Audio long read: How quickly are you ageing? What molecular ‘clocks’ can tell you about your health
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Start shopping at thrivemarket.com slash podcast for 30% off your first order and a free gift. This is an audio long read from nature. In this episode, how quickly are you aging? What molecular clocks can tell you about your health? Written by Heidi Ledford and read by me, Benjamin Thompson. If the number of on-camera screams is any indication, Kim Kardashian's first encounter with epigenetics was a thrilling one.

The reality television star and her family shrieked and squealed in the season finale of The Kardashians in Los Angeles, California last July as they each learnt the results of a commercial blood test that purportedly assessed their biological ages.

Although Kardashian was 43, the placement of chemical markers on her DNA, her epigenetic profile, matched that of a 34-year-old, according to the test. Her body, moreover, was ageing 18% more slowly than most people of her age. You should give yourself a pat on the back, said Matthew Dawson as he relayed the results.

Dawson is chief executive of True Diagnostic in Lexington, Kentucky, the company that sells the test. On the other side of the country, neuropsychologist Terry Moffitt says she was, quote, mortified, end quote, when she saw the segment.

Moffat, who works at Duke University in Durham, North Carolina, had spent decades with her colleagues collecting data from around 1,000 people to create the basis for one of the tests provided by True Diagnostic. She had hoped that her work might one day inform medical decisions or provide a way for researchers to assess whether an anti-aging treatment is having a positive effect on health.

A stunt on a reality TV show was not the kind of publicity she was aiming for. "I have a snob's view of reality TV," she adds. Mixed feelings of enthusiasm and apprehension were common among researchers who spoke to Nature about efforts to develop tests that measure the impact of aging on the body.

With money pouring into the field and an unprecedented level of public attention and excitement, scientists are publishing a steady stream of papers on ways to measure how rapidly a person's body is declining. Many of the measures look at chemical marks on DNA known as methylation, or at proteins or metabolites that can be found in the blood.

These biological markers, or biomarkers, could prove incredibly useful as part of burgeoning efforts to develop drugs and other therapies that would forestall the negative effects of aging and increase what gerontologists refer to as the healthy lifespan. Often, however, test results that use these biomarkers are interpreted and presented without a full reckoning of the uncertainties that plague them.

It's a problem not just for commercial tests, but also for media articles and even scientific publications. There's a lot of confusion, says Brian Chen, a molecular epidemiologist at California Pacific Medical Center Research Institute in San Francisco. I've seen in academia scientists trying to promote and hype up biological age and aging research in general to generate more interest and funding, he says.

Chen and others worry about the risk of elevated expectations, as scientists take on the long and arduous task of validating these tests. Whether or not, at the end of the day, this kind of thing is going to be positive or negative for the field is hard to know, says Matt Kaperlein, chief executive at Optispan, a healthcare technology company in Tukwila, Washington. If you lose your reputation, that's hard to get back, he says.

For the moment, the field is on fire. In December 2024, the US Advanced Research Projects Agency for Health announced a program to develop and validate biomarkers of aging.

Evolution Foundation, a charity in Riyadh, has invested US$400 million in HealthSpan research. And organisers of XPRIZE HealthSpan, a competition to find treatments for conditions associated with ageing, are planning a seven-year, US$101 million global competition that is dedicated to improving HealthSpan. A smorgasbord of tests to assess ageing already exists.

Geneticist Steve Horvath, now at Altos Labs in Cambridge, UK, developed one of the first epigenetic clocks more than a decade ago. He analysed data from 7,800 samples to catalogue which sites in the genome were tagged with methyl groups, a chemical modification to DNA that helps to regulate the expression of genes.

