Associations of Life’s Essential 8 With Mortality Among Individuals With Diabetes and/or Hypertension: Statistical Mediation by Inflammation and Biological Aging

BACKGROUND: Despite extensive evidence supporting the American Heart Association (AHA)'s life's essential 8 (LE8) framework for cardiovascular health (CVH) assessment, the underlying biological mechanisms linking LE8 to mortality outcomes in high-risk populations remain unexplored. This study aimed to investigate the association between LE8 scores and mortality risk among individuals with diabetes, hypertension, and their coexistence, and explored whether inflammation and biological aging statistically mediate these relationships. METHODS: We conducted a large-scale longitudinal analysis using National Health and Nutrition Examination Survey (NHANES) data (2005-2018), including 4939 individuals with diabetes, 13,298 with hypertension, and 3303 with both conditions. LE8 scores were calculated from eight CVH metrics, with mortality ascertained through the National Death Index (NDI). Mediation analyses examined the roles of inflammation markers (neutrophil-to-lymphocyte ratio [NLR] and pan-immune-inflammation value [PIV]) and phenotypic age acceleration (PhenoAgeAccel). RESULTS: Higher LE8 scores were significantly associated with reduced all-cause mortality and heart disease mortality across all groups (p < 0.001). Stratified analyses showed stronger associations among younger individuals (≤60 years) and those with higher socioeconomic status. In mediation analyses, inflammatory markers and PhenoAgeAccel statistically explained a meaningful proportion of the LE8-mortality associations, with different patterns across disease groups. For all-cause mortality, in diabetes, NLR and PIV accounted for larger proportions of the association (NLR: 31.6%; PIV: 26.9%), whereas in hypertension, PhenoAgeAccel accounted for a larger proportion (56.3%). Among individuals with both conditions, PhenoAgeAccel (26.1%) and NLR (5.3%) contributed to the association. Similar patterns were observed for heart disease mortality. CONCLUSION: Higher LE8 scores are associated with reduced mortality risk in individuals with diabetes and/or hypertension, with inflammation and biological aging statistically mediating these associations in an exploratory manner. These findings suggest potential statistical mediators that may inform future mechanistic research and therapeutic targets, but causal interpretation requires further longitudinal studies.