There aren’t many things in this world that we can be certain about, but aging marks an all too important exception. Towards the goal of understanding the marks of this unavoidable process, we’ve seen the epigenetic clock, which looks at CpG sites that are certainly differentially methylated as we age. However, a new perspective to interpret the sands of time has emerged and it takes advantage of the uncertainty in senescence by examining which CpG sites show variable differential methylation as we age.
This massive meta-analysis lead by the lab of Bastiaan Heijmans at the Leiden University Medical Center (the Netherlands) examined whole-blood CpG methylation profiles from 3295 people aged 18 to 88 using the 450K array. Here’s what they found:
- Of the 429,296 CpGs examined:
- 99,466 are age-related differentially methylated positions (aDMPs).
- 8,625 are age-related variably methylated positions (aVMPs).
- 321,565 are age-independent.
- To validate that their results weren’t confounded by the populations studied or alterations to cell-type composition, they compared their findings to large public data sets of whole-blood and purified monocytes, where 6,366 aVMPs (78.4 %) were validated in both and used for some in-depth analysis.
- Making use of the Epigenomics Roadmap, they found that aVMPs are depleted at active regions of the genome and enriched at polycomb-repressed regions.
- Taking advantage of matching RNA-seq gene expression profiles for most (2044) people, they compared the two and found:
- 1,988 aVMPs (31.2 %) are associated with gene expression of 1549 genes in cis, with those genes (e. Hox and clustered protocadherins) having functions related to neurodevelopment.
- 1816 aVMPs (28.5 %) are associated with the expression of 854 coding genes in trans. These regions are defined by either an age-related gain of methylation at CpG islands marked by PRC2 or a loss of methylation at enhancers.
- The trans-aVMP methylation pattern also extends to aging in other tissues and multiple cancer types.
- Genes associated with trans-aVMPs that are upregulated have functions related to DNA repair and apoptosis, while downregulated genes have functions related to cellular metabolism.
First author Roderick Slieker shares, “In cancer cells, we found changes in the regulation of the DNA at the same sites as if the differences occurring with ageing were a precursor of the disease. We therefore want to study whether a dysregulated DNA increases the risk of different forms of cancer and, conversely, a ‘youthful’ DNA is protective.”
Senior author Bastiaan Heijmans concludes, “Obviously, health depends on more than just the regulation of our DNA. But we do think that the dysregulation of the DNA is a fundamental process that could push the risk of different diseases in the wrong direction.”
Check out all the variation In Genome Biology, September 2016