GrimAge and GrimAge2 Age Acceleration effectively predict mortality risk: a retrospective cohort study

Epigenetic clocks have been widely applied to assess biological ageing, with Age Acceleration (AA) serving as a key metric linked to adverse health outcomes, including mortality. However, the comparative predictive value of AAs derived from different epigenetic clocks for mortality risk has not been systematically evaluated. In this retrospective cohort study based on 1,942 NHANES participants (median age 65 years; 944 women), we examined the associations between AAs from multiple epigenetic clocks and the risks of all-cause, cancer-specific, and cardiac mortality. Restricted cubic spline models were used to assess the shape of these associations, and Cox proportional hazards regression was employed to quantify risk estimates. Model performance was compared using the Akaike Information Criterion (AIC) and concordance index (C-index). Our findings revealed that only GrimAge AA and GrimAge2 AA demonstrated approximately linear and positive associations with all three mortality outcomes. Both were significantly associated with increased risks of death, and these associations were consistent across most subgroups. GrimAge and GrimAge2 AAs showed very similar performance in predicting all-cause, cancer and cardiac mortality, with only small differences in AIC values and C-index scores. These findings suggest that both GrimAge and GrimAge2 are effective epigenetic biomarkers for mortality risk prediction and may be valuable tools in future ageing-related research.

表观遗传时钟（Epigenetic clocks）已被广泛应用于生物学衰老的评估，其中年龄加速度（Age Acceleration，AA）作为核心指标，与包括死亡在内的多种不良健康结局密切相关。然而，不同表观遗传时钟所衍生的AA对死亡风险的比较预测价值，尚未得到系统性评估。本研究基于1942名美国国家健康与营养调查（NHANES）参与者（中位年龄65岁；女性944名）开展回顾性队列研究，考察了多种表观遗传时钟计算得到的AA与全因死亡、癌症特异性死亡及心脏性死亡风险之间的关联。研究采用限制性立方样条模型评估上述关联的形态，并借助Cox比例风险回归量化风险估计值。通过赤池信息准则（Akaike Information Criterion，AIC）与一致性指数（C-index）对模型性能进行比较。研究结果显示，仅GrimAge AA与GrimAge2 AA与三种死亡结局均呈现近似线性的正向关联。二者均与死亡风险升高存在显著相关性，且该关联在绝大多数亚组中保持稳定。GrimAge与GrimAge2 AA在预测全因死亡、癌症死亡及心脏性死亡方面表现极为相似，仅在AIC值与C-index得分上存在微小差异。本研究结果表明，GrimAge与GrimAge2均为可有效预测死亡风险的表观遗传生物标志物，有望成为未来衰老相关研究中的重要工具。