Abdominal adiposity and accelerated biological ageing in relation to general and cardiovascular ageing in Chinese...

Abdominal adiposity may contribute to both general and cardiovascular ageing, yet the extent to which accelerated biological age (BA) at distinct molecular levels mediates these effects has not been fully elucidated.

Three BA measures were constructed using metabolomics (MetaboAge, n=4391), clinical biomarkers (Klemera-Doubal method BA; KDM-BA, n=12 369) and DNA methylation (DNAm PhenoAge, n=980) within the prospective China Kadoorie Biobank and their predictive accuracy for all-cause mortality were evaluated. We explored the potential causal effects of abdominal adiposity, measured by waist-to-hip ratio (WHR) and WHR adjusted for body mass index (WHRadjBMI), on BA acceleration using observational study and Mendelian randomisation. We further investigated the extent to which BA accelerations mediated the effects of abdominal adiposity on cardiovascular ageing (assessed by atherosclerotic cardiovascular disease (ASCVD) incidence and mortality) and general ageing (assessed by all-cause mortality and frailty index).

Both MetaboAge and KDM-BA improved prediction for all-cause mortality beyond chronological age (area under the receiver operating characteristic curve (AUROC) difference: MetaboAge=0.040, KDM-BA=0.012, p<0.001). In observational analyses, abdominal adiposity was associated with accelerated ageing across all three BA clocks, with effect estimates ranging from 0.055 (95% CI 0.038 to 0.073) for the association between WHR and KDM-BA acceleration to 0.107 (0.044 to 0.170) for the association between WHRadjBMI and DNAm PhenoAge acceleration. These associations remained significant in Mendelian randomisation analyses. Mediation analyses revealed that acceleration of MetaboAge and KDM-BA partially explained the effects of abdominal adiposity on cardiovascular ageing (%mediated: 6.0%-25.3%), while all three BA clocks accelerations mediated associations with general ageing assessed by all-cause mortality (%mediated: 17.6%-60.6%), with MetaboAge contributing the largest proportion of mediation. Additionally, KDM-BA acceleration mediated the association between abdominal adiposity and frailty index.

Abdominal adiposity is associated with ageing acceleration across multiple biological domains, especially via metabolic alterations captured by MetaboAge. Our findings demonstrated that targeting abdominal adiposity-related metabolic dysfunction may mitigate age-related conditions.