The mediating role of epigenetic ageing in the nonlinear association between body mass index and survival: a prospective cohort analysis of the US Health and Retirement Study.

IF 10.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-09-01 Epub Date: 2025-08-16 DOI:10.1016/j.ebiom.2025.105883

Peggy Ler, Juulia Jylhävä, Sara Hägg, Deborah Finkel, Anna K Dahl Aslan, Alexander Ploner, Ida K Karlsson

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Abstract

Background: The role of biological ageing in the association between body mass index (BMI) and survival remains unclear. We examined whether epigenetic age acceleration (EAA), a biomarker of biological ageing, mediates the BMI-survival association.

Methods: We analysed data from 3840 participants (aged 51-100) in the 2016 US Health and Retirement Study, with survival information through 2020. Mediation analyses were performed using linear regression and Gompertz proportional hazards models with restricted cubic splines, adjusting for age, sex, ethnicity/race, smoking, education, and metabolic health. Average direct effects (ADE) of BMI and average causal mediation effects of EAA (HannumAgeAcc, PhenoAgeAcc, GrimAgeAcc, and DunedinPace) on survival time were estimated with 95% confidence intervals (CI).

Findings: Associations between BMI, EAA, and survival were nonlinear: high and low BMIs were associated with higher EAA and reduced survival time. ADEs of high BMI (35 kg/m² versus 27 kg/m²) were not statistically significant (reduced survival time: 1.21-1.58 years) but significant for low BMI (19 kg/m² versus 27 kg/m², reduced survival time: 5.60-6.38 years). For high BMI, mediation was significant through all EAAs, with reduced survival time ranging from 0.28 to 0.71 years, accounting for 15-37% of total effects. For low BMI, mediation was statistically significant through HannumAgeAcc (reduced survival time: 0.44, CI: 0.08-0.86) and GrimAgeAcc (reduced survival time: 0.73, CI: 0.15-1.38), accounting for 7-11% of total effects.

Interpretation: EAA partially mediated the high BMI-survival association, supporting the mediating role of accelerated ageing in the obesity-survival relationship. Mediation through EAA in the low BMI-survival association was weaker, indicating that alternative mechanisms, other than accelerated ageing, may dominate.

Funding: Forte, Vetenskaprådet, SFOepi, Karolinska Institutet's Research Foundation, Loo and Hans Osterman Foundation, the Foundation for Geriatric Diseases at Karolinska Institutet.

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表观遗传衰老在体重指数与生存之间非线性关联中的中介作用：美国健康与退休研究的前瞻性队列分析。

背景：生物老化在体重指数（BMI）和生存率之间的关系中所起的作用尚不清楚。我们研究了表观遗传年龄加速（EAA），一种生物衰老的生物标志物，是否介导bmi与生存的关联。方法：我们分析了2016年美国健康与退休研究中3840名参与者（51-100岁）的数据，包括到2020年的生存信息。采用线性回归和限制三次样条Gompertz比例风险模型进行中介分析，调整了年龄、性别、种族/种族、吸烟、教育和代谢健康等因素。BMI的平均直接效应（ADE）和EAA （HannumAgeAcc、PhenoAgeAcc、GrimAgeAcc和DunedinPace）对生存时间的平均因果中介效应以95%置信区间（CI）估计。研究结果：BMI、EAA和生存之间的关系是非线性的：高BMI和低BMI与较高的EAA和较短的生存时间相关。高BMI组的不良反应（35 kg/m2 vs 27 kg/m2）无统计学意义（减少生存时间：1.21-1.58年），但低BMI组的不良反应显著（19 kg/m2 vs 27 kg/m2，减少生存时间：5.60-6.38年）。对于高BMI，所有eaa均有显著的中介作用，减少生存时间从0.28年到0.71年不等，占总效应的15-37%。对于低BMI，通过HannumAgeAcc（减少生存时间：0.44,CI: 0.08-0.86）和GrimAgeAcc（减少生存时间：0.73,CI: 0.15-1.38）的中介作用具有统计学意义，占总效应的7-11%。解释：EAA部分介导了高bmi与生存的关联，支持加速衰老在肥胖与生存关系中的中介作用。通过EAA介导的低bmi与生存之间的关联较弱，表明除加速衰老之外的其他机制可能起主导作用。资助：Forte， vetenskapramatdet, SFOepi，卡罗林斯卡研究所研究基金会，Loo和Hans Osterman基金会，卡罗林斯卡研究所老年疾病基金会。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.