He then fed these data, along with the ages of the study participants, into a machine learning algorithm. The algorithm produced a collection of 353 methylation sites that, taken together, correlated with participants' chronological ages. Some of these sites were more methylated with age. Others were less so.

those markers became the basis for a test that can predict a person's chronological age with remarkable accuracy says chen who worked with horwarth but the test was not as good at predicting how long a person might expect to remain healthy or when they might die

So Horvath's team and others began to build new tests, searching for methylation sites that correlate with other age and health-related measures, such as white blood cell counts, the amount of glucose in the blood, and levels of a protein that serves as a marker for inflammation. This time, the goal was to create a clock that reflected a person's time to death, rather than merely the number of years lived.

A younger age, based on this test, tended to associate with a variety of lifestyle factors, including high income and a diet rich in fruits and vegetables. An older age score was associated with factors such as cigarette smoking or the risk of heart disease, among other ailments.

Moffat and her colleagues took this a step further, returning to the same study participants every few years to collect a fresh round of health data. This allowed them to create an epigenetic test that assessed the rate at which age takes its toll on the body, rather than one static number. It's capturing the slow, gradual progression of biological decline, Moffat says.

The biology underlying these tests, however, remains a puzzle. There is no clear mechanism that links the patterns of methylation measured in the tests with changes in a person's health. The patterns are simply correlations fished out from large datasets, with no obvious cause. Why did the methylation go up, and what went wrong? asks Horvath. What does it mean? Other kinds of tests can provide a clearer link to mechanisms.

Those that measure changes in the abundance of certain proteins or in the chemical products of metabolism allow researchers to draw conclusions about what triggered the change. This is why I chose metabolomics, says Alina Slagbaum, a molecular epidemiologist at Leiden University Medical Center in the Netherlands, referring to tests that try to survey all of the metabolites in an organism or tissue.

When we have a marker, we also understand a little about why it is important. Is it an inflammation marker? A lipid marker? Is it related to glucose? She says. Slagbaum and her colleagues created a test called MetaboHealth, which is based on 14 metabolites found in the blood that correlate with the likelihood of death from disease.

Others have turned to tests based on proteins. A team led by UK researchers developed one using data from more than 45,000 people that measures the levels of around 200 proteins in blood. For now, however, some researchers are foregoing molecular biomarkers in their clinical trials.

Therapies, interventions, or lifestyle changes aimed at extending a person's healthy lifespan must come with a measurable benefit, says Jamie Justice, a gerontologist in Grand Junction, Colorado, who is executive vice president of health at the XPRIZE Foundation in Culver City, California.

Quote, when we talk about that benefit, we're talking about the way that a person functions, feels or survives, end quote. Not simply the chemical composition of their DNA, she says. Experimental therapies tested in the XPRIZE HealthSpan program will not be evaluated on the basis of epigenetic tests. Instead, the competition will focus on factors such as muscle strength and cognition, as well as assays for immune function.

The prize will be structured so that teams gather data and samples in a standardized way. Justice also hopes to raise funds for a competition in which teams develop and test other biomarkers using those data. "I love biomarkers," she says. "I love them and I hate them because I know how hard it is to actually get one developed."

Researchers sometimes recoil when they learn just how much work it takes to vet a biomarker fully so it can be used in clinical trials, says Maddy Mockery, a computational biologist at Harvard Medical School in Boston, Massachusetts. Such tests must be studied repeatedly in a variety of populations and under the specific conditions in which they will be used in the clinic.

A biomarker of ageing that is based on data from people in their 40s and 50s, for example, might have little relevance to a frail 80-year-old who has multiple health conditions, says Slagba. We have a tendency to try to sell how valuable our marker is, she says. But valuable for which purpose?

The hype surrounding ageing research has also created a false impression of how well-tested the markers have been in different populations or in different settings, says Mockery. Although epigenetic clock markers have been used in a vast range of studies, they typically have not been sufficiently validated for use as primary outcomes in clinical trials, he says.

Even those who are running clinical trials, they think that these biomarkers are more advanced than they actually are, he says. There is also disagreement in the field about what the clocks really measure. Despite frequent references to biological age in both the media and scientific articles, a 2024 study found little agreement in the community as to what the term means.

