A Thorough Overview of Aging Clocks

A team of researchers, including Drs. Vadim Gladyshev and Steve Horvath, recently published a review of DNA methylation aging clocks, which use biomarkers to determine the biological age of a person.

Aging causes epigenetic alterations to occur, including changes to DNA methylation, histone modification, transcriptional alterations (variance in gene expression), and remodeling of chromatin (a DNA support structure that assists or impedes gene transcription).

The paper in question focuses on the changes to DNA methylation and the various aging clocks that use them to predict biological age. Each of the multiple aging clocks has its individual strengths and weaknesses, and this review takes a look at some of them, including the “PhenoAge” DNA methylation clock, which uses nine age-related biochemical measures in combination with chronological age, and the GrimAge clock, which gives a strong prediction of lifespan and healthspan.

This publication explores the challenges inherent in developing more accurate aging clocks and looks at the pros and cons of the methods that these clocks use. It details seven challenges, provides suggestions for experiments to support the refinement of DNA methylation clocks, and attempts to stimulate further discussion and experimentation in this direction.

Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.


Given the limitations of the current generation of clocks, publications like this provide a valuable foundation on which to build a future generation of clocks that could potentially address these inherent issues.

There is no doubt that the use of these kinds of epigenetic clocks will become increasingly widespread, especially given their growing popularity in the consumer market, where it is now cost-effective to buy epigenetic test kits to aid in monitoring one’s health, similar to how DNA test kits identify potential problem genes and gene variants.

However, such clocks have their limitations, and it is important that those limitations are understood and, if possible, addressed through the development of better aging clocks. We are only really starting to understand and appreciate what many of these clocks are reading in the context of aging, and there is almost certainly a long road ahead before we have refined them to the point where they become the gold standard of aging biomarkers. Publications like this review should be very valuable in driving that discussion and development in the future.

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[1] Bell, C. G., Lowe, R., Adams, P. D., Baccarelli, A. A., Beck, S., Bell, J. T., … & Ideker, T. (2019). DNA methylation aging clocks: challenges and recommendations. Genome Biology, 20(1), 249.