GDF11—Not So Fast

A research report from Novartis may temper our excitement about GDF11, which was a runner-up for Science Magazine’s 2014 Breakthrough Of the Year.

Bakground

“Heterochronic parabiosis” is the sanitized word for sewing together as Siamese twins two animals of the same species but different ages.  Modern implementation as a research technique was pioneered by Clive McCay in the 1950s, the same McCay who brought us caloric restriction in the 1930s.

The two animals share a common pool fo blood.  What is clear is that the older animal in the pair benefits from young blood.  Healing is improved, and some tissues are rejuvenated.  What is less clear:  what are the elements in the blood that are responsible for the rejuvenation?  Is there a “youth serum”, transferred from the young animal to the old; or in fact is there a blood factor responsible for deterioration, and the old animal is benefiting from dilution of his elder toxins?  Are there a few such blood factors, or too many to form the basis of a practical therapy?

In the last ten years, there has been a diaspora of researchers from the Stanford lab of Tom Rando, young researchers now at Berkeley and Harvard who are pursuing advanced techniques of blood transfer, seeking to isolate the active ingredients.  A consensus is emerging that

  • It is not the red or white blood cells, but dissolved proteins in the blood that make the difference.
  • There are both pro-aging and anti-aging factors in the blood.

The big questions remaining:

  • There are at least several factors of each kind, pro- and anti-aging.  Is the number of essential blood factors small and manageable, so we might hope to make a “bloody Mary” cocktail?  Or is the number so large this is impractical?
  • Will these blood factors reboot the body’s epigenetics so the old body starts producing the young mix itself?  How long must the body be exposed to the young mix before it starts to produce the young mix itself?

Last year in particular saw eye-popping results from the Berkeley lab of Irina and Mike Conboy, and from the Harvard lab of Amy Wagers.  The Conboys claimed that oxytocin is a blood factor promoting longevity.  [ref, my blog]  Wagers identified GDF11 as a blood factor that declines with age, and enhances strength and endurance when administered to muscle tissue in mice.  [ref, my blog]  In humans, GDF11 has been shown to increase nerve growth.

 

Cousins of GDF11

A rejuvenating role for GDF11 was a surprise because it is in the TGFβ class of hormones, which generally have negative effects on muscles.  In a 2013 blog, I identified TGFβ as one of the blood factors that we have too much of as we age.  Myostatin is the best-known member of this group, and it inhibits muscle growth.  Mice lacking the myostatin gene grow double-size muscles and have better insulin sensitivity.  Creatine is a myostatin inhibitor that is popular among muscle-builders.

Genes for GDF11 and for myostatin are 90% identical.  But mice lacking GDF11 don’t have bigger muscles, and in fact they die soon after birth.  So it’s possible that GDF11 is good and myostatin is bad.

 

The latest news

Last week, David Glass and a team at Novartis report that they have failed to reproduce Wagers’s results about GDF11.  From a Nature News report by Sara Reardon:

Glass and his colleagues set out to determine why GDF11 had this apparent effect.  First, they tested the antibodies and other reagents that Wagers’ group had used to measure GDF11 levels, and found that these chemicals could not distinguish between myostatin and GDF11. When the Novartis 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 Wagers’ group had found.

Glass’s team 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 Wagers and her team had used. Rather than regenerating the muscle, Glass found, GDF11 seemed to make the damage worse by inhibiting the muscles’ ability to repair themselves. He and his colleagues report their results on 19 May in Cell Metabolism.

Woops.  The Wagers results may prove to be an error, or it may be that the story is more nuanced.  It would not be surprising if there is such a thing as too little GDF11 and too much GDF11.

Wagers, however, stands by her findings. She says that although at first glance the Novartis group’s data seem to conflict with her team’s results, 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, she says. She adds that the Novartis group injured the muscle more extensively and then treated it with more GDF11 than her 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,” Wagers says.

Rando expects that researchers will now investigate the finding2 that GDF11 affects the growth of neurons and blood vessels in the brain. “I’m not sure which result is going to stand the test of time,” he says.

Two Unrelated Items of Interest

Life Extension magazine for June claims that fear of Testosterone has been unwarranted, that the benefits of T for strength and heart health do not come at a cost in increased cancer risk or decreased longevity.  (June edition is not yet on-line at LEF, but has been uploaded to Dropbox by a colleague here.)

Low endogenous bioavailable testosterone levels have been shown to be associated with higher rates of all cause and cardiovascular-related mortality…

Testosterone replacement therapy has also been shown to improve the homeostatic model of insulin resistance and hemoglobin A1c in diabetics and to lower the BMI in obese patients. These findings suggest that men with lower levels of endogenous testosterone may be at a higher risk of developing atherosclerosis.


Here is an intriguing news release from Yale about a protein found only in primates that is useful for making ordinary cells into stem cells.

 

18 thoughts on “GDF11—Not So Fast

  1. I know this is sure unscientific but when I keep reading of genes being turned on that speed aging it just seems like some one or thing has purposely altered us to be shorter lived, less muscular and even dumber that our true genetic structure could do if not inhibited by these proteins that show up later in our life’s that aren’t there when younger.

    • I was right there with you, until you said “when younger”.

      I mean, youngster can be pretty dumb.

      But I tell you whodunit.. Evolution did. The dumber you are, the less prone to philosophising and get suicidal over this hopeless existence you are.
      The dumber you are, the more anxious you are, the less prone to questioning your instincts or societal peer pressure you are, and thus heighten your probability of reproducing (probably marrying) and taking caring of your children, which will go the same path.

      Similar arguments can be made for the other traits, but they hinge on the individual not being smart enough to obviate them.

      • I definitely don’t support creationism but on the other side there are just to many holes to support Darwin evolution, the one trillion chances in one of some certain chemical combinations were needed to get where we are today. It still seems like something was involved with our creation and that doesn’t mean a god. It’s evident since we are already able to start modifying the genetic make up of many things, why wouldn’t a culture a little more advance that ours do better at it? A theory that should be considered if maybe we need to decode those alterations and eliminate the ones holding us back.

  2. I am skeptical about this youth cocktail. I think much more likely the young organism in parabiosis just adds extra cleaning up capacity to the old body. Dilutes all the garbage the SASP cells keep pumping out,

    • That logic is flawed considering rejuvenation is also seen using hpe plasma transfer as well as in true parabiosis. The two animals do not share biological “space” so blood factors obviously do work. One scientist has likely got it wrong but that does not mean factors in the blood do not regenerate, it just shows gdf11 is not the factor.

          • Hi Josh,
            thanks but it seems to be behind a paywall (and I am not a researcher with online journal access) also seems to be in Russian which I dont speak. From the abstract it also seems like its a review with only a proposal for new experiments.
            What I would like to read about is the actual plasma transfusion experiments done. I could as well do some search by myself, but I hope you or Steve can point me to the best papers as you are probably already familiar with these results.

          • Gabor –
            Thanks for your interest. I believe that there is just this one study by Wyss-Coray in mice last year, yet unconfirmed. There was a plan to replicate the experiment with humans last winter, and I don’t know if that has been published yet.
            – Josh

  3. From what I gather they are one shot AAVs that deliver a single payload to the cell and they are unable to spread and infect other cells. As far as I am aware and I have brought this up the AAV would permanently turn on the gene rather than create a transient effect. I believe that would be a bad idea and either transient or the ability to “toggle” the gene on or off would be a better approach. However we shall see what happens.

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