Sex-specific body fat distribution predicts cardiovascular ageing

Abstract Background and Aims Cardiovascular ageing is a progressive loss of physiological reserve, modified by environmental and genetic risk factors, that contributes to multi-morbidity due to accumulated damage across diverse cell types, tissues, and organs. Obesity is implicated in premature ageing, but the effect of body fat distribution in humans is unknown. This study determined the influence of sex-dependent fat phenotypes on human cardiovascular ageing. Methods Data from 21 241 participants in the UK Biobank were analysed. Machine learning was used to predict cardiovascular age from 126 image-derived traits of vascular function, cardiac motion, and myocardial fibrosis. An age-delta was calculated as the difference between predicted age and chronological age. The volume and distribution of body fat was assessed from whole-body imaging. The association between fat phenotypes and cardiovascular age-delta was assessed using multivariable linear regression with age and sex as co-covariates, reporting β coefficients with 95% confidence intervals (CI). Two-sample Mendelian randomization was used to assess causal associations. Results Visceral adipose tissue volume [β = 0.656, (95% CI, .537–.775), P < .0001], muscle adipose tissue infiltration [β = 0.183, (95% CI, .122–.244), P = .0003], and liver fat fraction [β = 1.066, (95% CI .835–1.298), P < .0001] were the strongest predictors of increased cardiovascular age-delta for both sexes. Abdominal subcutaneous adipose tissue volume [β = 0.432, (95% CI, .269–.596), P < .0001] and android fat mass [β = 0.983, (95% CI, .64–1.326), P < .0001] were each associated with increased age-delta only in males. Genetically predicted gynoid fat showed an association with decreased age-delta. Conclusions Shared and sex-specific patterns of body fat are associated with both protective and harmful changes in cardiovascular ageing, highlighting adipose tissue distribution and function as a key target for interventions to extend healthy lifespan.