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Retroviruses Contribute to the Spread of Cellular Senescence

Old cells can express long-dormant sequences.

Old DNAOld DNA
 

Scientists have found that the remnants of the ancient retrovirus family HERVK, which reside in our genome, are transcribed more frequently in aged cells. This is caused by cellular senescence and accelerates it, including in the neighboring cells, when those are infected by retroviral particles [1].

Hitchhiker’s guide to the genome

Retroviruses, such as HIV, propagate by inserting their DNA into the host’s genome, and they have been doing this since the dawn of life. At least 8% of the human genome has retroviral origins [2], indicating when retroviruses had managed to insert themselves into germline DNA to ensure their passage down the generations of hosts. Over eons, most of those chunks of retroviral DNA have accumulated disabling mutations. Their transcription is also impeded by heterochromatin tightening.

However, with time, heterochromatin becomes less organized. This leads to dysregulation of gene expression and to increased transcription of retrotransposons. The former is an accepted hallmark of aging, while the latter is a proposed one [3].

In this new study, scientists investigated the retrovirus family HERVK, which is thought to be the most recent retroviral addition to our genome [4]. HERVK still maintains sequences that encode proteins required for the formation of viral particles but cannot load them with viral DNA to propagate.

HERVK and senescence: a feedback loop

Since retrotransposons are known to be more active in senescent cells, the researchers used human mesenchymal progenitor cells (MPC) in which senescence had been induced by numerous divisions (replicative senescence). They found increased expression of several transposable elements, including HERVK proteins, compared to non-senescent cells.

The researchers also observed decreased methylation and levels of repressive histones in HERVK-related loci, indicating that the uptick in HERVK transcription was indeed caused by chromatin loosening. Moreover, the researchers detected the presence in cytoplasm of retrovirus-like particles (RVLP), which are basically empty virions that do not contain viral DNA. Similar findings were confirmed for human primary fibroblasts.

To elucidate the cause-effect relationship between HERVK and cellular senescence, the researchers induced HERVK transcription in otherwise healthy cells using a targeted CRISPR-based gene activation system. It turns out that HERVK is not only driven by senescence, it exacerbates it in a positive feedback loop. Conversely, silencing of HERVK transcription alleviates some symptoms of senescence.

One HERVK protein works as a reverse transcriptase, producing viral DNA from RNA transcripts. The researchers hypothesized that the resulting increase in cytoplasmic DNA would trigger immune response. Indeed, they discovered activation of the STING pathway, which facilitates immune reaction in response to cytoplasmic DNA sensing, and elevated levels of proinflammatory cytokines. Treating cells with Abacavir, a potent reverse transcriptase inhibitor, diminished HERVK DNA content and substantially reduced several senescence markers.

Viral invaders

RVLPs were also detected outside the senescent cells. Using electron microscopy, the researchers were able to observe viral-like particles exiting the cells they originated in. When young cells were treated with culture media collected from old cells, electron microscopy detected many RVLPs entering those young cells. Culture medium from senescent cells induced senescence in healthy cells, but using antibodies to neutralize RVLPs significantly alleviated this effect. Moreover, healthy cells infected with purified RVLPs also developed senescent phenotypes and increased immune response. This shows that RVLPs play a certain role in the cell-to-cell signaling that “broadcasts” cellular senescence.

Mice, of course, also have retroviral remnants in their genomes, with one called MMTV being a close analogue of HERVK. The researchers found that MMTV proteins were substantially upregulated in the cartilage of aged mice. Deactivating MMTV caused alleviation of some symptoms of cartilage aging. The treated mice showed increased cartilage thickness, bone density, and grip strength. Similar results were achieved with Abacavir treatment. Giving aged mice Abacavir injections into their joints or oral Abacavir administered in water seemed to work well.

Graphical abstract

HERVK

Conclusion

This study brings us one step closer to understanding how important derepressed retroviral elements are for cellular senescence and aging. If cellular senescence is indeed caused in part by our “genetic parasites” let loose, this opens the door to new anti-aging treatments, which the researchers essentially demonstrated by using an anti-viral medication.

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Literature

[1] Liu, X., Liu, Z., Wu, Z., Ren, J., Fan, Y., Sun, L., … & Liu, G. H. (2023). Resurrection of endogenous retroviruses during aging reinforces senescence. Cell.

[2] Johnson, W. E. (2019). Origins and evolutionary consequences of ancient endogenous retroviruses. Nature Reviews Microbiology, 17(6), 355-370.

[3] Gorbunova, V., Seluanov, A., Mita, P., McKerrow, W., Fenyö, D., Boeke, J. D., … & Sedivy, J. M. (2021). The role of retrotransposable elements in ageing and age-associated diseases. Nature, 596(7870), 43-53.

[4] Subramanian, R. P., Wildschutte, J. H., Russo, C., & Coffin, J. M. (2011). Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology, 8, 1-22.

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About the author
Arkadi Mazin

Arkadi Mazin

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span from politics to science and philosophy. Having studied economics and international relations, he is particularly interested in the social aspects of longevity and life extension. He strongly believes that life extension is an achievable and noble goal that has yet to take its rightful place on the very top of our civilization’s agenda – a situation he is eager to change.
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