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

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.

In 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.

WWI 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.

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. Structured Graphical Abstract Key Question Does 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 Finding In 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 Message This 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement The study was funded through grants from the Natural Science Foundation of Hunan Province (2023JJ40801), Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (ZLRK202309), and Beijing Hospitals Authority Ascent Plan (DFL20240401). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the National Center for Health Statistics gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Disclosures The authors report no financial relationships with commercial interests. Data Availability The data underlying this article are available in a public, open access repository. The NHANES data can be accessed at https://wwwn.cdc.gov/nchs/nhanes/.