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.

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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.