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Background <p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to metabolic dysfunction. Lactate and the glucose-lactate index may reflect systemic glucose-lactate metabolic dysregulation, but their associations with MASLD and the potential mediating role of accelerated biological aging remain unclear.</p> Methods <p>This cohort study included 175,612 UK Biobank participants. Plasma metabolites were quantified by nuclear magnetic resonance spectroscopy. Cox models assessed associations with incident MASLD, and mediation analyses evaluated PhenoAge acceleration (PhenoAge Accel), KDM-BA acceleration (KDM-BA Accel), and relative leukocyte telomere length (rLTL). Complementary transcriptomic analyses were conducted using GSE126848, and the co-expression of selected gene pairs was further assessed using the ChIPBase v3.0 Co-Expression tool.</p> Results <p>Higher lactate and the glucose-lactate index were associated with increased MASLD risk (tertile 3 vs. 1 hazard ratios: 1.19 [95% CI, 1.07–1.32; <i>P</i> = 0.001] and 1.29 [95% CI, 1.16–1.43; <i>P</i> &lt; 0.001], respectively). Both biomarkers were associated with higher PhenoAge Accel and KDM-BA Accel and lower rLTL. PhenoAge Accel mediated 32.3% and 20.8% of the respective associations, whereas KDM-BA Accel mediated 8.2% and 11.8%; rLTL mediation was not significant. Seven lactate metabolism-related genes and 20 representative aging-related genes were differentially expressed between healthy and MASLD liver tissues, and the corresponding transcriptional scores were positively correlated. Selected gene pairs also showed significant co-expression in the ChIPBase v3.0 Co-Expression analysis.</p> Conclusion <p>Elevated lactate and the glucose-lactate index were associated with higher MASLD risk, with these associations partly mediated by accelerated biological aging. These findings provide prospective population-based and tissue-level evidence suggesting potential interrelationships among metabolic dysregulation, accelerated aging, and MASLD risk.</p>

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Accelerated biological aging mediates the associations of plasma lactate and the glucose-lactate index with MASLD: a prospective cohort study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Xuejiao Pu,
  • Binyu Bai,
  • Jing Yu,
  • Kai Zhang,
  • Ting Zhou,
  • Biao Xie,
  • Peng Wang,
  • Dan Shi

摘要

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to metabolic dysfunction. Lactate and the glucose-lactate index may reflect systemic glucose-lactate metabolic dysregulation, but their associations with MASLD and the potential mediating role of accelerated biological aging remain unclear.

Methods

This cohort study included 175,612 UK Biobank participants. Plasma metabolites were quantified by nuclear magnetic resonance spectroscopy. Cox models assessed associations with incident MASLD, and mediation analyses evaluated PhenoAge acceleration (PhenoAge Accel), KDM-BA acceleration (KDM-BA Accel), and relative leukocyte telomere length (rLTL). Complementary transcriptomic analyses were conducted using GSE126848, and the co-expression of selected gene pairs was further assessed using the ChIPBase v3.0 Co-Expression tool.

Results

Higher lactate and the glucose-lactate index were associated with increased MASLD risk (tertile 3 vs. 1 hazard ratios: 1.19 [95% CI, 1.07–1.32; P = 0.001] and 1.29 [95% CI, 1.16–1.43; P < 0.001], respectively). Both biomarkers were associated with higher PhenoAge Accel and KDM-BA Accel and lower rLTL. PhenoAge Accel mediated 32.3% and 20.8% of the respective associations, whereas KDM-BA Accel mediated 8.2% and 11.8%; rLTL mediation was not significant. Seven lactate metabolism-related genes and 20 representative aging-related genes were differentially expressed between healthy and MASLD liver tissues, and the corresponding transcriptional scores were positively correlated. Selected gene pairs also showed significant co-expression in the ChIPBase v3.0 Co-Expression analysis.

Conclusion

Elevated lactate and the glucose-lactate index were associated with higher MASLD risk, with these associations partly mediated by accelerated biological aging. These findings provide prospective population-based and tissue-level evidence suggesting potential interrelationships among metabolic dysregulation, accelerated aging, and MASLD risk.