Associations of weight change and different obesity indices with all-cause and cause-specific mortality: the mediating role of epigenetic aging

Abstract

Abstract Background and Aims Obesity shortens life expectancy, yet its prognostic value in older adults remains unclear due to the obesity paradox and limitations of body mass index (BMI) in capturing visceral fat. We compared eight obesity indices and lifelong weight changes for mortality prediction and tested whether epigenetic age acceleration (EAA) mediates these associations in a US cohort. Methods In 2,222 NHANES (1999 to 2002) adults aged 50 years or order, we calculated BMI, waist circumference, waist to height ratio, weight adjusted waist index (WWI), body roundness index, relative fat mass, conicity index (CI), and 10 year/long term weight change. EAA was derived from five clocks (Horvath, Hannum, PhenoAge, GrimAge, GrimAge2). Cox regression, restricted cubic splines, and bootstrap mediation assessed hazard ratios (HRs), dose response curves, and indirect effects. Results WWI and CI outperformed other indices. Highest quartiles raised all cause mortality by 91% (HR 1.91, 95% CI 1.36 to 2.68) and 56% (HR 1.56, 95% CI 1.17 to 2.08), respectively. Each SD increase in WWI/CI was associated with higher GrimAge and GrimAge2 acceleration. Conversely, 10 year and long term weight gain reduced mortality risk. Additionally, EAA was lowest with stable or mildly increased weight. Mediation analysis confirmed that EAA significantly mediates the association of both WWI/CI with mortality risk, as well as the protective effect of weight stability. Conclusions Novel obesity indices (WWI, CI) are superior mortality predictors in older adults. Epigenetic ageing partly explains both the hazard of central adiposity and the survival benefit of weight homeostasis, supporting age-stratified obesity metrics and weight-stability targets. Keywords: Obesity, Biological aging, Epigenetic age, Apigenetic age acceleration, Death