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Aging through the epitranscriptomic lens

Nature Aging published the work of the well-known Rochelle Baffenstein. In which she draws attention to a very little explored area in the fight against aging – the epitranscriptome. It’s called “Aging Through the Epitranscriptomic Lens”. Read to the end, at the end about business.


What do we know about the epitranscriptome today?

Most people who are interested in the biology of aging have heard of epigenetics. On DNA methylation, the Horvath clock, and epigenetic rollback. With all this, many associate hopes for the rejuvenation of the body. Even there are already several startups in America.

But it’s not all thank God. Everything is more difficult.

In addition to the epigenome, there is also an epitranscriptome – that is, a biochemical modification of RNA bases. Which, of course, plays a significant role in the functioning of the body. But it seems like it can be adjusted and can be useful to us in the fight against aging.

To date, more than 100 types of chemical modifications have been identified in RNA molecules. Of these, the most common modification of RNA is the methylation of adenosine, N 6-methyladenosine (m6A is methylation at the nitrogen atom in the sixth position).

Such methylation is dynamic; it is established, removed, and recognized by methyltransferases, demethylases, and readers, respectively.

This modification has been found in many eukaryotes, from plants to mammals, as well as in viruses.

The processes that are regulated by this DNA methylation are quite an impressive list.

First, it is the regulation of gene expression. Modification of m6A RNA regulates gene expression, affecting splicing, translation, stability, and localization of mRNA.

The second main direction of participation of RNA methylation is the development of the organism. Research shows that m6A modification is essential for normal embryonic development.

In addition, m6A is involved in various physiological processes such as stem cell self-renewal and differentiation, lipid metabolism, glucose metabolism, DNA damage repair, control of response to heat shock, and circadian rhythm.

In addition, modification of the m6A cRNA converts this RNA from a non-coding to a protein-coding one. Also, such a modification of the circular RNA “marks”1 them so that the innate immune system considers them “own”.

And we have already given  a lot of material about circular RNA .

Characteristically, the obesity-associated FTO protein (carriers of some variants of this gene are significantly at increased risk of obesity and diabetes) acts as a demethylase (that is, removes) methylated RNA.

Studies have shown that m6A RNA modification is most closely associated with the development of the nervous system2, memory formation3, and the occurrence of neurological, metabolic4, reproductive5, onco- and cardiovascular6 pathologies.

In addition, a very recent 2021 study7 showed that L1 retrotransposons use the m6A RNA modification system for their successful replication.

It should be noted here that, like transposons, m6A RNA modification actively occurs during various viral infections (such as HIV, influenza, herpesviruses, etc.). Moreover, modifications of m6A during viral infections can be either proviral or antiviral.

As this year’s study showed8, during infection with coronavirus, m6A can be modified by the host methyltransferase METTL3. which reduces the viral load.

As R. Buffenstein et al. write in their recent paper, the9 age change in the epitranscriptome, covering more than 150 chemically different post-transcriptional modifications and editing events, requires investigation as an important modulator of aging.

Because the epitranscriptome acts as a key regulator of RNA function, a variety of cellular processes, and tissue regenerative capacity. And an accurate description of epitranscriptome changes in the context of aging, despite being an unexplored area of ​​research, can add a lot of unknown to us. And to help define therapeutic targets to combat aging and age-related diseases.

Now a question, cats. Who will create the epitranscriptomic aging clock? Investments of a million for three dollars, an estimate of $70 million in the next round of investments. I can’t guarantee anything like that, but I study biotech a lot - they have something like this in Boston.
Misha Batin

Image by Matt Gondek (USA) just for fun

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  1. Chen, Y. G., Chen, R., Ahmad, S., Verma, R., Kasturi, S. P., Amaya, L., Broughton, J. P., Kim, J., Cadena, C., Pulendran, B., Hur, S., & Chang, H. Y. (2019). N6-Methyladenosine Modification Controls Circular RNA Immunity. Molecular cell, 76(1), 96–109.e9. https://doi.org/10.1016/j.molcel.2019.07.016[]
  2. Du, K., Zhang, L., Lee, T., & Sun, T. (2019). m6A RNA Methylation Controls Neural Development and Is Involved in Human Diseases. Molecular neurobiology, 56(3), 1596–1606. https://doi.org/10.1007/s12035-018-1138-1[]
  3. Leonetti , AM , Chu , MY , Ramnaraign , FO , Holm , S. , & Walters , BJ (2020). An Emerging Role of m6A in Memory: A Case for Translational Priming. International Journal of Molecular Sciences, 21(20), 7447. https://doi.org/10.3390/ijms21207447[]
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  5. Ivanova, I., Much, C., Di Giacomo, M., Azzi, C., Morgan, M., Moreira, P. N., Monahan, J., Carrieri, C., Enright, A. J., & O’Carroll, D. (2017). The RNA m6A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence. Molecular cell, 67(6), 1059–1067.e4. https://doi.org/10.1016/j.molcel.2017.08.003[]
  6. Qin, Y., Li, L., Luo, E., Hou, J., Yan, G., Wang, D., Qiao, Y., & Tang, C. (2020). Role of m6A RNA methylation in cardiovascular disease (Review). International journal of molecular medicine, 46(6), 1958–1972. https://doi.org/10.3892/ijmm.2020.4746[]
  7. Hwang, S. Y., Jung, H., Mun, S., Lee, S., Park, K., Baek, S. C., Moon, H. C., Kim, H., Kim, B., Choi, Y., Go, Y. H., Tang, W., Choi, J., Choi, J. K., Cha, H. J., Park, H. Y., Liang, P., Kim, V. N., Han, K., & Ahn, K. (2021). L1 retrotransposons exploit RNA m6A modification as an evolutionary driving force. Nature communications, 12(1), 880. https://doi.org/10.1038/s41467-021-21197-1[]
  8. Zhang, T., Yang, Y., Xiang, Z., Gao, C. C., Wang, W., Wang, C., Xiao, X., Wang, X., Qiu, W. N., Li, W. J., Ren, L., Li, M., Zhao, Y. L., Chen, Y. S., Wang, J., & Yang, Y. G. (2021). N6-methyladenosine regulates RNA abundance of SARS-CoV-2. Cell discovery, 7(1), 7. https://doi.org/10.1038/s41421-020-00241-2[]
  9. McMahon, M., Forester, C., & Buffenstein, R. (2021). Aging through an epitranscriptomic lens. Nature Aging, 1(4), 335-346. https://doi.org/10.1038/s43587-021-00058-y[]