Jiahui Si, Yu Ma, Canqing Yu, Dianjianyi Sun, Yuanjie Pang, Pei Pei, Ling Yang, Iona Y Millwood, Robin G Walters, Yiping Chen, Huaidong Du, Xiaoyan Zheng, Daniel Avery, Junshi Chen, Zhengming Chen, Liming Liang, Liming Li, Jun Lv
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引用次数: 0
Abstract
Background: Alterations in lipid metabolism and DNA methylation are 2 hallmarks of aging. Connecting metabolomic, epigenomic, and aging outcomes help unravel the complex mechanisms underlying aging. We aimed to assess whether DNA methylation clocks mediate the association of circulating metabolites with incident atherosclerotic cardiovascular disease (ASCVD) and frailty.
Methods: The China Kadoorie Biobank is a prospective cohort study with a baseline survey from 2004 to 2008 and a follow-up period until December 31, 2018. We used the Infinium Methylation EPIC BeadChip to measure the methylation levels of 988 participants' baseline blood leukocyte DNA. Metabolite profiles, including lipoprotein particles, lipid constituents, and various circulating metabolites, were measured using quantitative nuclear magnetic resonance. The pace of DNA methylation age acceleration (AA) was calculated using 5 widely used epigenetic clocks (the first generation: Horvath, Hannum, and Li; the second generation: Grim and Pheno). Incident ASCVD was ascertained through linkage with local death and disease registries and national health insurance databases, supplemented by active follow-up. The frailty index was constructed using medical conditions, symptoms, signs, and physical measurements collected at baseline.
Results: A total of 508 incident cases of ASCVD were documented during a median follow-up of 9.5 years. The first generation of epigenetic clocks was associated with the risk of ASCVD (P<0.05). For each SD increment in LiAA, HorvathAA, and HannumAA, the corresponding hazard ratios for ASCVD risk were 1.16 (1.05-1.28), 1.10 (1.00-1.22), and 1.17 (1.04-1.31), respectively. Only LiAA mediated the association of various metabolites (lipids, fatty acids, histidine, and inflammatory biomarkers) with ASCVD, with the mediating proportion reaching up to 15% for the diameter of low-density lipoprotein (P=1.2×10-2). Regarding general aging, a 1-SD increase in GrimAA was associated with an average increase of 0.10 in the frailty index (P=2.0×10-3), and a 33% and 63% increased risk of prefrailty and frailty at baseline (P=1.5×10-2 and 5.8×10-2), respectively; this association was not observed with other clocks. GrimAA mediated the effect of various lipids, fatty acids, glucose, lactate, and inflammatory biomarkers on the frailty index, with the mediating proportion reaching up to 22% for triglycerides in very small-sized very low-density lipoprotein (P=6.0×10-3).
Conclusions: These findings suggest that epigenomic mechanisms may play a role in the associations between circulating metabolites and the aging process. Different mechanisms underlie the first and second generations of DNA methylation age in cardiovascular and general aging.
背景：脂质代谢和 DNA 甲基化的改变是衰老的两大标志。将代谢组学、表观基因组学和衰老结果联系起来有助于揭示衰老的复杂机制。我们旨在评估DNA甲基化钟是否介导循环代谢物与动脉粥样硬化性心血管疾病（ASCVD）和虚弱的关联：中国嘉道理生物库是一项前瞻性队列研究，基线调查时间为2004年至2008年，随访期至2018年12月31日。我们使用 Infinium Methylation EPIC BeadChip 芯片测量了 988 名参与者基线血液白细胞 DNA 的甲基化水平。使用定量核磁共振测量了代谢物谱，包括脂蛋白颗粒、脂质成分和各种循环代谢物。DNA 甲基化年龄加速度（AA）是通过 5 种广泛使用的表观遗传时钟（第一代：Horvath、Hannum 和 S. M. K. 等）计算得出的：Horvath、Hannum 和 Li；第二代：Grim和Pheno）。通过与当地死亡和疾病登记处以及国家医疗保险数据库的连接，并辅以积极的随访，确定了心血管疾病的发病情况。虚弱指数是根据基线收集的医疗条件、症状、体征和身体测量结果构建的：结果：在中位 9.5 年的随访期间，共记录了 508 例急性心血管疾病病例。第一代表观遗传时钟与 ASCVD 风险相关（PP=1.2×10-2）。在总体衰老方面，GrimAA每增加1个标准差，虚弱指数就会平均增加0.10（P=2.0×10-3），虚弱前和虚弱基线风险分别增加33%和63%（P=1.5×10-2和5.8×10-2）；其他时钟没有观察到这种关联。GrimAA介导了各种血脂、脂肪酸、葡萄糖、乳酸和炎症生物标志物对虚弱指数的影响，在极小尺寸的极低密度脂蛋白中，甘油三酯的介导比例高达22%（P=6.0×10-3）：这些研究结果表明，表观基因组机制可能在循环代谢物与衰老过程之间的关联中发挥作用。在心血管衰老和一般衰老过程中，第一代和第二代 DNA 甲基化年龄的机制不同。
期刊介绍：
Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies.
Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities.
In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field.
Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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