In a recent paper published in Cell, researchers from Harvard Medical School investigated if loss of epigenetic information was a cause of ageing.
To do this, they developed a mouse model that enabled the investigation of DNA damage mechanisms, particularly double strand breaks, without inducing additional mutations previously linked to ageing.
Mice that had induced DNA breaks showed a wide range of phenotypic changes usually associated with age, such as reduced muscle mass and cognitive function, and were suggested to have aged approximately 50% faster than control mice.
As well as physical markers of age, the group investigated epigenetic changes associated with accelerated ageing. They integrated genetic and DNA methylation sequencing data to identify DNA methylation sites linked to age and demonstrated that mice with induced DNA breaks had approximately 50% accelerated epigenetic ageing – their DNA methylation profiles corresponded to those of control mice that were 1.5x older.
The group investigated histone accessibility changes and showed that there was genome-wide erosion of epigenetic information and an increase in epigenetic entropy associated with accelerated ageing. The loss of epigenetic information interrupted processes important for cell development and cell identity. And, the team subsequently showed it was easier to reprogram DNA damage-induced cells into different cell types, suggesting DNA damage compromised cell identity. The histone accessibility changes, and the associated changes in other epigenetic systems, were correlated with the natural DNA repair mechanism. This suggests that the loss of epigenetic information and accelerated ageing may be a result of the cell’s natural response to DNA breaks.
Finally, accelerated epigenetic ageing in induced DNA damage mice was reversed using Yamanaka factors which reduced epigenetic age by up to 57% with age-related markers reverting to control levels.
This study suggests that natural repair of DNA damage can over time result in a loss of epigenetic information, including changes in DNA methylation profile, contributing to mammalian ageing.
The integration of genetic and epigenetic information is vital to fully understand processes of ageing. CEGX’s technology combines simultaneous genetic and epigenetic sequencing, providing unparalleled insight into interactions between them. This insight could reveal new ageing mechanisms, and how both internal and environmental factors contribute.
Yang JH, Hayano M, Griffin PT, Amorim JA, Bonkowski MS, Apostolides JK, Salfati EL, Blanchette M, Munding EM, Bhakta M, Chew YC, Guo W, Yang X, Maybury-Lewis S, Tian X, Ross JM, Coppotelli G, Meer MV, Rogers-Hammond R, Vera DL, Lu YR, Pippin JW, Creswell ML, Dou Z, Xu C, Mitchell SJ, Das A, O’Connell BL, Thakur S, Kane AE, Su Q, Mohri Y, Nishimura EK, Schaevitz L, Garg N, Balta AM, Rego MA, Gregory-Ksander M, Jakobs TC, Zhong L, Wakimoto H, El Andari J, Grimm D, Mostoslavsky R, Wagers AJ, Tsubota K, Bonasera SJ, Palmeira CM, Seidman JG, Seidman CE, Wolf NS, Kreiling JA, Sedivy JM, Murphy GF, Green RE, Garcia BA, Berger SL, Oberdoerffer P, Shankland SJ, Gladyshev VN, Ksander BR, Pfenning AR, Rajman LA, Sinclair DA. Loss of epigenetic information as a cause of mammalian ageing. Cell. 2023 Jan 19;186(2):305-326.e27. doi: 10.1016/j.cell.2022.12.027. Epub 2023 Jan 12. PMID: 36638792.