DNA Methylation Age Mediates Effect of Metabolic Profile on Cardiovascular and General Aging
Jiahui Si, Yu Ma, Canqing Yu, Dianjianyi Sun, Yuanjie Pang, Pei Pei, Ling Yang, Iona Y. Millwood, Robin Walters, Yiping Chen, Huaidong Du, Xiaoyan Zheng, Daniel Avery, Junshi Chen, Zhengming Chen, Liming Liang, Liming Li, Jun Lv, Rory Collins, Richard Peto, Ruth Boxall, Derrick Bennett, Yu‐Mei Chang, Robert Clarke, Simon Gilbert, Alex Hacker, Michael V. Holmes, Andri Iona, Christiana Kartsonaki, Rene Kerosi, Ling Kong, Om Kurmi, Garry Lancaster, Sarah Lewington, Kuang Lin, John McDonnell, Xue W. Mei, Qunhua Nie, Jayakrishnan Radhakrishnan, Sajjad Rafiq, Paul Ryder, Sam Sansome, Dan Schmidt, Paul Sherliker, Rajani Sohoni, Iain Turnbull, Jenny Wang, Lin Wang, Xiaoming Yang, Zheng Bian, Ge Chen, Yu Guo, Can Hou, LV Jun, Shuzhen Qu, Yunlong Tan, Canqing Yu, Zengchang Pang, Ruqin Gao, Shaojie Wang, Yongmei Liu, Huaidong Du, Yajing Zang, Liang Cheng, Xiaocao Tian, Hua Zhang, Jun Lv, Junzheng Wang, Wei Hou, Jiyuan Yin, Ge Jiang, Xue Zhou, Liqiu Yang, Hui He, Bo Yu, Yanjie Li, Huaiyi Mu, Qinai Xu, Meiling Dou, Jiaojiao Ren, Shanqing Wang, Ximin Hu, Hongmei Wang, Jinyan Chen, Yan Fu, Zhenwang Fu, Xiaohuan Wang, Min Weng, Xiangyang Zheng, Yilei Li, Huimei Li, Yanjun Wang, Ming Wu, Jinyi Zhou, Ran Tao, Jie Yang, Chuanming Ni, Jun Zhang, Yihe Hu, Yan Lü
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.