Exploring the mediating role of TyG-related indicators in the relationship between biological aging and late-stage cardiovascular-kidney-metabolic in middle-aged and older adults

BACKGROUND: Cardiovascular-Kidney-Metabolic (CKM) syndrome poses a growing challenge in aging adults, yet its connection to biological agingremains unclear. The triglyceride-glucose (TyG) index, a reliable marker of insulin resistance, may represent a plausible common pathway linking these seemingly distinct conditions. METHODS: This cross-sectional study analyzed data from 3,710 U.S. adults aged ≥45 years from the NHANES (1999-2018). Biological aging was assessed using the Klemera-Doubal method and phenotypic age. Late-stage CKM was defined as stages 3-4, including stage 3 (end-stage renal disease or high 10-year cardiovascular disease risk) and stage 4 (established cardiovascular disease, e.g., coronary heart disease). We calculated three TyG-related indicators (TyG, TyG-BMI, and TyG-WHtR) and employed weighted multivariate regression to examine their cross-sectional associations with biological aging and late-stage CKM. Mediation analysis was used to quantify indirect effects in these relationships. RESULTS: The late-stage CKM group wascharacterized bya greater degree of accelerated biological aging (p < 0.001). In this cross-sectional sample, a one-year increase in KDM biological age wasassociated withan OR of 1.02 (95 % CI: 1.01-1.03) for late-stage CKM,reflecting a positive association. A 1-unit higher TyG value was similarlyassociated withan OR of 1.45 (95 % CI: 1.20-1.76). Theconcurrent associationsof biological aging and TyG with late-stage CKM were partly explained by mediation effects, strongest for TyG-WHtR. CONCLUSION: Biological aging is closely related to the risk of late-stage CKM, with TyG metrics playing a partial mediating role. The cross-sectional association identified in our study, while noteworthy, precludes causal inference and therefore warrants future research to explore if modulating biological aging holds clinical significance for CKM syndrome.