Hidden minefield
In Aging Cell, a team of researchers has announced Retroelement-Age, a novel clock that focuses on the expression of buried pieces of DNA that are normally suppressed.
Corrupted but unexpressed
The natural human genome has a large number of artifacts left over from ancient viral infections along with pieces of DNA that transpose themselves into the genome. These human endogenous retroviruses (HERVs) and long interspersed nuclear elements (LINEs) make up a surprisingly large portion of the human genome [1].
Most of these retroelements are normally suppressed by epigenetics: the DNA is simply never translated into RNA, and so they lie dormant. However, epigenetic alterations can drive them out of dormancy, and this can have harmful consequences [2], some of which are related to further aging [3]. Because this epigenetic uncovering has harmful, age-related consequences, these researchers decided to build an epigenetic clock out of it.
A new model built on a new system
To begin building the first version of Retroelement-Age, the researchers used MethylationEPIC version 1.0, a standard methylation analysis platform, and then discovered that 10,917 epigenetic CpG sites were on HERVs and LINEs. Then, they pulled epigenetic data from a set of 12,670 people with ages ranging from 12 to 100. After cross-validation, the researchers’ elastic net algorithm determined that 1,317 of these CpG sites were useful in guessing chronological age with high accuracy.
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However, with the development of MethylationEPIC version 2.0, the researchers sought to create a clock that used this latest version with updated methylation information. This clock, which considered 1,378 CpG sites to be of use, was even stronger than the first version, which the researchers ascribe to the newer version of MethylationEPIC having more reliable probes [4]. These findings were additionally confirmed by entirely separate datasets involving blood cells.
Retroelement-Age Strength
There was no overlap at all between the CpG sites of Retroelement-Age and most previous clocks, including first-generation clocks such as Horvath and Hannum along with the later PhenoAge and GrimAge and the Dunedin Pace of Aging clock. The only commonalities were found between the second version of Retroelement-Age and nine CpG sites used in AdaptAge, CausAge, and DamAge, a trio of clocks built around sites that were found to be causal in aging [5].
Antiretroviral therapies, which are used in the treatment of HIV, were able to significantly reduce the Retroelement-Age of the treated groups. The researchers suggest that this is because these therapies also suppress HERVs. However, there was no trial undertaken to determine if antiretroviral therapies reduce Retroelement-Age in the absence of HIV.
Epigenetic reprogramming, a known method of rejuvenating the epigenetics of cells, was found to successfully rejuvenate fibroblasts as measured by both versions of Retroelement-Age, but this did not work in endothelial cells. The researchers concluded that responses to this reprogramming are cell-type specific.
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The researchers then concluded their paper with information on a multi-tissue version and a pan-mammalian version of their novel clock. Like with their original clock, the pan-mammalian version did not overlap with the sites used by any previous clocks.
Ultimately, this clock does more than just measure age: it identifies problems that are known to lead to age-related diseases. It is as of yet unclear whether it is feasible to develop approaches that can silence, or even permanently remove, dangerous elements in the genome.
Together, these findings support the hypothesis of dysregulation of endogenous retroelements as a potential contributor to the biological hallmarks of aging and suggest that therapeutic interventions modifying the epigenetic states of specific retroelements in the human genome could have beneficial effects against a root cause of aging and disease.
Literature
[1] Nurk, S., Koren, S., Rhie, A., Rautiainen, M., Bzikadze, A. V., Mikheenko, A., … & Phillippy, A. M. (2022). The complete sequence of a human genome. Science, 376(6588), 44-53.
[2] Dopkins, N., & Nixon, D. F. (2024). Activation of human endogenous retroviruses and its physiological consequences. Nature Reviews Molecular Cell Biology, 25(3), 212-222.
[3] Zhang, H., Li, J., Yu, Y., Ren, J., Liu, Q., Bao, Z., … & Liu, G. H. (2023). Nuclear lamina erosion-induced resurrection of endogenous retroviruses underlies neuronal aging. Cell reports, 42(6).
[4] Noguera-Castells, A., García-Prieto, C. A., Álvarez-Errico, D., & Esteller, M. (2023). Validation of the new EPIC DNA methylation microarray (900K EPIC v2) for high-throughput profiling of the human DNA methylome. Epigenetics, 18(1), 2185742.
[5] Ying, K., Liu, H., Tarkhov, A. E., Sadler, M. C., Lu, A. T., Moqri, M., … & Gladyshev, V. N. (2024). Causality-enriched epigenetic age uncouples damage and adaptation. Nature aging, 4(2), 231-246.