In a survey of more than 100 participants at a scientific conference on ageing research, about 30% defined ageing as the loss of function that comes with time. Other definitions included the accumulation of damage with time, a developmental stage and an increase in disability and death. Defining biological age is a whole touchy subject in itself, says Marija Slauskas, a biostatistician at Leiden University Medical Centre.

The lack of consensus also complicates how studies involving epigenetic clocks are interpreted. One recent analysis tracked these markers in pregnant women and found that pregnancy had aged them by two years. After people had given birth, that apparent acceleration in aging seemed to reverse. Some participants in the study were younger, as judged by DNA methylation, after childbirth than when they were pregnant.

But what some describe as an acceleration and then deceleration in the rate of ageing, others could interpret as a transient response to the physiological stress of pregnancy, or as changes in the immune system that occur during it, says Keperlein.

Another study published last year analysed changes in a whole host of measures, including metabolites, proteins and microbes, in 108 people aged 25 to 75. The researchers found that molecular markers of ageing changed in a non-linear way, with bursts of change when people reached their mid-40s and when they hit 60.

Some news articles labelled these as periods of accelerated ageing, but the study authors say that this could be due to other factors, such as behavioural changes that are associated with those ages. Chen says that the relatively small number of people studied could also influence the results. It's hard to rule out the possibility that the 60-year-olds that were recruited didn't differ in other unique ways compared to the 40-year-olds, he says.

Reliability of the tests has also been a concern. A 2022 study found that six epigenetic clocks frequently used by researchers can yield variable results, with some varying by up to nine years even when the same samples were used. Researchers conducting large studies can account for variability in their experimental design and statistical analyses, but that's harder for individual consumers to do.

Kaeberlein says he recently tried out several consumer tests on himself and got mixed results. And although direct-to-consumer tests sometimes rely on well-characterised clocks, such as Moffat's, in the United States, many are not overseen by the Food and Drug Administration.

Despite that, some physicians are advising their patients to take the tests, says K. Berline. He has decided not to incorporate the tests into Optispan's clinical program. Researchers also worry that consumers run the risk of becoming overconfident in their health if an epigenetic clock result suggests that their biological age is younger than their chronological age.

Conversely, they might become discouraged and discontinue efforts to live a healthier lifestyle if the test suggests that they are ageing more rapidly than they should be, Kaeberlein says. True Diagnostics says that its tests aim to empower users rather than create false security or anxiety. We believe knowledge is power, says Ryan Smith, founder of the company.

This test is not diagnosing disease and we do not recommend any health interventions in our reporting. Chen has first-hand knowledge of how consumers react when they get an unwanted test result.

Before launching his laboratory at the University of California, San Francisco, he worked for a start-up company that was developing a commercial epigenetic aging clock targeted at the life insurance industry. Get a better score and one might get a better rate for insurance. In pilot studies, people who opted to take the test tended to be fitness enthusiasts who had invested significant time and money in their health, he says.

When they got a disappointing result, the reaction was always the same. They don't get sad or confused. They get angry, says Chen. They say your test is wrong. Life insurance companies also proved to be a hard sell. Knowing someone's age, sex, BMI and smoking status gets you a decent mortality prediction, says Chen. Biological age doesn't give you that much more bang for your buck, he says.

Chen decided to go back to academic research and has shifted his attention more towards trying to understand the biology of ageing, with the goal of building new markers from there. "Let's focus on the mechanism first, so that we know why it might cause ageing," he says. "I'm just trying to follow the breadcrumbs." As for Moffat, she is working on developing an ageing test that is based on brain scans.

And she has come to see the bright side of her work's moment in the Kardashian spotlight. The TV episode was a rare opportunity to inform the public about the science behind the test. Millions of followers of the Kardashians now know what DNA methylation is, she says. To read more of Nature's long-form journalism, head over to nature.com slash news.

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