Abstract 4368296: Epigenetic Age Acceleration Mediates the Link Between Dietary Inflammatory Index, Oxidative Balance Score, and Mortality in U.S. Adults with Cardiovascular-Kidney-Metabolic Syndrome

Background: The interplay between dietary patterns, epigenetic aging, and cardiovascular-kidney-metabolic (CKM) syndrome remains poorly understood. This study investigated the associations of the Dietary Inflammatory Index (DII) and Dietary Oxidative Balance Score (DOBS) with CKM stages, epigenetic age acceleration (DNAmAA), and mortality, as well as the mediating role of DNAmAA in these relationships. Methods: Data from the National Health and Nutrition Examination Survey (NHANES) 1999–2002 were analyzed, including 2,109 non-pregnant adults aged ≥20 years. DII and DOBS were derived from 24-hour dietary recalls. CKM stages (0–4) were defined based on metabolic disorders, chronic kidney disease, and cardiovascular disease. DNAmAA was calculated using multiple epigenetic clocks. Multivariable-adjusted regression models assessed associations, and mediation analysis evaluated the role of DNAmAA in mortality outcomes. Results: Higher DII (pro-inflammatory diet) was significantly associated with advanced CKM stages (OR for Tertile 3 vs. Tertile 1: 1.97, 95% CI: 1.38–2.80, P=0.001) and accelerated GrimAge (OR: 3.63, 95% CI: 2.32–5.70, P<0.001) and DunedinPoAm (OR: 1.19, 95% CI: 1.08–1.28, P<0.001). Conversely, higher DOBS (antioxidant-rich diet) correlated with lower CKM risk (OR for Tertile 3: 0.62, 95% CI: 0.44–0.89, P=0.017) and slower epigenetic aging. Anti-inflammatory/antioxidant diets showed the strongest protective effects. Mediation analysis revealed that GrimAge2Mort and DunedinPoAm significantly mediated the associations of DII (proportion mediated: 23.2% and 10.7%, respectively, P<0.001) and DOBS (16.3% and 7.5%, P<0.001) with all-cause mortality, with similar trends for cardiovascular death. Conclusions: Pro-inflammatory diets are linked to worse CKM outcomes and accelerated epigenetic aging, while antioxidant-rich diets exhibit protective effects. Epigenetic aging, particularly GrimAge and DunedinPoAm, partially mediates the diet-mortality relationship. These findings highlight the potential of dietary interventions to mitigate CKM progression and reduce mortality risk through epigenetic mechanisms.