Epigenetic age acceleration mediates the association between pro-inflammatory and pro-oxidant diets and the progression and mortality of cardiovascular-kidney-metabolic syndrome.

backgroundThe cardiovascular-kidney-metabolic (CKM) syndrome is a major public health challenge driven by intertwined cardiometabolic and renal dysfunction. Diet-related inflammation and oxidative stress may accelerate biological aging, as reflected by DNA methylation age acceleration, thereby contributing to CKM progression and mortality. However, these pathways have not been comprehensively examined.

methodsWe analysed data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002, including non-pregnant adults aged ≥ 20 years with complete dietary, epigenetic, and cardiometabolic data. Dietary inflammatory potential and antioxidant capacity were assessed using the Dietary Inflammatory Index (DII) and Dietary Oxidative Balance Score (DOBS), derived from 24-hour dietary recall data. DNA methylation age acceleration (DNAmAA) was quantified using multiple established epigenetic clocks. Cardiovascular-kidney-metabolic (CKM) syndrome was defined and staged according to contemporary criteria. Associations of dietary indices with DNAmAA, CKM stages, and all-cause and cause-specific mortality were examined using weighted regression and Cox proportional hazards models. Mediation analyses were performed to evaluate the role of DNAmAA in linking dietary patterns with CKM progression and mortality. All analyses accounted for the complex NHANES survey design and relevant confounders.

resultsParticipants with higher dietary inflammatory potential (higher DII) and lower antioxidant capacity (lower DOBS) exhibited less favourable sociodemographic and cardiometabolic profiles and more advanced CKM stages at baseline. Higher DII was consistently associated with accelerated epigenetic aging across multiple DNAmAA measures, whereas higher DOBS showed protective associations. Pro-inflammatory and pro-oxidative dietary patterns were associated with increased odds of advanced CKM stages and higher risks of all-cause and cardiovascular mortality, while anti-inflammatory and antioxidant dietary patterns were associated with lower risks. Mediation analyses demonstrated that GrimAge acceleration and DunedinPoAm partially mediated the associations of dietary indices with CKM progression and mortality, supporting a role for biological aging in linking diet-related inflammation and oxidative stress to adverse CKM outcomes.

conclusionsDietary inflammatory and oxidative potential is associated with epigenetic aging, CKM progression, and mortality, partly mediated by GrimAge and DunedinPoAm. Improving dietary quality may represent a modifiable strategy to reduce CKM burden.