Epigenetic Clocks: New Types, New Promises, New Skepticism

Will birthdays go the way of the Betamax and Blackberry? Our culture is always eager to move away from old things toward new things and these days if you want to know how old you are, the number of candles on your cake is just one clue — and maybe not even the best clue.
Epigenetic clocks measure what's happening inside you on a cellular level and they might say you're aging faster (or slower) than you thought based on changes to your DNA.
First developed in 2013 as research tools, epigenetic clocks are now widely accessible through direct-to-consumer test kits. Send in a sample of your DNA and receive your results — your 'biological age' — within weeks.
Can this give the average layperson valuable insights? Should doctors be using them to help predict how one patient might get sick or how long another might live?
Yes, no, and maybe are all legit answers here depending on who's asking and who's being asked.
Right now, epigenetic clocks are in the same spot as other highly hyped medical tech — like artificial intelligence, like wearables, like implantables — in that they're not really 'there' yet and yet everyone wants them to be. Researchers already use them, of course. They have extensive clinical potential and simultaneously excite health-conscious consumers: How quickly can I know how old I really am?
The tests have evolved quickly and will continue to do so. For example: Some tests require you to draw a little blood or spit in a tube, but one of the latest tests uses an at-home cheek swab instead. In a study published in Frontiers in Aging , US company Tally Health showed its CheekAge epigenetic clock can predict the risk for early death. For every SD increase in CheekAge score, study participants faced a 21% higher risk for death before their next check-in with researchers, which was scheduled every 3 years.
'We believe that epigenetic aging clocks currently can serve as useful indicators of health and lifestyle, which is often missing from the care conversation, and should be part of routine preventative care,' said Max Shokhirev, PhD, head of Computational Biology and Data Science at Tally Health.
Epigenetic clocks can also help researchers compare populations over time, track users in specific contexts, or stratify clinical trial participants into high-risk or low-risk groups, Shokhirev said.
However, some experts say there is plenty of room for improvement as the science behind epigenetic clocks advances. Although companies tout the accuracy of their clocks, results can vary by years or decades, leaving test takers confused. Sometimes the test results come with suggestions for boosting longevity, including products the testing companies want to sell you.
Then there's the biggest question: If you can improve your score, will you truly live better or longer?
How to Build a Clock
Instead of tracking time, epigenetic clocks detect patterns in DNA methylation, a chemical reaction that attaches molecules called methyl groups to DNA. All your cells have the same DNA, and methylation determines which genes get turned on and off, said Eric Verdin, MD, president and chief executive officer of the Buck Institute for Research on Aging. For example, the gene for hemoglobin is turned on in red blood cells through methylation. The same gene is switched off in other cells, such as neurons.
'As we age, the precision of this epigenetic mechanism gets a little loose,' said Verdin. Cells lose some specificity, and genes turn on and off in the wrong places, a phenomenon known as epigenetic drift. 'Now we can measure this epigenetic drift during aging, and that's what the clocks are based on,' said Verdin.
Methylation happens in about 28 million spots, known as methylation sites, in our genomes. To make the first epigenetic clocks, the Hannum and Horvath clocks, researchers analyzed blood samples from hundreds to thousands of people. They examined DNA methylation in a small fraction of methylation sites. They used the data to build a mathematical model that predicts age based on DNA methylation.
The math behind the first clocks revolved around age. Today, scientists use second-generation epigenetic clocks such as PhenoAge and GrimAge, which also incorporate health-related variables, such as white blood cell counts and smoking history. One clock, DunedinPACE, reveals a rate of aging rather than a set number. Second-generation clocks likely have more predictive value for your health than earlier versions, said Verdin.
Research suggests epigenetic age can foretell some health outcomes, such as working memory or surviving a stay at the intensive care unit, better than chronological age, the number you celebrate on your birthday. However, more research is needed to see how epigenetic clocks stack up to more established tests and screening tools. In one new study in the Journal of the American Heart Association , PhenoAge and GrimAge were not as good at predicting cardiovascular disease as the widely used Framingham Risk Score.
Marketing to consumers is the most predictable advance in the tech. The cost for a single test runs between $250 and $500. Some companies also offer monthly subscriptions including repeat testing and recommended supplements.
Insurance companies don't cover these tests for healthy people. Some insurers, like Aetna, will cover epigenetic tests when someone has symptoms of a specific disease and knowing the results could affect treatment. But these tests are different from epigenetic clocks — they detect specific epigenetic disease signatures instead of the markers that give an overall picture of health. (And it's difficult to get coverage for these, too: In one study in Genetics in Medicine , insurers covered just 11% of methylation-based genetic tests ordered by physicians for people with a diagnosis suspected to have a genetic component.)
Clocking Test Results
Some longevity testing companies use one or more second-generation clocks to estimate age. Some use their own proprietary clocks. So let's say you take a test: How much stock should you put in your results?
As Verdin said, 'I've done all of my clocks, and my age varies from 40 to 67, all DNA methylation, which is, in my opinion, an indication that these tools are not ready for prime time.' (Note: As of publication time, Verdin is 68 years old.)
Results vary because each clock has its own math, based on a unique combination of methylation sites and study participants.
The numbers on your reports might not be useful in isolation, said Verdin. Instead, think of them as variables you can track over time. 'Where they have more value is if you use always the same clock, and you introduce a number of interventions,' said Verdin. 'For example, you start intermittent fasting, or you start metformin, or you do this intervention or that intervention, and if you see your clock moving in the right direction, that will be a good sign.'
