DNA Methylation Age Mediates Effect of Metabolic Profile on Cardiovascular and General Aging
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.
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© 2024 American Heart Association, Inc.
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Received: 12 June 2024
Revision received: 2 September 2024
Accepted: 9 September 2024
Published online: 23 September 2024
Published in print: 11 October 2024
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Funding Information
National Natural Science Foundation of China (CN)501100001809
Kadoorie Charitable Foundation (HK)501100017647
National Key Research and Development Program of China (CN)501100012166: 2016YFC0900500
National Natural Science Foundation of China (CN)501100001809
National Natural Science Foundation of China (CN)501100001809: 82404348
National Key Research and Development Program of China (CN)501100012166: 2023YFC3606300
This work was supported by the National Natural Science Foundation of China (82388102, 82404348, 82192904, 82192900) and the Fund of Key Laboratory of Epidemiology of Major Diseases (Peking University), Ministry of Education (2024102). The CKB baseline survey and the first resurvey were supported by the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up has been supported by grants (2016YFC0900500, 2023YFC3606300) from the National Key R&D Program of China, National Natural Science Foundation of China (81390540, 91846303, 81941018), and Chinese Ministry of Science and Technology (2011BAI09B01). The UK Medical Research Council (MC_UU_00017/1, MC_UU_12026/2, MC_U137686851), Cancer Research UK (C16077/A29186; C500/A16896) and the British Heart Foundation (CH/1996001/9454), provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University for the project.
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- Unraveling the causal impact of smoking and its DNA methylation signatures on cardiovascular disease: Mendelian randomization and colocalization analysis, Clinical Epigenetics, 17, 1, (2025).https://doi.org/10.1186/s13148-024-01808-6
- Depression and Accelerated Aging: The Eveningness Chronotype and Low Adherence to the Mediterranean Diet Are Associated with Depressive Symptoms in Older Subjects, Nutrients, 17, 1, (104), (2024).https://doi.org/10.3390/nu17010104
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