Phenotypic Age Mediates the Association Between Dietary Index for Gut Microbiota and Mortality: A Prospective Cohort Study Based on NHANES 1999–2018

Background: The gut microbiota influences metabolism, immunity, and aging, and diet shapes microbiota composition. The Dietary Index for Gut Microbiota (DI-GM) quantifies dietary quality favoring microbial diversity; however, its relationship with mortality remains unclear. Objective: We assessed associations of DI-GM with all-cause and cardiovascular disease (CVD) mortality, and evaluated phenotypic age as a potential mediator. Methods: We included 40,314 adults aged ≥20 years from the U.S. National Health and Nutrition Examination Survey (NHANES) cycles 1999–2018, with mortality follow-up through linkage to the National Death Index up to December 31, 2019. DI-GM scores were derived from dietary recalls, and phenotypic age was computed from blood biomarkers. Cox regression and mediation analyses were performed to assess associations and mediating effects.Results: Over a median follow-up of 115 months, 6,156 all-cause and 1,933 CVD deaths occurred. Compared to participants in the lowest quartile (Q1, scores 0–2), those in the highest quartile (Q4, scores ≥5) showed reduced risks of all-cause (HR: 0.84; 95% CI: 0.73–0.97) and CVD mortality (HR: 0.76; 95% CI: 0.57–1.02). Each 1-score increment was associated with lower all-cause (HR: 0.97; 95% CI: 0.94–0.99) and CVD mortality (HR: 0.94; 95% CI: 0.90–0.99). Phenotypic age mediated 31.9% and 13.4% of these associations, respectively. Conclusions: Greater adherence to a gut microbiota–supportive dietary pattern, as measured by the DI-GM, was associated with reduced risks of all-cause and CVD mortality. These associations were partially mediated by phenotypic age, suggesting that biological aging may be an important pathway linking diet to longevity and cardiovascular health. Our findings highlight the potential of microbiota-targeted dietary strategies for promoting healthy aging in the general population.