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A computational solution for bolstering reliability of epigenetic clocks: implications for clinical trials and longitudinal tracking

Higgins-Chen, Albert T., Thrush, Kyra L., Wang, Yunzhang, Minteer, Christopher J., Kuo, Pei-Lun, Wang, Meng, Niimi, Peter, Sturm, Gabriel, Lin, Jue, Moore, Ann Zenobia, Bandinelli, Stefania, Vinkers, Christiaan H., Vermetten, Eric, Rutten, Bart P. F., Geuze, Elbert, Okhuijsen-Pfeifer, Cynthia, van der Horst, Marte Z., Schreiter, Stefanie, Gutwinski, Stefan, Luykx, Jurjen J., Picard, Martin, Ferrucci, Luigi, Crimmins, Eileen M., Boks, Marco P., Hägg, Sara, Hu-Seliger, Tina T., Levine, Morgan E.·2022·Nature Aging
DOI 10.1038/s43587-022-00248-2PMC PMC9586209

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  • Age-related methylation varies across different circulating immune cells.

    “For example, there is evidence that age-related methylation varies across different circulating immune cells 51.”

    From Validation of biomarkers of aging (2024) · cites this paper as [51]

    The Results (page unavailable) report that shifts in blood-cell composition affect epigenetic clocks. Extended Data Fig. 9 identifies five circulating immune-cell types whose estimated proportions correlate with the clocks. These passages support a role for immune-cell composition in measured epigenetic age, but do not show that age-related methylation itself varies across those cell types. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • The primary analysis used PC versions of PhenoAge and GrimAge and DunedinPACE, which show exceptional test-retest reliability in technical replicates.

    “Our primary analysis focused on the PC versions of the PhenoAge and GrimAge second-generation clocks and DunedinPACE, all of which show exceptional test–retest reliability in technical replicates.”

    From Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial (2023) · cites this paper as [25]

    The Results section (‘Reliable epigenetic clocks trained from principal components’; page unavailable) reports exceptional agreement between technical replicates for PC clocks, including PCPhenoAge and PCGrimAge. Our copy does not establish the same test–retest reliability for DunedinPACE, so it does not support the claim about all three measures. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • When several DNAm clocks are residualized for chronological age, values show only moderate test-retest reliability across technical replicates.

    “A limitation of several DNAm clocks is that when residualized for chronological age, values show only moderate test–retest reliability across technical replicates.”

    From Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial (2023) · cites this paper as [25]

  • Second-generation (generation 2+) DNAm biomarkers, such as PCGrimAge, SystemsAge and DunedinPACE, showed the strongest and most consistent responsiveness.

    “Importantly, we found that second-generation (generation 2+) DNAm biomarkers, such as PCGrimAge12, SystemsAge11 and DunedinPACE10, showed the strongest and most consistent responsiveness.”

    From Responsiveness of epigenetic aging biomarkers to longevity interventions in humans (2026) · cites this paper as [12]

  • PC clocks have superior technical reliability as compared with the original versions of PhenoAge and GrimAge.

    “We analyzed versions of the PhenoAge and GrimAge clocks constructed from DNAm principal components (PCs) (hereafter ‘PC clocks’), which have superior technical reliability as compared with the original versions of these measures25; DunedinPACE was originally designed to have high technical reliability.”

    From Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial (2023) · cites this paper as [25]

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Metadata

Authors
Higgins-Chen, A. T., Thrush, K. L., Wang, Y., Minteer, C. J., Kuo, P.-L., Wang, M., Niimi, P., Sturm, G., Lin, J., Moore, A. Z., Bandinelli, S., Vinkers, C. H., Vermetten, E., Rutten, B. P. F., Geuze, E., Okhuijsen-Pfeifer, C., van der Horst, M. Z., Schreiter, S., Gutwinski, S., Luykx, J. J., Picard, M., Ferrucci, L., Crimmins, E. M., Boks, M. P., Hägg, S., Hu-Seliger, T. T., & Levine, M. E.
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2022-07-15
Volume
2
Issue
7
Pages
644-661
ISSN
2662-8465
DOI
10.1038/s43587-022-00248-2
PMC
PMC9586209
Cited by
502
References
23
Language
en
Licence
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (2T32MH019961-21A1)
  • Yale University
  • U.S. Department of Veterans Affairs
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG066828, R01AG060110, U01AG009740, 1R01AG068285, 1R01AG065403, 1R01AG057912)
  • Rudolf Magnus Talent Fellowship

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