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<p>Associations of caffeine (the most routinely consumed bioactive compound worldwide) and caffeine metabolites (CAF/CAFMs) with cardiovascular-kidney-metabolic (CKM) syndrome (a newly-introduced high-burden clinical condition) and role of biological aging and underlying mechanisms are uncharted territories warranting pressing decryption. Among 3020 adults, 15 urinary CAF/CAFMs were determined to investigate their single-analyte (by weighted logistic regression) and mixture (by Bayesian kernel machine regression [BKMR] and weighted quantile sum [WQS]) relationships between advanced CKM syndrome. Role of emerging biological aging metric—Gompertz-Law-Based Biological Age Difference (GOLD BioAgeDiff)—was explored by mediation analysis. Underlying mechanisms were explored by network pharmacology. Specific CAF/CAFMs (1-methylxanthine, theophylline, paraxanthine, and theobromine) were negatively linked to advanced CKM syndrome (<i>P</i> and false discovery rate &lt; 0.05). WQS and BKMR uncovered negative CAF/CAFMs mixture-advanced CKM syndrome association (odds ratio = 0.782; 95% confidential interval: 0.670, 0.912). Exploratorily, GOLD BioAgeDiff mediated 13.85–20.06% of the CAF/CAFMs-advanced CKM syndrome associations. Metabolic, mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase-protein kinase B (PI3K-Akt), and apoptosis signaling pathways were exploratorily enriched in the CAF/CAFMs-CKM syndrome relationships. Overall, several CAF/CAFMs and, especially, their mixture showed protective associations with CKM syndrome, which was exploratorily mediated by delayed biological aging, while metabolic, MAPK, PI3K-Akt, and apoptosis signaling pathways might be involved in the underlying mechanisms.</p><p></p>

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Urinary caffeine and caffeine metabolites, biological aging, and cardiovascular-kidney-metabolic syndrome: deciphering association, mediation, and mechanism via epidemiology and bioinformatics

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月24日

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  • Jie Liu,
  • Wenshan Shi,
  • Shuhui Wan,
  • Da Shi,
  • Jiahao Song,
  • Le Hong,
  • Feifei Wang,
  • Yani Xiong,
  • Wendi Shi,
  • Qing Liu,
  • Zhiying Huo,
  • Jinqiang Li,
  • Pengfei Chen,
  • Yongfang Zhang,
  • Jiamin Xu,
  • Weihong Chen,
  • Bin Wang

摘要

Associations of caffeine (the most routinely consumed bioactive compound worldwide) and caffeine metabolites (CAF/CAFMs) with cardiovascular-kidney-metabolic (CKM) syndrome (a newly-introduced high-burden clinical condition) and role of biological aging and underlying mechanisms are uncharted territories warranting pressing decryption. Among 3020 adults, 15 urinary CAF/CAFMs were determined to investigate their single-analyte (by weighted logistic regression) and mixture (by Bayesian kernel machine regression [BKMR] and weighted quantile sum [WQS]) relationships between advanced CKM syndrome. Role of emerging biological aging metric—Gompertz-Law-Based Biological Age Difference (GOLD BioAgeDiff)—was explored by mediation analysis. Underlying mechanisms were explored by network pharmacology. Specific CAF/CAFMs (1-methylxanthine, theophylline, paraxanthine, and theobromine) were negatively linked to advanced CKM syndrome (P and false discovery rate < 0.05). WQS and BKMR uncovered negative CAF/CAFMs mixture-advanced CKM syndrome association (odds ratio = 0.782; 95% confidential interval: 0.670, 0.912). Exploratorily, GOLD BioAgeDiff mediated 13.85–20.06% of the CAF/CAFMs-advanced CKM syndrome associations. Metabolic, mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase-protein kinase B (PI3K-Akt), and apoptosis signaling pathways were exploratorily enriched in the CAF/CAFMs-CKM syndrome relationships. Overall, several CAF/CAFMs and, especially, their mixture showed protective associations with CKM syndrome, which was exploratorily mediated by delayed biological aging, while metabolic, MAPK, PI3K-Akt, and apoptosis signaling pathways might be involved in the underlying mechanisms.