A study of how ageing reshapes human genes has produced the most comprehensive “epigenetic atlas” ever assembled, and it may point the way to new anti-ageing treatments.

An article published in the Nature analyzed more than 15,000 human tissue samples, mapping DNA methylation changes – chemical tags that regulate gene activity – across 17 types of organs. The findings suggest that ageing is not uniform throughout the body, with some tissues ageing faster than others, and reveal common genetic markers that could be targeted to slow age-related decline.

“The visible effects of ageing on our body are in part linked to invisible changes in gene activity,” the study notes. DNA methylation, an epigenetic process – the addition or removal of methyl groups – becomes less precise as we age,”  says the article. 

The result, the article adds, is changes to gene expression that are linked to reduced organ function and increased susceptibility to disease as people age.

“I think this is a great resource to understand ageing,” says Joao Pedro Magalhaes, a molecular biologist at the University of Birmingham, UK, quoted by the Nature. “This meta-analysis of methylation data across organs is, to my knowledge, the largest such resource assembled to date. I am sure that it will be valuable to researchers.”

The work, posted on the preprint server Research Square and not yet peer reviewed, provides “the clearest picture yet” of how DNA methylation evolves over the human lifespan.

“We had examples from people from 18 years old till 100 or so,” says Nir Eynon who led the research at Monash University in Melbourne, Australia. “So we can look at the epigenetic markers and how they change across the human lifespan.”

The study found that some organs accumulate ageing-related methylation changes more quickly than others. “The retina and stomach, for example, accumulate more ageing-related DNA methylation changes than do the cervix or skin,” the authors report. On average, methylation levels range widely: 35% in the cervix, 48% in skin, 51% in muscle, 53% in the heart, 57% in the stomach and as high as 63% in the retina.

Almost all tissues have increased DNA methylation as they age, says study co-author Macsue Jacques of Monash University. The exceptions, according to him, are skeletal muscle and lung, “which has more of a loss of methylation with age.”

The atlas also reveals that different organs follow distinct ageing patterns. “Each tissue has a different shift that happens,” Jacques explains.

Beyond organ-level differences, the team looked for shared ageing mechanisms. “We wanted to find a common ageing mechanism that goes across all the tissue types,” Jacques says. The researchers found several genes whose methylation changes appear to be universal markers of ageing, including HDAC4 and HOX, regulators linked to senescence, and MEST, which has been associated with diabetes and obesity, two known accelerators of ageing.

Perhaps most strikingly, they identified high methylation of the protocadherin gamma (PCDHG) gene family as a driver of the ageing process in multiple different organs. Previous studies have tied PCDHG hypermethylation to reduced white matter in the brain, a marker of accelerated cognitive decline.

“This epigenetic atlas might help researchers to study the link between DNA methylation and ageing and could aid the identification of molecular targets for anti-ageing treatments,” the article says. 

Also read: Aging not linear: Study finds human body ages faster after 50