A new study published in the Journals of Gerontology has shown that the epigenetic clock GrimAge is a strong predictor of the effects of aging, particularly all-cause mortality: the likelihood of dying from any cause.
Did previous clocks use the wrong target?
As the researchers explain, the first-generation epigenetic clocks of Drs. Horvath (who contributed to this paper) and Hannum are very good at guessing calendar age: it is possible to take a cell sample, analyze it using one of these clocks, and accurately guess how old the donor is.
Ideally, it would be possible to use this kind of analysis to measure age acceleration effects. If such a clock is truly measuring the effects of aging, if a person is epigenetically older than the clock signifies, that person should be at greater risk for age-related diseases than a person who has not experienced such age acceleration.
Unfortunately, these two first-generation clocks are ill-suited for measuring the physical effects of age acceleration. This study has found that with these clocks, increases of epigenetic age over calendar age do not correlate with physical ability tests, cognitive tests, or the need for a patient to be prescribed multiple drugs (polypharmacy). Most importantly, they are not significantly correlated with all-cause mortality, making them practically useless for estimating the efficacy of a therapy that is designed to extend lifespan and healthspan.
This is where the second-generation clocks shine. The PhenoAge clock, as its name suggests, was trained against the phenotypes (effects) of aging, and the GrimAge clock was specifically trained against plasma proteins and the effects of smoking.
A total of 490 people were tested as part of the epigenetic study, and they were tested for eight metrics: walking speed, grip strength, polypharmacy, the Fried Frailty Score, the Mini-Mental State Exam, the Montreal Cognitive Assessment, the Sustained Attention Reaction Time Task, and the Choice Reaction Time Task.
All four clocks were studied with this cohort, and the cohort was investigated for social mobility, which is a strong predictor of health outcomes, as well as other factors known to affect health, such as body mass index (BMI), smoking history, and alcohol consumption; while such things may affect epigenetics as well, it is of marginal value to have a clock that turns out to only successfully measure their influence.
In an simple, minimally adjusted analysis that did not control for these factors, the PhenoAge clock predicted four of the tested items, but “none of these associations survived multivariable adjustment.” GrimAge, by contrast, was associated with seven of the eight, and after multivariable adjustment, it still continued to predict three of them.
Most notably, GrimAge was very successful at predicting all-cause mortality, and none of the other clocks came close. People whose age acceleration, as measured by GrimAge, were one standard deviation above the mean were twice as likely to die over this 10-year study, and this association held true even when controlling for other factors.
The researchers state that GrimAge may already be a useful clinical endpoint for testing the efficacy of rejuvenation therapies that directly affect aspects of aging. If researchers already have a cellular biomarker that reliably correlates with a therapy’s effects on human beings, they can use it to evaluate therapies even in the earliest preclinical phases, which utilize human cells.
Furthermore, the researchers hypothesize that even more efficient epigenetic clocks can be developed. Such third-generation clocks would be built specifically to the purpose, being directly trained on frailty indices and similar predictors of mortality rather than on calendar age. In the future, we may have a large variety of clocks trained on individual age-related conditions and diseases; such clocks would be limited in scope but would provide specifically useful information on the efficacy of any given therapy.