Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex

Shireby, GL, Davies, JP, Francis, PT, Burrage, J, Walker, EM, Neilson, GWA, Dahir, A, Thomas, AJ, Love, S, Smith, RG, Lunnon, K, Kumari, M, Schalkwyk, LC, Morgan, K, Brookes, K ORCID: https://orcid.org/0000-0003-2427-2513, Hannon, EJ and Mill, J, 2020. Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex. Brain. ISSN 0006-8950

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Abstract

Human DNA methylation data have been used to develop biomarkers of ageing, referred to as ‘epigenetic clocks’, which have been widely used to identify differences between chronological age and biological age in health and disease including neurodegeneration, dementia and other brain phenotypes. Existing DNA methylation clocks have been shown to be highly accurate in blood but are less precise when used in older samples or in tissue types not included in training the model, including brain. We aimed to develop a novel epigenetic clock that performs optimally in human cortex tissue and has the potential to identify phenotypes associated with biological ageing in the brain. We generated an extensive dataset of human cortex DNA methylation data spanning the life course (n = 1397, ages = 1 to 108 years). This dataset was split into ‘training’ and ‘testing’ samples (training: n = 1047; testing: n = 350). DNA methylation age estimators were derived using a transformed version of chronological age on DNA methylation at specific sites using elastic net regression, a supervised machine learning method. The cortical clock was subsequently validated in a novel independent human cortex dataset (n = 1221, ages = 41 to 104 years) and tested for specificity in a large whole blood dataset (n = 1175, ages = 28 to 98 years). We identified a set of 347 DNA methylation sites that, in combination, optimally predict age in the human cortex. The sum of DNA methylation levels at these sites weighted by their regression coefficients provide the cortical DNA methylation clock age estimate. The novel clock dramatically outperformed previously reported clocks in additional cortical datasets. Our findings suggest that previous associations between predicted DNA methylation age and neurodegenerative phenotypes might represent false positives resulting from clocks not robustly calibrated to the tissue being tested and for phenotypes that become manifest in older ages. The age distribution and tissue type of samples included in training datasets need to be considered when building and applying epigenetic clock algorithms to human epidemiological or disease cohorts.

Item Type:	Journal article
Publication Title:	Brain
Creators:	Shireby, G.L., Davies, J.P., Francis, P.T., Burrage, J., Walker, E.M., Neilson, G.W.A., Dahir, A., Thomas, A.J., Love, S., Smith, R.G., Lunnon, K., Kumari, M., Schalkwyk, L.C., Morgan, K., Brookes, K., Hannon, E.J. and Mill, J.
Publisher:	Oxford University Press
Date:	28 October 2020
ISSN:	0006-8950
Identifiers:	Number Type 10.1093/brain/awaa334 DOI 1355119 Other
Rights:	© the author(s) (2020). This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	27 Aug 2020 11:04
Last Modified:	31 May 2021 15:13
URI:	https://irep.ntu.ac.uk/id/eprint/40540

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