Association between genome-wide DNA methylation and all-cause mortality in nonagenarians

Changes in the DNA methylation (DNAm) landscape have been implicated in aging and cellular senescence. To unravel the role of specific DNAm patterns in late-life survival, we performed genome-wide methylation profiling in nonagenarians (n=111) and determined the performance of the methylomic predictors and conventional risk markers in a longitudinal setting. The survival model containing only the methylomic predictors was superior in terms of predictive accuracy compared with the models containing the conventional predictors body mass index and mini-mental state examination. At the 2.55-year follow-up, we identified 19 mortality-associated (false-discovery rate <0.5) CpG sites that mapped to genes functionally clustering around the nuclear factor kappa B (NF-κB) complex. Interestingly, none of the mortality-associated CpG sites overlapped with the established aging-associated DNAm sites. Our results are in line with previous findings on the role of NF-κB in controlling animal life spans and demonstrate the key role of this complex in human longevity. Bisulphite converted DNA from 122 samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip

DNA甲基化（DNA methylation, DNAm）图谱的改变已被证实与衰老及细胞衰老过程密切相关。为阐明特定DNAm模式在高龄生存中的作用，我们对111名九十岁及以上老年人（nonagenarians）开展了全基因组甲基化分析，并在纵向队列中评估了甲基组学预测因子与传统风险标志物的预测性能。仅包含甲基组学预测因子的生存模型，其预测准确性优于纳入了传统预测因子——体质量指数（body mass index, BMI）与简易精神状态检查（mini-mental state examination, MMSE）——的模型。在2.55年的随访周期内，我们共鉴定出19个与死亡率相关的CpG位点（错误发现率<0.5），这些位点所在的基因在功能上均聚集于核因子κB（nuclear factor kappa B, NF-κB）复合体周围。值得注意的是，所有与死亡率相关的CpG位点均未与已确立的衰老相关DNAm位点重合。本研究结果与此前关于NF-κB调控动物寿命的研究结论一致，并证实了该复合体在人类长寿过程中的关键作用。本研究将122份样本的亚硫酸氢盐转化DNA与Illumina Infinium 450k人类甲基化微珠芯片进行了杂交。