Biological Aging Mediates the Associations Between Multiple Serum Micronutrients and All-Cause Mortality Among U.S. Adults.

Abstract

Background: Serum micronutrients are highly intercorrelated in general populations and may affect longevity via biological aging-related pathways. Nevertheless, it remains unclear whether biological aging mediates the associations of serum micronutrient mixtures with all-cause mortality.

Methods: This prospective cohort analysis included adults from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 and 2017-2018, with mortality follow-up until December 31, 2019. Six serum micronutrients were assessed: vitamin C, 25-hydroxyvitamin D (25(OH)D), α-tocopherol, β-carotene, lycopene, and folate. Biological aging was estimated based on nine clinical biomarkers: albumin, creatinine, glucose, C-reactive protein, lymphocyte percentage, mean cell volume, red cell distribution width, alkaline phosphatase, and white blood cell count. PhenoAgeAccel was defined as phenotypic age minus chronological age. Cox proportional hazards regression and restricted cubic splines (RCS) were applied to assess the associations of individual serum micronutrients with all-cause mortality. Quantile g-computation (QGC) and Bayesian kernel machine regression (BKMR) were used to explore the joint effects of micronutrient mixtures on mortality. Mediation analysis was further conducted to quantify the mediating role of PhenoAgeAccel.

Results: A total of 6,387 participants were included, with a median follow-up of 14.08 years and 932 all-cause deaths recorded. In fully adjusted Cox models, higher levels of β-carotene, lycopene, vitamin C, and 25(OH)D were significantly associated with reduced mortality risk. Compared with the lowest tertile (tertile 1), the HRs (95% CIs) for all-cause mortality were 0.80 (95% CI: 0.64-1.00, P = 0.048) for tertile 2 and 0.74 (95% CI: 0.60-0.90, P = 0.003) for tertile 3 of β-carotene. Both QGC and BKMR analyses revealed a protective joint effect of the micronutrients mixture on all-cause mortality (HR = 0.723, 95% CI: 0.646-0.809), with lycopene contributing the largest negative weight (0.455). PhenoAgeAccel significantly mediated the associations of β-carotene, lycopene, vitamin C, and 25(OH)D with all-cause mortality, with mediating proportions of 35.65%, 15.66%, 27.30%, and 6.87%, respectively.

Conclusion: Higher serum micronutrient concentrations were inversely associated with all-cause mortality, and these associations were partially mediated by decelerated biological aging. Within the micronutrient mixture, lycopene exhibited the greatest relative contribution to the overall protective effect.