Assessing metabolic ageing via DNA methylation surrogate markers: a multicohort study in Britain, Ireland and the USA
Author(s)
Type
Journal Article
Abstract
Metabolomics and epigenomics have been used to develop ‘ageing clocks’ that assess biological age and identify ‘accelerated ageing’. While metabolites are subject to short-term variation, DNA methylation (DNAm) may capture longer-term metabolic changes. We aimed to develop a hybrid DNAm-metabolic clock using DNAm as metabolite surrogates (‘DNAm-metabolites’) for age prediction. Within the UK Airwave cohort (n = 820), we developed DNAm metabolites by regressing 594 metabolites on DNAm and selected 177 DNAm metabolites and 193 metabolites to construct ‘DNAm-metabolic’ and ‘metabolic’ clocks. We evaluated clocks in their age prediction and association with noncommunicable disease risk factors. We additionally validated the DNAm-metabolic clock for the prediction of age and health outcomes in The Irish Longitudinal Study of Ageing (TILDA, n = 488) and the Health and Retirement Study (HRS, n = 4018). Around 70% of DNAm metabolites showed significant metabolite correlations (Pearson's r: > 0.30, p < 10−4) in the Airwave test set and overall stronger age associations than metabolites. The DNAm-metabolic clock was enriched for metabolic traits and was associated (p < 0.05) with male sex, heavy drinking, anxiety, depression and trauma. In TILDA and HRS, the DNAm-metabolic clock predicted age (r = 0.73 and 0.69), disability and gait speed (p < 0.05). In HRS, it additionally predicted time to death, diabetes, cardiovascular disease, frailty and grip strength. DNAm metabolite surrogates may facilitate metabolic studies using only DNAm data. Clocks built from DNAm metabolites provided a novel approach to assess metabolic ageing, potentially enabling early detection of metabolic-related diseases for personalised medicine.
Date Issued
2025-05-01
Date Acceptance
2024-12-26
Citation
Aging Cell, 2025, 24 (5)
ISSN
1474-9718
Publisher
Wiley
Start Page
e14484
Journal / Book Title
Aging Cell
Volume
24
Issue
5
Copyright Statement
© 2025 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39829316
Subjects
DNA methylation
ageing
biological age
cohort studies
epigenetics
metabolism
metabolomics
risk factors
Publication Status
Published
Coverage Spatial
England
Article Number
ARTN e14484
Date Publish Online
2025-01-20