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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 et al.. Brain : a journal of neurology, 2020-12-01
Topic: Risk, prevention and care in population studies
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.
Key findings
- 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.
- 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.
Why it matters
This study developed a new epigenetic clock for human cortex tissue to measure biological ageing in the brain. It suggests that some previous links between predicted DNA methylation age and neurodegenerative conditions might be false positives from clocks not calibrated to the tissue tested, but it does not test any treatment, cure or prevention.
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Study details
- Participants1,397
- Evidence strengthLow
How this study scored 59/100
Published in a leading specialty journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| Journal's citation record | 4 / 4 | Brain: journal h-index 503 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2020 — within 10 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,397 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 204 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 25.5 citations a year over 8 year(s) since 2020 |
| Impact for its field and year | 3 / 6 | Cited 6.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 3 / 4 | Cited 112 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Jonathan S. Mill: h-index 104 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | King's College London: institution h-index 1,348 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 33300551) |
| Free to read | 2 / 2 | Free to read |
| Total | 59 / 100 | — |
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Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Shireby, G. L., Davies, J. P., Francis, P. T., Burrage, J., Walker, E. M., Neilson, G. W. A., et al. (2020). Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex. Brain : a journal of neurology. https://doi.org/10.1093/brain/awaa334
Vancouver
Shireby GL, Davies JP, Francis PT, Burrage J, Walker EM, Neilson GWA, et al. Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex. Brain : a journal of neurology. 2020. doi:10.1093/brain/awaa334. PMID: 33300551.
BibTeX
@article{shireby2020-33300551,
author = {Shireby, G. L. and Davies, J. P. and Francis, P. T. and Burrage, J. and Walker, E. M. and Neilson, G. W. A. and Dahir, A. and Thomas, A. J. and others},
title = {{Recalibrating the epigenetic clock: implications for assessing biological age in the human cortex}},
journal = {Brain : a journal of neurology},
year = {2020},
doi = {10.1093/brain/awaa334},
pmid = {33300551},
url = {https://doi.org/10.1093/brain/awaa334}
}
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