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A race against the ageing clock
A race against the ageing clock
About the study
- Ageing in humans and animals is a process that is still very poorly understood.
- Researchers identified a mouse epigenetic ageing clock, a tool that can accurately predict the age of individuals.
- Future research could use the mouse epigenetic clock to gain better insight into ageing and what can speed up or slow down the process.
Researchers at the European Bioinformatics Institute (EMBL-EBI) and the Babraham Institute in Cambridge have identified an accurate mouse epigenetic clock that uses DNA methylation to accurately estimate an animal’s age. Published in Genome Biology, the study confirmed that lifestyle interventions known to shorten lifespan also accelerated the clock, underscoring its effectiveness. The mouse epigenetic clock can be used to better understanding how ageing works and what interventions could accelerate or delay the process.
Building on the human clock
DNA methylation is a process that alters how DNA is read and expressed, without changing the underlying DNA sequence. In 2013, research by Steve Horvath showed that changes in DNA methylation at distinct sites in the human genome can be used to predict both the chronological and biological ages of an individual. The two ages are distinctly different: your chronological age is a measure of how long you have been alive, whereas your biological age is a measure of how well your body functions. The human epigenetic clock proposed by Horvath is accurate to within around three and a half years, making it by far the best biomarker of age available.
However, more precise tools are needed to answer a burning question in ageing research: Do DNA methylation changes cause the ageing process, or are they a consequence of it? To explore how these epigenetic changes affect biological clockwork, researchers on today's study developed a new tool: the mouse epigenetic clock.
What is an epigenetic clock?
An epigenetic clock works by measuring DNA methylation levels in different sites across the genome. DNA methylation is a process by which methyl groups are added to the DNA molecule, which can modify the function of a gene without changing its underlying DNA sequence. DNA methylation is essential for the healthy growth and development of cells.
Epigenetic clocks can be used to estimate the biological age of a tissue, cell type or organ. The most well-known example is Horvath’s epigenetic clock, publicised in a 2013 paper in Genome Biology.
By comparing 'DNA methylation age' (biological age) with chronological age in different tissues, scientists can gain insights into how ageing works, the factors that influence the speed of the process, and how ageing is linked to cancer, obesity, Alzheimer’s disease and many other conditions.
An epigenetic clock for mouse studies helps researchers probe the underlying biology of ageing, which differs not only between individuals but between different organs within an individual.
Accurate age predictor
“The mouse epigenetic clock will be instrumental for understanding how ageing works and what kind of changes speed up or slow down the process,” explains Oliver Stegle, Group Leader at EMBL-EBI. “Bioinformatics has allowed us to create an extremely accurate model, which we can compare to other epigenetic clocks, including the human one, and draw conclusions about how mammals age.”
Today's study shows that changes in DNA methylation at 329 sites in the genome can predict a mouse’s age with an accuracy of around 3.3 weeks - similar in accuracy to the human model.
Slowing down the clock
Using the mouse model, researchers showed that lifestyle interventions known to shorten lifespan sped up the clock. For example, removing the ovaries in female mice accelerated the clock. A high fat diet, which we know is detrimental to human health, also accelerated the mouse ageing clock.
Remarkably, researchers were able to detect changes to the epigenetic clock in mice as young as three weeks old.
“Dissecting the mechanism of this mouse epigenetic ageing clock will yield valuable insights into the ageing process and how it can be manipulated in a human setting to improve health span,” adds Marc Jan Bonder, postdoctoral researcher at EMBL-EBI.
Further study will allow scientists to understand the inner mechanistic workings of such a clock and change its ticking rate in the mouse model. This will reveal whether the clock is causally involved in ageing, or whether it is a read-out of other underlying physiological processes. These studies will also suggest approaches to wind the ageing clock back to rejuvenate tissues or even a whole organism.
“It is fascinating to imagine how such a clock could be built from molecular components we know a lot about: the DNA methylation machinery. We can then make subtle changes in these components and see if our mice live shorter, or more interestingly, longer,” concluded Wolf Reik, Head of the Epigenetics Programme at the Babraham Institute and Associate Faculty member at the Sanger Institute. “Such studies may provide deeper mechanistic insights into the ageing process and whether lifespan in a species is in some way programmed.”
Stubbs TM, et al. (2017). Multi-tissue DNA methylation age predictor in mouse. Genome Biology. Published online 11 April; DOI: 10.1186/s13059-017-1203-5
Image credit: T. Stubbs, Babraham Institute