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What makes biological age epigenetic clocks tick

Nature Aging volume 5, pages 335–336 (2025)Cite this article

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Epigenetic clocks are increasingly used to study aging1. However, confusion persists regarding the specific signals that clocks capture, as these encompass intrinsic, extrinsic, stochastic and programmatic changes. As such, it is important to understand the factors that drive potentially discordant results between clocks and how such complexities may be reconciled. Here, we highlight five important signals that are captured to different extents by epigenetic clocks and suggest additional standard analyses to more specifically represent these factors. These steps will ultimately improve our understanding of the various factors that make different clocks tick.

Epigenetic clocks are based on the age-dependent gain and loss of DNA methylation (DNAm). The gain or loss of DNA methylation at a given CpG site may occur in one of two ways: (1) in a ‘drifting’ manner in which the methylation state at a given CpG stochastically changes, which results in an increase in epigenetic disorder at that CpG site2, or (2) in a ‘steady’ manner in which an increasing number of cells change their methylation state at that CpG from one state to the opposite state, which results in a constant increase or decrease in the overall rate of methylation at that CpG (across cells)3.

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Fig. 1: Five factors that affect the epigenetic landscape as a function of age and how to properly address them in modeling biological aging.

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Acknowledgements

The work is supported in part by grants from the National Institute on Aging, Hevolution Foundation, and Methuselah Foundation and affiliated with the Biomarkers of Aging Consortium (https://www.agingconsortium.org).

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Authors and Affiliations

  1. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Mahdi Moqri, Jesse R. Poganik & Vadim N. Gladyshev

  2. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Steve Horvath

Authors
  1. Mahdi Moqri
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  2. Jesse R. Poganik
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  3. Steve Horvath
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  4. Vadim N. Gladyshev
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Contributions

M.M. conceived the idea and wrote the initial draft. J.R.P., S.H. and V.N.G. contributed to discussions and manuscript revisions. All authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Mahdi Moqri or Vadim N. Gladyshev.

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Competing interests

M.M., J.R.P., S.H. and V.N.G. have filed patents on measuring aging. S.H. is a founder of the nonprofit Epigenetic Clock Development foundation.

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Moqri, M., Poganik, J.R., Horvath, S. et al. What makes biological age epigenetic clocks tick. Nat Aging 5, 335–336 (2025). https://doi.org/10.1038/s43587-025-00833-1

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