spectrum of age-related morbidities, such as cardiovascular disease and metabolic syndrome.  This study provides new epidemiological evidence for delaying biological aging by controlling serum uric acid levels.