A Reduction in Epigenetic Age is not at this Time Sufficient Proof of Slowed Aging

Geroprotective therapies are those that slow aging. While true rejuvenation therapies capable of reversing aging may also fall under that broad umbrella, discussion of geroprotectors usually focuses on drugs such as mTOR inhibitors that can at least modestly slow aging in animal studies. One area of growing interest in the field is the use of epigenetic clocks to assess aging, and the degree to which the clock measurements are affected by potentially geroprotective interventions.

The challenge in epigenetic clocks - and other conceptually similar clocks - is that they are fitted to observed age-related changes in biochemical data without any understanding of what causes those changes. Perhaps characteristic epigenetic changes that take place with age reflect all of the underlying processes of aging, and perhaps they do not. Thus one cannot take any given result in the treatment of aging at face value until the specific clock has been calibrated to the specific intervention in life span studies, a lengthy prospect that entirely defeats the point of a simple measure of aging, and which has yet to be undertaken for any class of intervention.

As researchers point out here, this means that clocks, while interesting and meriting further study, must be relegated to the second tier of data for the foreseeable future. Whether or not a given intervention produces slowed aging, and is thus geroprotective, can only be assessed robustly at the present time via established measures of health and age-related disease.

Does Modulation of an Epigenetic Clock Define a Geroprotector?

The geroscience hypothesis, that the rate of aging can be changed, is indeed an exciting one, and one that will likely receive considerable attention in the future. Geroprotectors arising from studies exploring the geroscience hypothesis would undoubtedly revolutionize health care and result in dramatic societal changes, and for these reasons should be taken extremely seriously. However, the biomedical science community should be very sensitive to overenthusiasm concerning ways in which geroprotectors are vetted, since reliance on a solitary measure of aging, for example an epigenetic clock, to vet candidate geroprotectors might not be necessary. If geroprotectors, by definition, should improve health during the aging process, and health can be measured in myriad ways, then relevant trials should focus on these health measures directly.

In fact, as we have argued, it would be hard to make the case that a geroprotector that is only known or shown to modulate an epigenetic clock will extend health span or lifespan without impacting anything associated with health from traditional clinical perspectives. In addition, if one could show that a geroprotector actually does modulate age-related disease processes using routine and accepted clinical measures then the mechanism of action of that geroprotector is likely to be a key to an underlying universal aging clock. Ultimately, a purported geroprotector that has either no observable effect on many available common sense, well-accepted measures of health and vitality, or will only have an effect on health via some cryptic mechanism after the many years of use during which an individual is at typical risk for disease, is a tough sell.

Simply put, geroprotectors should provide overt health and disease prevention benefits but the time-dependent relationships between epigenetic clocks and health-related phenomena are complex and in need of further scrutiny. Therefore, studies that enable understanding of the relationships between epigenetic clocks and disease processes while simultaneously testing the efficacy of a candidate geroprotector are crucial to move the field forward.


I've been saying something similar for a while. I think the term "clock" is a misnomer. There's nothing wrong with just calling them biomarkers and leaving it at that for now until more is understood. The whole point is to decouple time from all of these parameters which measure the state of the human body.

Posted by: Curry B. Taylor at May 15th, 2022 11:11 AM

Except that we have a theory of aging predicated on progressive changes in DNA methylation leading to silenced genes and stereotyped dysfunction. In other words, there is a good reason to believe these clocks may not just be a biomarkers, but also a cause of altered genetic transcription.

Posted by: mert erogul at May 15th, 2022 7:21 PM
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