A new preprint on blood DNA methylation in over 7,500 people shows that aging preserves most connections between CpG marks and visibly reorganizes only a fraction of them
A new preprint on blood DNA methylation in over 7,500 people shows that aging preserves most connections between CpG marks and visibly reorganizes only a fraction of them
On September 18, researchers posted a preprint on DNA methylation in whole blood from more than 7,500 individuals aged 17 to 99. The study focuses on CpG sites, positions in DNA where chemical marks are attached; groups of such sites that typically change together are referred to by the authors as modules.
Methylation is usually studied one CpG site at a time: with age, the average level of a mark at a given site may rise or fall. The authors posed a different question: whether modules retain their coherence, that is, whether the connections among the sites within a module remain the same as a person ages. A connection between two sites can persist, weaken, or shift to a different configuration.
To address this, the researchers first removed the average age-related shift in methylation from the data. They then built a network of modules in the youngest age group, under 36 years old, and compared it with seven older age groups. This way the test captured specifically changes in connections between marks, rather than the already known age-related drift of individual sites.
The network contained 69 modules; 53 were kept for further analysis, because the largest ones were excluded on the grounds that they might reflect a general background of correlations rather than a specific connection. The first test gave the overall picture: for most modules, roughly 70%, the stability of connections did not change appreciably with age. The second, more stringent test, based on the percentage change in connectivity, identified the extreme cases within the same sample: 11 modules lost more than 5% of their connectivity from the youngest to the oldest age group, 19 remained stable, and a number of modules did not fall clearly into either category. Age-related changes in methylation are therefore distributed unevenly across the network: connections hold in most modules, while a subset undergoes pronounced reorganization.
Stable modules were more often located near promoters, regions at the beginning of a gene that initiate its transcription, and at sites of long-range spatial contacts between different regions of DNA. Changing modules more frequently fell in late-replicating and densely packed chromatin regions, the material into which DNA is packaged inside the cell nucleus.
The network-level question grew out of a 2023 study that compared similar methylation modules across 348 mammalian species with their biological traits. The new preprint carries this logic over to human aging: the resulting map shows which connections between marks travel through adult life together and which change configuration.