Work

The caffeine spectrum: associations of intake, metabolites, and metabolite ratios with biological aging acceleration, frailty and mortality

Year: 2026

Type: article

Abstract: While caffeine consumption is linked to numerous health outcomes, its role in the aging process remains unclear. We aimed to investigate the cross-sectional associations of caffeine exposures (intake, metabolites, metabolite ratios) with biological age acceleration (BAA) and frailty, as well as their prospective associations with all-cause mortality, while assessing BAA’s mediating role. This study included 6,150 representative U.S. adults (median age: 46.00 years, 49.5% male). Dietary caffeine intake and 14 caffeine metabolites were assessed. BAA was derived from both clinical ( N = 5,890 for KDMAgeAccel and N = 3,229 for PhenoAgeAccel) and epigenetic biomarkers ( N = 619), and frailty was quantified using a 36-item modified Frailty Index (FI). Associations between caffeine-related exposures and aging outcomes (FI and mortality) were evaluated using survey-weighted regression models, and mediation analysis was employed to test the mediating role of BAA. Benjamini-Hochberg false-discovery-rate (FDR) correction was applied to account for multiple testing. Higher dietary caffeine intake, selected caffeine metabolites (mainly xanthines), and higher spot-urine metabolite ratios were significantly and inversely associated with BAA, FI, and all-cause mortality, with the association for the paraxanthine-to-caffeine ratio remaining robustly significant after FDR correction. Significant interactions between dietary caffeine intake and caffeine-related indicators were observed. Exploratory mediation analyses suggested that physiology-based BAA metrics (KDMAgeAccel and PhenoAgeAccel) represent a potential mediation pathway in the associations of selected caffeine-related indicators with both FI and mortality. The spot-urine caffeine metabolite ratios, particularly the paraxanthine-to-caffeine ratio, showed the strongest inverse associations with various aging-related outcomes in both the primary analyses and rigorous sensitivity analyses, and contributed to the most significant mediation pathways. Our findings provide epidemiological evidence that the spot-urine paraxanthine-to-caffeine ratio correlates with healthier aging-related phenotypes cross-sectionally and reduced mortality prospectively. Rather than a validated biological marker, this ratio represents an exploratory association signal requiring future prospective and mechanistic validation.

Source: Nutrition & Metabolism

DOI: 10.1186/s12986-026-01192-3

Authors: Xiaoying Huang, Jieli Lan, Yifei Liu, Jiequn Zhang, Weitao Su

Institutions: Fujian Medical University, First Affiliated Hospital of Fujian Medical University, Second Affiliated Hospital of Fujian Medical University

Language: English

Topic: Coffee research and impacts

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,590