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

Background and AimsObesity 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. MethodsIn 2,222 NHANES (1999 - 2002) adults aged [≥]50 years, 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. ResultsWWI and CI outperformed other indices. Highest quartiles raised all-cause mortality by 91% (HR 1.91, 95% CI 1.36-2.68) and 56% (HR 1.56, 95% CI 1.17-2.08), 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. ConclusionsNovel 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. Structured Graphical Abstract Key QuestionDoes the type of obesity and historical weight fluctuations in middle-aged and elderly populations influence the acceleration of epigenetic aging and the associated risk of mortality? Additionally, could epigenetic aging acceleration serve as a potential mechanism linking obesity and weight changes to mortality? Key FindingIn middle-aged and older adults, WWI and CI, unaffected by the obesity paradox, exhibit superior predictive power for all-cause and cause-specific mortality compared to traditional obesity metrics, with EAA serving as the key mechanistic link. Furthermore, weight stability or mild weight gain sustained over 10 years or more substantially mitigates diverse mortality risks in this population by attenuating EAA progression. Take Home MessageThis study underscores the need to move beyond traditional obesity metrics such as BMI and body weight by incorporating newer indices like WWI and CI, which more accurately capture fat distribution and visceral adiposity. This integrated approach improves the identification of high-risk populations and helps reduce obesity-related mortality. Furthermore, it calls for a shift in weight management goals among older adults--from weight loss to weight stability--supporting the development of age-specific clinical guidelines. Importantly, given that EAA is a key mediator in the obesity-mortality relationship, slowing its progression may disrupt pathways leading to death, establishing EAA as a measurable biomarker and a potential target for interventions aimed at extending longevity in middle-aged and older adults. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=132 SRC="FIGDIR/small/25339825v1_ufig1.gif" ALT="Figure 1"> View larger version (72K): org.highwire.dtl.DTLVardef@15eb5aorg.highwire.dtl.DTLVardef@10e92feorg.highwire.dtl.DTLVardef@1d48209org.highwire.dtl.DTLVardef@a548e4_HPS_FORMAT_FIGEXP M_FIG Graphic Abstract C_FIG