Distinct Methylation May Explain Why Some People’s DNA Ages More Slowly


MedicalResearch.com Interview with:
Dr. Bastiaan Heijmans
Leiden University Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages.

In a large-scale analysis of the methylome of over 3000 individuals, we discovered and validated 6000 sites in the genome that became more variable in their DNA methylation level with age. These sites frequently co-localized with repressed regions that are characterized by polycomb repression. While sites accumulating variability with age were commonly associated with the expression of (neuro)developmental genes in cis, they were linked to transcriptional activity of genes in trans that have a key role in well-established ageing pathways such as intracellular metabolism, apoptosis, and DNA damage response.

MedicalResearch.com: What should readers take away from your report?

Response: Our results link age-related changes in DNA methylation to fundamental mechanisms that are thought to drive human ageing. In contrast to the well-established sites at which DNA methylation levels track chronological age, the sites we identified show a striking variability in DNA methylation at higher ages. Two individuals of the same age may display highly distinct methylation patterns across such sites, where one of them may have a DNA methylation profile that is similar to that of young individuals.

Therefore, these sites fulfill a primary prerequisite for a biomarker of biological age.

Finally, our study shows that large-scale integrative genomics studies are an effective approach toward the identification of fundamental processes involved in ageing and are complementary to experimental work in model organism

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: Not everyone in the study showed equal evidence of an age-related dysregulation of the DNA. Some elderly people had DNA that was regulated as if they were still 25 years old. In these individuals, genes characteristic of the ageing process were much less active. The next step will be to find out whether such people stay healthier for longer. 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.

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.

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Roderick C. Slieker, Maarten van Iterson, René Luijk, Marian Beekman, Daria V. Zhernakova, Matthijs H. Moed, Hailiang Mei, Michiel van Galen, Patrick Deelen, Marc Jan Bonder, Alexandra Zhernakova, André G. Uitterlinden, Ettje F. Tigchelaar, Coen D. A. Stehouwer, Casper G. Schalkwijk, Carla J. H. van der Kallen, Albert Hofman, Diana van Heemst, Eco J. de Geus, Jenny van Dongen, Joris Deelen, Leonard H. van den Berg, Joyce van Meurs, Rick Jansen, Peter A. C. ‘t Hoen, Lude Franke, Cisca Wijmenga, Jan H. Veldink, Morris A. Swertz, Marleen M. J. van Greevenbroek, Cornelia M. van Duijn, Dorret I. Boomsma, P. Eline Slagboom, Bastiaan T. Heijmans. Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms. Genome Biology, 2016; 17 (1)

DOI: 10.1186/s13059-016-1053-6

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