DNA Methylation Age Mediates Effect of Metabolic Profile on Cardiovascular and General Aging
Authors: Si Jiahui , Ma Yu , Yu Canqing , Sun Dianjianyi , Pang Yuanjie , Pei Pei , Yang Ling , Millwood Iona Y. , Walters Robin G. , Chen Yiping , Du Huaidong , Zheng Xiaoyan , Avery Daniel , Chen Junshi , Chen Zhengming , Liang Liming , Li Liming , Lv Jun , Collins Rory , Peto Richard , Boxall Ruth , Bennett Derrick , Chang Yumei , Clarke Robert , Gilbert Simon , Hacker Alex , Holmes Michael , Iona Andri , Kartsonaki Christiana , Kerosi Rene , Kong Ling , Kurmi Om , Lancaster Garry , Lewington Sarah , Lin Kuang , McDonnell John , Mei Winnie , Nie Qunhua , Radhakrishnan Jayakrishnan , Rafiq Sajjad , Ryder Paul , Sansome Sam , Schmidt Dan , Sherliker Paul , Sohoni Rajani , Turnbull Iain , Wang Jenny , Wang Lin , Yang Xiaoming , Bian Zheng , Chen Ge , Guo Yu , Hou Can , Lv Jun , Qu Shuzhen , Tan Yunlong , Yu Canqing , Pang Zengchang , Gao Ruqin , Wang Shaojie , Liu Yongmei , Du Ranran , Zang Yajing , Cheng Liang , Tian Xiaocao , Zhang Hua , Lv Silu , Wang Junzheng , Hou Wei , Yin Jiyuan , Jiang Ge , Zhou Xue , Yang Liqiu , He Hui , Yu Bo , Li Yanjie , Mu Huaiyi , Xu Qinai , Dou Meiling , Ren Jiaojiao , Wang Shanqing , Hu Ximin , Wang Hongmei , Chen Jinyan , Fu Yan , Fu Zhenwang , Wang Xiaohuan , Weng Min , Zheng Xiangyang , Li Yilei , Li Huimei , Wang Yanjun , Wu Ming , Zhou Jinyi , Tao Ran , Yang Jie , Ni Chuanming , Zhang Jun , Hu Yihe , Lu Yan , Ma Liangcai , Tang Aiyu , Zhang Shuo , Jin Jianrong , Liu Jingchao , Tang Zhenzhu , Chen Naying , Huang Ying , Li Mingqiang , Meng Jinhuai , Pan Rong , Jiang Qilian , Zhang Weiyuan , Liu Yun , Wei Liuping , Zhou Liyuan , Chen Ningyu , Guan Hairong , Wu Xianping , Zhang Ningmei , Chen Xiaofang , Tang Xuefeng , Luo Guojin , Li Jianguo , Chen Xiaofang , Zhong Xunfu , Liu Jiaqiu , Sun Qiang , Ge Pengfei , Ren Xiaolan , Dong Caixia , Zhang Hui , Mao Enke , Wang Xiaoping , Wang Tao , Zhang Xi , Zhang Ding , Zhou Gang , Feng Shixian , Chang Liang , Fan Lei , Gao Yulian , He Tianyou , Sun Huarong , He Pan , Hu Chen , Lv Qiannan , Zhang Xukui , Yu Min , Hu Ruying , Wang Hao , Qian Yijian , Wang Chunmei , Xie Kaixue , Chen Lingli , Zhang Yidan , Pan Dongxia , Huang Yuelong , Chen Biyun , Yin Li , Jin Donghui , Liu Huilin , Fu Zhongxi , Xu Qiaohua , Xu Xin , Zhang Hao , Xiong Youping , Long Huajun , Li Xianzhi , Zhang Libo , Qiu Zhe 
Published: September 2024

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.