LUMC study questions the interpretation of popular ageing tests

DNA age

To appreciate the significance of these findings, it is important to understand how these ageing tests work.

Human DNA contains millions of epigenetic markers, chemical modifications that help regulate gene activity. Biological ageing tests analyse patterns of these markers to estimate an individual's DNA age. Although DNA age often closely corresponds to chronological age, the two do not always match. For example, one 60-year-old may have a DNA age of 65, while another individual of the same chronological age may have a DNA age of 55.

These differences are not solely driven by the passage of time. Epigenetic patterns are influenced by a wide range of environmental, lifestyle, and health related factors, including smoking, obesity, psychological stress, insufficient sleep, and chronic disease. Positive factors such as regular physical activity, a healthy diet, and other beneficial lifestyle habits can also affect these patterns.

As a result, individuals of the same chronological age may differ in their health status, physiological condition, and DNA age.

The immune system as a measure of ageing

But how can researchers determine whether a higher DNA age truly reflects faster biological ageing? To answer this question, the LUMC researchers looked at changes in the immune system, which have long been recognised as a key feature of ageing.

One of the best known characteristics of immune ageing is a shift in the balance between two types of T cells in the blood. Younger individuals typically have relatively high numbers of naive T cells, immune cells that have not yet encountered many pathogens. As people age, the number of these cells declines, while the number of memory T cells increases. Memory T cells are formed after exposure to pathogens and retain information about previous infections, allowing the immune system to respond more rapidly when the same pathogen is encountered again.

The new LUMC study showed that the shift from naïve to memory T cells serves as a reliable marker of both chronological age and DNA age.

Unexpected result

Commercial ageing tests assume that people age faster when their DNA age is higher than their chronological age. Conversely, a lower DNA age is often interpreted as a sign of slower ageing. The researchers wanted to determine whether this assumption is valid.

"If the difference between DNA age and chronological age truly reflects the rate of ageing, you would expect people who are ageing faster to show more signs of an older immune system. In other words, they should have more memory T cells and fewer naïve T cells," says Professor Bas Heijmans, who led the research.

"But that was not what we found," says Thomas Jonkman, first author of the study. "In fact, the difference between DNA age and chronological age was largely associated with the amount of another type of immune cell, the neutrophil, which does not change with age. For us, this is an important indication that the calculation of DNA age minus chronological age measures something other than just the rate at which a person ages."

A loose shoelace during a long hike

"Think of ageing as going on a long, arduous hike," says Heijmans. "The farther you walk, the more tired you become and the more aches and pains you develop. That mirrors the changes we see in the immune system as people age, such as the shift from naïve T cells to memory T cells."

"Other factors, such as lifestyle or innate biological differences, can influence a person's risk of developing disease. Think of these factors as a loose shoelace during the march. Whether your shoelace comes undone, has nothing to do with becoming more tired during the hike. But you could trip, and then you would have a problem anyway."

"That is exactly why we think that a higher DNA age does not automatically mean faster ageing," Jonkman explains. "People whose ageing test indicates a higher DNA age do, on average, have an increased risk of health problems. However, that risk does not appear to be driven by the processes that cause the body to age over time."

Implications for commercial ageing tests

The findings of this study also have implications for the growing market of commercial ageing tests. Providers claim that these tests can measure a person's ‘real’ age.

According to the researchers, these claims are not scientifically supported. "It is unlikely that these tests measure the rate at which the body ages biologically. Moreover, they are not accurate enough to be used at the level of individual people. If the test result indicates that someone's body is five years older than their chronological age, that person is likely to worry unnecessarily or worry about the wrong thing. For example, the high score may be the result of smoking rather than accelerated ageing," Heijmans says.

The opposite can be equally problematic, as it may give people a false sense of reassurance. "The American tech billionaire Bryan Johnson spends millions of dollars on himself every year in an effort to, as he puts it, 'defeat death'," Heijmans says. "According to these tests, he has become biologically five years younger than his chronological age, which is presented as evidence that his approach is working. Yet, he was recently diagnosed with an incurable autoimmune disease, in addition to the autoimmune condition he has lived with since he was 21. This example illustrates how complex human health and ageing are, and why commercial ageing tests are simply not good enough to draw meaningful conclusions about either one of them."

This does not mean that insights derived from DNA age are without value. Quite the contrary. The study shows that the chemical markers on our DNA contain important information about the state of our bodies. However, how this information can be reliably used in the future remains one of the key questions.

Heijmans: "There is a tremendous amount of information about health and ageing hidden in the chemical markers on our DNA. We have seen the smoke. Now, we need to find the fire."

More information

This research is part of the Medical Genomics and Lifecourse research themes.

How does a DNA age test work?

Every cell in your body contains the same DNA. You can think of DNA as a huge cookbook containing tens of thousands of recipes. Those recipes are your genes. Although every cell has the same cookbook, not every cell uses the same recipes. A muscle cell, for example, needs different recipes than an immune cell. And a recipe does not always have to be used to the same extent. When cooking for two people, you use fewer ingredients than when cooking for ten.

Our cells contain a control system that determines which recipes are used and to what extent. This control system is known as epigenetics. It determines which genes are active and how active they are. One important epigenetic mechanism is DNA methylation. These are small chemical markers on the DNA that act like dimmer switches, determining whether a gene is used and how much of it is used.

As we age, the text of the cookbook changes very little. What does change are these chemical markers. As a result, some genes become more active, while others are expressed at lower levels. These changes follow recognisable patterns. Researchers have been studying those patterns for many years. This research has led to the development of epigenetic clocks.

"An epigenetic clock looks at hundreds of methylation markers at the same time and uses them to calculate a person's DNA age," says Professor Bas Heijmans. The fact that these clocks work well is illustrated by several examples. In forensic investigations, they can be used to estimate the age of an unknown individual. Even more remarkably, some clocks calculate a negative age for babies born prematurely.