The visible signs of ageing – wrinkles, greying hair, aching joints – are only the surface expression of something far more intricate happening inside our cells. Beneath the surface, every organ in the body undergoes its own subtle molecular transformation as we grow older.
Now, scientists have built the most comprehensive map yet of how that process unfolds.
Drawing on data from more than 15,000 samples, the findings, detailed in a preprint study awaiting peer review, offer an unprecedented view of how ageing rewrites our genome's operating manual from head to toe.
Researchers from around the world teamed up to create a sweeping ‘ageing atlas’ that charts DNA methylation – chemical tags that regulate gene activity – across 17 types of human tissue, tracking changes as we grow older.
“DNA methylation, very simply, is a chemical modification on your DNA,” Dr Jesse Poganik, an instructor in medicine at Harvard Medical School and one of the co-authors of the new study, told BBC Science Focus.
“At the very basic level, the main function is to control which genes get expressed and which don’t.”
Each of your cells has, essentially, the same genetic information in the form of your genome, barring any mutations here and there. How then does a lung cell know to be a lung cell, while a stomach cell behaves like a stomach cell? This is the role of methylation.
“Depending on the methylation or unmethylation status of particular points on the genome, the expression of particular genes is turned on or off,” Poganik said.
But what does all of this tell us about ageing?
DNA methylation is one of the body’s key epigenetic mechanisms – molecular switches that turn genes on or off without altering the DNA code itself. By attaching or removing small molecules called methyl groups, cells can fine-tune which genes are active in response to diet, exercise, infection and other environmental factors.
As the years pass, these methylation patterns shift in characteristic ways, forming the basis for so-called epigenetic clocks – molecular measures of biological age. Until now, most of those clocks have been based on blood samples, leaving scientists unsure whether other tissues follow the same rules.
“Those DNA methylation patterns are different between tissues – they’re tissue-specific, even cell-type-specific,” Prof Nir Eynon, senior author of the study and a research group leader at Monash University, told BBC Science Focus. “So measuring blood doesn’t necessarily reflect what’s happening in the liver, the muscle or the brain.”
That gap motivated the team to gather every publicly available dataset on methylation they could find, supplemented by new data from international collaborators.
The result: an analysis covering 17 organs, from the brain and heart to the skin, liver, stomach and retina, analysed at nearly a million points across the genome.
An atlas of ageing
The researchers found that the amount of the genome that has methylation tags varies widely between tissues – from about 38 per cent in the cervix to more than 60 per cent in the retina. Yet, the changes with age were remarkably consistent: most tissues showed a gradual shift towards hypermethylation as we age, where more DNA sites became tagged and certain genes switched off.
Two tissues, however, bucked the trend. Skeletal muscle and lung tissues lost methyl tags over time, potentially leading to overactive or unstable gene expression.
“Most tissues show more hypermethylation with age,” Dr Macsue Jacques, the study’s first author, told BBC Science Focus in an email. “But when you break it down to methylation fractions, you actually start to untangle tissue-specific patterns.”
For example, fat tissue shifts almost entirely toward hypermethylation, while in the brain, the changes are more balanced. These patterns, Jacques said, may reveal how different organs respond to shared ageing pressures such as inflammation.
Overall, the brain, liver and lung tissues exhibited the largest age-related methylation changes, though skin and colon also changed significantly. Pancreas, retina and prostate tissues, meanwhile, showed the fewest detectable age-associated changes, possibly reflecting limited data or greater resistance to ageing.
Correlation, not causation (for now)
At first glance, the data seem to suggest that some organs age faster than others. But the researchers cautioned that these differences can’t yet be interpreted as literal rates of ageing.
Part of the reason is statistical: some tissues were represented by thousands of samples, others by only a few dozen.
Another part is relational. “We know changes in methylation happen as a function of ageing,” Poganik said. “We do not know the extent to which they are causal to the ageing process.”
In other words, scientists know methylation changes as people age, but they don’t know whether those changes cause ageing or whether ageing causes those changes.
Poganik believes it's likely that the methylation changes are at least partly to blame for some of what we see in ageing. “Even a conservative scientist would tell you there’s some element of causality going on,” he said.
What makes this new atlas so compelling, he added, is the way it reveals a shared molecular theme running through the body.
“One of the most interesting things about this study is that it shows there’s some sort of universality to the ageing process. When we look across the different tissues, we find many of the same methylation changes, and that suggests there is something universal about the process."
Still, he cautioned that not every change is causal. With so many changes in methylation going on, it’s almost certain some are part of ageing, while others are inconsequential.
The ageing atlas may not tease out exactly which changes are important and which are not, but it does provide a treasure trove of data for scientists to explore that question in more detail than ever. The atlas is now freely available through an online portal for other scientists to access and use.
“We’ve always focused on open-source research,” Jacques said. “And with this, we want to not only advance research by making it available to all but also initiate collaborative efforts.”
Next, the team plans to look into some of the universal links they found stretching across all tissues with age, as well as looking at other biomarkers that may be influencing the ageing process.
“The progress that has been made in ageing pales in comparison to the progress that has been made in cancer,” Poganik said. With the help of this atlas, scientists may finally be closing the gap.
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