Linking RAGE, DNA Damage, Cellular Senescence, and Reversible Fibrosis

Researchers here find that loss of RAGE in mice produces accelerated fibrosis that is reversible if RAGE is restored. It is a little early in this line of research to be enthused by it; I think that all that is being shown here is that fibrosis is principle reversible, though this is interesting enough to merit comment in and of itself. It is frequently the case that a form of accelerated disease progression has little relevance to the biochemistry of the real thing. Acceleration usually takes the form of one aspect of the disease progress being exaggerated out of proportion, and that aspect may well not play a significant role in comparison to the other aspects of its biochemistry.

This research is also of interest because RAGE, the receptor for advanced glycation end-products (AGEs), is implicated in age-related inflammation. AGEs come in a variety of types, and readers here are probably more familiar with the persistent glucosepane AGEs that form cross-links in tissue, damaging structural properties and function. There are a whole range of other types of AGEs that are more transient, more dependent on diet, and which cause issues via their interaction with RAGE. The better known activities of RAGE are unrelated to the focus in this paper, however.

Like many proteins, RAGE has more than one job, and those jobs have little relation to one another. Of relevance here, RAGE is vital to DNA repair, and so loss of RAGE produces greater levels of cell dysfunction and cellular senescence, and that in turn leads to fibrosis. The link between cellular senescence and fibrosis is becoming fairly well established at this point: the signaling produced by these cells causes disarray in regenerative processes, and that in turn results in the scarring of fibrosis instead of functional tissue structure. Does restoration of RAGE as shown in this paper perhaps allow senescent cells sufficient self-control to destroy themselves? If so, this work, showing reversal of fibrosis, would be promising support for senolytic therapies, those capable of clearing senescent cells, to be a treatment for fibrosis. Still, as I said, it is way too early to be excited; too many questions remain to be answered.

The endogenous protein RAGE, which has usually been negatively associated with chronic inflammation and diabetic complications, plays a major role in the repair of DNA damage - and also appears to heal tissue damaged as a result of accelerated cell senescence. Researchers discovered the potential therapeutic benefit of the protein in mice that are unable to produce RAGE. As a result of the limited DNA repair, they develop pronounced pulmonary fibrosis, i.e. scarring in the lungs. After treatment with the protein, the scarring healed. "This is astonishing in that fibrosis has so far been considered irreversible. With RAGE, we could for the first time have found a possible starting point to cure this frequent tissue damage. Many questions - e. g. how this healing works in detail - are still unanswered."

RAGE (Receptor of Advanced Glycation Endproducts) is well known in medical research. The protein plays a decisive role not only in diabetes but also in chronic and excessive inflammatory reactions such as atherosclerosis and sepsis, but also in Alzheimer's disease and cancer development. The protein is mainly active on the surfaces of tissue cells and cells of the immune system. On the other hand, inside the cells, to be more precise in the cell nucleus, RAGE shows a completely different side of itself: Here it is responsible for the error-free repair of severe DNA damage, known as double-strand breaks. In these cases of damage, the two interconnected and twisted strands of DNA are completely cut off. Without immediate repair, the cell would quickly perish.

Mice that are unable to form RAGE due to a genetic defect will develop pulmonary fibrosis. The lungs are particularly susceptible to tissue damage, as they are in constant contact with the outside world through the air they breathe and are particularly exposed to environmental influences. In the animal model, the researchers succeeded in elucidating the hitherto unknown molecular mechanism of DNA repair under RAGE involvement and in identifying further important protagonists. If they introduced RAGE into the mice's lungs with the help of modified viruses, it was not only DNA repair that normalized: To the scientists' surprise, the scarred tissue regenerated and regained some of its functionality.

Link: https://www.dzd-ev.de/en/press/press-releases/press-releases-2017/endogenous-protein-reverses-scarring-in-the-lungs/index.html

Comments

The sirtuin SIRT6 is found in the nucleus and repairs single-strand and double-strand DNA repair. Deficiencies in SIRT6 result in mutations, senescence and tissue fibrosis, or cancer. With age, SIRT6 activity declines, and more of these diseases result. Probably the main cause of this decline in activity is that there is not enough metabolically available energy to accomplish the repair of complex breaks like the double-strand DNA breaks.

Posted by: Biotechy at November 28th, 2017 8:58 AM

Not a surprising result. Tinkering with the AGE receptor seems like a waste of time to me.

Posted by: JohnD at November 28th, 2017 8:35 PM

The lungs are one of the areas in which cellular turnover is particularly fast, and hence pulmonary fibrosis is known as a telomere disease. Therefore it is not suprising that a loss of the ability to repair DNA damage would very quickly lead to increased cellular senescence and hence fibrosis. Given what we know of the importance of senescence in wound repair (where it is important to seal it off quickly, rather than to heal it back to its previous state), I wonder if it would be possible to upregulate DNA repair in specific areas of the skin to remove scarring?

Posted by: Mark at November 29th, 2017 3:48 AM

Could it be: if you have a lot of AGEs then RAGE will be downregulated and you'll get fibrosis, if you have few AGEs then RAGE will be upregulated and revert fibrosis?

Posted by: Alessandro at April 8th, 2019 12:41 AM

Nevermind, it looks like the explanation is that RAGE has a different role inside of cells, that of DNA repair.

Posted by: Alessandro at April 8th, 2019 12:46 AM

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