Biological aging mediates the associations of metabolic score for insulin resistance with all‐cause and cardiovascular disease mortality among US adults: A nationwide cohort study

Abstract Aim To investigate the associations of metabolic score for insulin resistance (METS‐IR) with all‐cause and cardiovascular disease (CVD)‐specific mortality and the potential mediating role of biological ageing. Methods A cohort of 19 204 participants from the National Health and Nutrition Examination Survey (NHANES) 1999–2018 was recruited for this study. Cox regression models, restricted cubic splines, and Kaplan–Meier survival curves were used to determine the relationships of METS‐IR with all‐cause and CVD‐specific mortality. Mediation analyses were performed to explore the possible intermediary role of biological ageing markers, including phenotypic age (PhenoAge) and biological age (BioAge). Results During a median follow‐up of 9.17 years, we observed 2818 deaths, of which 875 were CVD‐specific. Multivariable Cox regression showed that the highest METS‐IR level (Q4) was associated with increased all‐cause (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.14–1.67) and CVD mortality (HR 1.52, 95% CI 1.10–2.12) compared with the Q1 level. Restricted cubic splines showed a nonlinear relationship between METS‐IR and all‐cause mortality. Only METS‐IR above the threshold (41.02 μg/L) was positively correlated with all‐cause death. METS‐IR had a linear positive relationship with CVD mortality. In mediation analyses, we found that PhenoAge mediated 51.32% ( p < 0.001) and 41.77% ( p < 0.001) of the association between METS‐IR and all‐cause and CVD‐specific mortality, respectively. For BioAge, the mediating proportions of PhenoAge were 21.33% ( p < 0.001) and 15.88% ( p < 0.001), respectively. Conclusions This study highlights the detrimental effects of insulin resistance, as measured by METS‐IR, on all‐cause and CVD mortality. Moreover, it underscores the role of biological ageing in mediating these associations, emphasizing the need for interventions targeting both insulin resistance and ageing processes to mitigate mortality risks in metabolic disorders.