If you try this method, time follow-up tests carefully. DNA methylation isn't as static as people assume, said Verdin. Like measuring cortisol or blood sugar, it varies by time of day, skewing clock results by up to 5 years.
'You should always do them at exactly the same time, and hopefully, do it the same kind of day,' he said. 'You don't want to do one on a Sunday, when you're well rested, you're not stressed versus the Tuesday or Friday morning when you're super stressed.'
Timing isn't the only problem that can affect your results and how to interpret them. 'Emerging research shows that there are race and ethnic disparities in terms of how the clock performs,' said Andres Cardenes, PhD, an assistant professor of epidemiology and population health at Stanford University, Stanford, California.
Blame a lack of diversity in the data used to develop many epigenetic clocks. Most samples came from White people in the western part of the world. Cardenes' team is collecting more DNA methylation samples from underrepresented groups so future clocks can be applicable to all.
The Lure of Slow Aging and Cheating Death
An interesting way to think about this: Getting old is very new to the human experience. And some humans handle it better than others.
An epigenetic clock can signal how well you are aging. But no one has figured out how to cheat death forever, so the question remains: How much can you realistically increase your life expectancy?
A new study in Nature Aging shows that improvements in human life expectancy have slowed since 1990. Study author S. Jay Olshansky, PhD, professor of epidemiology and biostatistics at the University of Illinois, Chicago, said this isn't bad news — it reflects how dramatically we improved survival during the 20th century through developments like antibiotics and refrigeration.
'This slowdown in the rate of increase is a product of us doing our job exceedingly well in medicine and public health and enabling people to live long enough to experience aging,' he said.
Olshansky's team said it's unlikely that more than 15% of women and 5% of men will live to 100 unless we find a way to slow down biologic aging drastically.
'The problem is that when you succeed so well as humanity has, you expose the population to the underlying biological process of aging when they get to older ages, which is currently an immutable process,' he said.
That's not for lack of effort. Many scientists are searching for ways to reverse aging.
Epigenetic clocks might help people measure the effectiveness of interventions aimed at improving health and extending life, said Olshansky. But pay attention to what else testing companies are selling, like dietary supplements, he said.
'As long as they're not accompanied by embellished claims that you can somehow reverse your biological aging, or slow your biological aging, or live longer and healthier as a result of whatever it is that they're selling, then I think they're okay,' said Olshansky. 'I think they can actually provide some useful and valuable information.'
The results might simply push you to do things that have already been shown to help people live healthier and longer, such as eating well and exercising.
'What we need to understand is that these biomarkers are becoming attractive because they track with general things that we know are helpful and healthy as well,' said Cardenes. 'For example, a diet rich in fruits and vegetables, particularly vegetables, has been shown to decelerate some of these clocks.'
Research in Aging Cell also suggests that exercise slows down aging as measured by epigenetic clocks.
On the Clock: What Does the Future Hold?
The science behind epigenetic clocks is evolving fast. Researchers are working to make them more accurate and useful.
For example, using epigenetic clocks, Verdin's team noticed that SARS-CoV-2 infections increased people's biologic ages by about 15 years. Postinfection, people had influxes of memory T cells that mirrored age-related changes in immune function. Verdin's team then made a clock that excluded methylation sites sensitive to these changes. It's now available through TruDiagnostic.
More opportunity lies in the millions of DNA methylation sites yet to be tapped, said Verdin. Today's epigenetic clocks only probe hundreds to thousands of them. 'There's going to be even more interesting data coming in the future,' he said.
Also new will be what and how clocks measure. A study in Aging late last year showed strong results of cell-specific clocks analyzing brain cells for Alzheimer's and liver cells for liver disease.
Meanwhile, a new blood-based clock measures 'intrinsic capacity,' the sum of mobility, cognition, mental health, vision, hearing, and nutrition/vitality. All aimed at improving function in aging patients (and perhaps addressing health span and lifespan simultaneously).
Researchers have also developed phenotypic clocks that examine biomarkers like blood pressure and cholesterol.
The organ-specific clocks look to be most useful in detecting early deterioration by body part. 'Your longevity is determined by your frailty point,' said Verdin. 'In your case, it might be your heart, and some other person, it might be their liver. The first organ that's going to fail is going to determine your longevity.'
Cardenes and others are also exploring how environmental factors affect clocks. 'We want to understand the very early marks that either chemical or social environments might leave in our genome,' he said.
Will epigenetic clocks make their way into routine clinical practice? Probably, proponents say, but in what form?
'In the future, patients might be prescribed a low-cost biological age test for their doctors to know the rate of biological aging and detect any organs that need particular attention, years before the patient develops a disease of aging,' said David Sinclair, PhD, professor in the Department of Genetics at Harvard Medical School, Boston, co-founder of Tally Health, and chairman of the Scientific Advisory Board at InsideTracker. 'The test could also be used one day to confirm lifestyle and health factors such as smoking history and alcohol intake.'
Verdin sees potential in pairing epigenetic clocks with other new clocks based on blood proteins and metabolites. 'My argument is that for these clocks, as clinical tools, to become important or more relevant, you have to use several,' said Verdin. 'I would not rely only on epigenetic. I would use proteomics, metabolomics, and hopefully get to a picture that is sort of a comprehensive picture.'
More research is still needed to determine the value of epigenetic clocks, said Cardenes. 'What does it mean for people to get this test?' he said. 'Is it changing outcomes? At the end of the day, are people going to do things that will improve their health and longevity? It's still unclear whether this is helpful or not.'

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