Aging and Retroviruses

  

BY DEREK LOWE

There are a lot of weird things about the human genome, and one of them is the amount of it that seems to be detritus from old viruses. I mentioned this as part of this post in 2021 - the idea is that ancient retroviruses have (over millions of years) taken the occasional opportunity to insert viral DNA sequences into the human germline, which is interesting in itself because we don’t know of any current retroviruses that do that in humans. We are still carrying this stuff around, and by that I mean carrying between five and ten per cent of our entire genomes. A lot of it has deteriorated with time, accumulating mutations of various kinds, but some of these things can still be translated into RNA, and some of those can still be transcribed into proteins. And since we know that both proteins and RNA species can have numerous activities in the cell, and we also know that functional genes can emerge from previously nonfunctional RNA sequences. . .well, it makes these things worth keeping an eye on.

It’s already known that these endogenous retrovirus sequences have influenced the evolution of the human immune system and can be involved in some forms of cancer as well. in this new paper, that list grows to include aging in general. That builds on recent work showing that another form of viral debris, LINE1 sequences (which were mentioned in the 2021 blog post linked above), seem to be involved in cellular senescence. There were reports about ten years ago that these genetic elements became more actives in senescent cells, and that’s starting to look prescient. The new culprit described here is HERV-K, which is probably the most recently integrated retrovirus in humans, and (surely not by coincidence) one of the most transcriptionally active as well.

The paper shows that HERVK envelope proteins (and their associated mRNAs) are detectable at greater and greater levels as cells age, and that this relationship holds in rodents and primates (by cell, tissue, and serum assays), and even in tissue and serum from aged human donors. They even say that they are able to detect entire retrovirus-like-particles (RVLPs) in the cytoplasm of aged cells. The claim is that increased expression of these things actually helps drive cellular senescence, and this is demonstrated in two directions. Deliberately increasing the expression of these proteins does seem to lead to senescence in cell culture (as compared to controls), and exposing cells to extracellular levels of them does as well. This effect could be reversed by treatment with an anti-HERVK-envelope-protein antibody.

These retroviral proteins set off a constant immune response, which ties in with the general observation that nonstop inflammation is a characteristic of aging in many tissues. The paper extends the connection in vivo by looking at a similar mouse retrovirus (MMRV). It’s found to be expressed at greater levels in degenerating joint tissues, and this phenotype could be alleviated by siRNA knockdown. Taken together, the proposal is that retroviral proteins (HERVK envelope in particular, and likely others?) are being reactivated as cells age, that this is directly responsible for some parts of the aging phenotype, and that this presents an opportunity for therapeutic intervention.

A lot of this story has not been filled out yet, but this very much looks like it’s worth investigating. It would be particularly interesting to see what happens when you target these proteins in aged rodents or primates, perhaps through antibody treatment or through genetic modifications as a proof-of-concept. You’d also want to try treating them before they show signs of aging to see how that progresses. My own guess - and that’s all it is - is that this is all still secondary to aging itself (i.e., I don’t think we get old just because of retroviruses). But it’s certainly possible that the underlying aging phenotype is being exacerbated, perhaps greatly, by this route, and that we could alleviate things by targeting it. Let’s find out!

https://www.science.org/content/blog-post/aging-and-retroviruses