Leukocyte telomere length and epigenetic-based mortality risk score: associations with all-cause mortality among older adults

Telomere length (TL) has been established as a biomarker of aging and aging-related health outcomes, but showed only a weak or inconsistent association with all-cause mortality in previous epidemiological studies. Recently, an epigenetic ‘mortality risk score’ (MS) based on whole blood DNA methylation at 10 mortality-related CpG sites has been demonstrated to be strongly related to all-cause mortality at the population level. This study aimed to address the association between TL and this MS, and to assess and compare their associations with all-cause mortality. The MS was derived from the DNA methylation profiles measured by Illumina Human Methylation450K Beadchip and TL was measured by quantitative PCR at baseline among 1517 participants aged 50–75 of the German ESTHER cohort study. In cross-sectional bi- and multivariable analyses, the MS was strongly associated and showed monotonic dose-response relationships with TL (<i>p</i>-values &lt;0.05). However, only the MS but not TL was associated with all-cause mortality during a median follow-up of 12.5 years. After controlling for potential covariates and TL, hazard ratios (95% CI) for all-cause mortality for low, moderate and high levels of the MS defined by 1, 2–5 and &gt;5 CpG sites with aberrant methylation were 2.24 (1.13–4.41), 3.31 (1.76–6.22) and 6.33 (3.22–12.41) compared to a MS of 0, respectively. Our investigation shows that the epigenetic-based MS is strongly associated with TL, a broadly accepted aging biomarker, and at the same time shows much stronger associations with all-cause mortality than the latter.端粒长度（Telomere length, TL）已被确立为衰老及衰老相关健康结局的生物标志物，但既往流行病学研究显示其与全因死亡率仅存在微弱或不一致的关联。近期，一项基于10个死亡相关CpG位点的全血DNA甲基化构建的表观遗传死亡风险评分（Epigenetic Mortality Risk Score, MS）被证实与人群水平的全因死亡率密切相关。本研究旨在探讨TL与该MS之间的关联，并评估和比较二者与全因死亡率的关联强度。研究对象为德国ESTHER队列研究中1517名年龄50~75岁的基线参与者，其MS由伊卢米纳人类甲基化450K芯片（Illumina Human Methylation450K Beadchip）检测的DNA甲基化谱推导而来，TL则通过定量PCR（quantitative PCR）进行基线测量。横断面双变量及多变量分析显示，MS与TL呈强相关且存在单调剂量反应关系（p值<0.05）。然而，在中位随访12.5年期间，仅MS与全因死亡率相关，而TL并未显示出此类关联。在控制潜在混杂因素及TL后，以甲基化异常的CpG位点数量为0的MS组为参照，由甲基化异常CpG位点1个、2~5个及>5个定义的低、中、高水平MS组的全因死亡率风险比（95%置信区间）分别为2.24（1.13~4.41）、3.31（1.76~6.22）及6.33（3.22~12.41）。本研究表明，基于表观遗传构建的MS与公认的衰老生物标志物TL密切相关，且其与全因死亡率的关联强度远高于TL。