22 May 2015

GDF-11 out of trust

The molecule of "eternal youth" has put everyone at a dead end

Kirill Stasevich, "Science and Life" based on the materials of The Scientist: Studies Conflict on Regenerative Molecule.

We hear so often that we have discovered a memory protein, or a gene for eternal youth, or a molecule that kills cancer cells on the spot, that it may seem that in the very near future we will have a long healthy life – for everyone. However, the progress of mankind, driven by science, is still developing more slowly than we expect from it. One of the reasons for the inflated expectations is that the shadow side of experimental research rarely appears in popular scientific texts: all sorts of clarifications and refutations of the results that they wanted to double-check in other laboratories. Figuratively speaking, the general public does not hear the rumble and crash of collapsing hypotheses and theories.

A slice through the cardiac ventricle of a mouse: on the left — in a young individual, in the middle — in an old one,
on the right — the old one who received young blood. (Photo by Francesco Loffredo / Harvard Stem Cell Institute.)

A typical example is the recent history of a protein called tissue differentiation factor 11 (GDF–11). Not so long ago, it became another molecular "rejuvenating apple": experiments have shown that it can reverse some age-related changes. We discovered this in an amazing experiment when we combined the circulatory system of two mice, young and old. It turned out that young blood has a beneficial effect on the heart muscle. With age, the walls of the heart thicken, which has a bad effect on its work, and young blood, on the contrary, made the cardiac muscle walls thinner. When we tried to find out what kind of molecules can play a role here, we found 13 potential candidates, and among them – GDF-11. We checked – and it turned out that it itself has a rejuvenating effect on the heart muscle.

In addition, GDF-11 stimulated neurogenesis and the development of blood vessels in the brain in old mice, and also contributed to the restoration of the functionality of ordinary skeletal muscles. The data obtained confused many, because the picture turned out to be extremely contradictory. On the one hand, it was known that there is a lot of GDF-11 in young animals and very little in old ones. On the other hand, for a long time, its functions were known only that it controls the formation of olfactory receptors and receptors in the spinal cord. And finally, most importantly, back in 2009, David Glass, along with colleagues from the Institute of Biomedical Research, discovered that the same GDF-11 suppresses muscle growth. Then they were not surprised at this – since it is similar to the protein myostatin, which inhibits muscle differentiation, they expected about the same from GDF-11. I had to be surprised later when it turned out that in other people's experiments it shows absolutely opposite properties.  

And then the properties of GDF-11 decided to double-check again. The first thing we found out was that it has not been analyzed by a very specific method so far: firstly, it has two forms, monomeric and dimeric (when two molecules combine into one functional module), and secondly, as it was said, it is similar to myostatin. The immunological method used earlier did not distinguish GDF-11 monomers from dimers (and the "sticking" of their molecules together can affect the functions of proteins quite strongly), and even myostatin sometimes grabbed. Having developed a more accurate method of analysis, the researchers tested how the protein level changes with age. In mice, its level was generally too low to be reliable, but in rats and humans it was high enough – and it turned out that with age, the amount of GDF-11 certainly does not decrease, or even increases. When it was injected into old animals, no muscle regeneration occurred. Moreover, the muscles recovered even more slowly after damage – which is logical if we assume that GDF-11 suppresses rather than stimulates regeneration. The full results of the experiments are published in the journal Cell Metabolism (Egerman et al., GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration).

How can it be that the same molecule behaves so differently in different hands? The obvious answer is that some research group got the wrong results. But it is possible that both are right. So, Amy Wagers from Harvard, under whose leadership the work with young and old blood was carried out (after which everyone started talking about GDF-11 as a rejuvenation factor), says that it's all about different forms of protein, that some of its forms still decrease with by age. In addition, the Wager group and the Glass group used different methods to damage the muscles: some – cardiotoxin, others – strong cooling. And it may well be that the regenerating effect of GDF-11 depends on the etiology of damage.

Finally, in a certain sense, there is no contradiction between both works, since both of them talk about the optimal level of protein needed to maintain muscle functionality. It's just that some authors have shown that this level should not be lowered, and others that it should not be raised. And finally, the rejuvenating effect of young blood may not necessarily take place only because of GDF–11; we mentioned above that we managed to count as many as 13 potential candidates for "rejuvenating apples".

One way or another, the future of GDF-11 as a therapeutic agent that slows down aging remains in question. And here it becomes clear that the standard phrase about "further research", which such texts usually end with, is not just a rhetorical turn, but something that needs to be kept in mind when talking about the next phenomenal results and the speedy onset of a bright future. And yet – one can only be happy for scientists, because in the modern world science has remained almost the only area where the revision of results and the recognition of one's own mistakes is a routine routine procedure that continues to operate, despite all sorts of extra-scientific "interests".

Portal "Eternal youth" http://vechnayamolodost.ru 22.05.2015

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