Doubt Cast on GDF-11 Mechanism for Improved Health in Mice

The path of scientific discovery is never direct, and if something appears simple in an investigation of biochemistry then it is perhaps time to wonder what was missed and when the other shoe will drop. In the past couple of years researchers have demonstrated improved health in aged mice through reactivation of stem cell activity via increased levels of GDF-11. The situation may well be more complex than first thought, however, as a second group is having issues replicating the effect. This work calls into question present hypotheses on the nature of the underlying mechanisms exhibited in previous work on GDF-11, and points to the need for a better and more complete analysis of what is going on under the hood. The observed improvements to health seen in past studies are not yet disputed, but clearly something is missing:

In 2013, a team found that levels of a protein called GDF11 decreased in the blood of mice as they grew older. When the researchers injected the protein into the heart muscle of old mice, it became 'younger' - thinner and better able to pump blood. Two subsequent studies found that GDF11 boosted the growth of new blood vessels and neurons in the brain and spurred stem cells to regenerate skeletal muscle at the sites of injuries. Those results quickly made GDF11 the leading explanation for the rejuvenating effects of transfusing young blood into old animals. But that idea was confusing to many because GDF11 is very similar to the protein myostatin, which prevents muscle stem cells from differentiating into mature muscle - the opposite effect to that seen.

Researchers set out to determine why GDF11 had this apparent effect. First, they tested the antibodies and other reagents used to measure GDF11 levels, and found that these chemicals could not distinguish between myostatin and GDF11. When the team used a more specific reagent to measure GDF11 levels in the blood of both rats and humans, they found that GDF11 levels actually increased with age - just as levels of myostatin do. That contradicts what the former group had found. The researchers next used a combination of chemicals to injure a mouse's skeletal muscles, and then regularly injected the animal with three times as much GDF11 as the former team had used. Rather than regenerating the muscle, GDF11 seemed to make the damage worse by inhibiting the muscles' ability to repair themselves.

Researchers suggest that there could be multiple forms of GDF11 and that perhaps only one decreases with age. Both papers suggest that having either too much or too little GDF11 could be harmful. The more recent research group injured the muscle more extensively and then treated it with more GDF11 than the former group had done, so the results may not be directly comparable. "We look forward to addressing the differences in the studies with additional data very soon."



The fact that GDF-11 is a Myostatin and that they generally prevent muscle rejuvenation rings alarm bells for me. Also considering that a recent test of a gene therapy for Beckers MD at Nationwide Childrens Hospital inhinited Myostatin on the same pathway and it rejuvenated makes me think GDF-11 is not the factor that was doing the rejuvenating and they got the wrong factor from the dozen or so they assayed and compared.

I recall at the time Wagers mention that they chose GDF-11 partly due to cost as well as it appearing in both young and old. It makes me think the rejuvenation factor or factors were in fact others on that common assay list.

If GDF-11 rises with age that for me is a red flag as gene expression generally increases with age as Telomeres shorten and cease silencing increasing numbers of genes as they shorten. So if GDF-11 rises it suggests to me it is bad or at the very least plays some other role and is not for muscle regeneration. I think it is something that increases with age and it is bad personally.

We will know soon enough as it will be investigated but I think they have got the wrong factor and it is something else in the plasma that is doing it. Adrogens for example have been demonstrated of being capable of restoring Telomeres in certain cells so it could be those or something similar that are restoring Telomeres which in turn is rejuvenating the muscle tissue. Telomerase has been shown to do this so it isnt out of the realms of possibilty.

In any event these are not the droids (factors) we are looking for... move along :)

Posted by: Steve H at May 20th, 2015 9:31 AM

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