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

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.