Aging Protein Signature
Larry H Bernstein, MD, FCAP, Curator
LPBI
Anti-Aging Protein GDF11: Does it Work?
The protein is called GDF11 and some scientists claim that is can rejuvenate older laboratory animals and make them healthier. Sounds like science fiction, but could it be true?
Several decades ago, in the 1950s, some creative and enterprising scientists connected the circulatory systems of two inbred mice, one of which was old and the second of which was young. The blood from the young mouse seemed to rejuvenate the older mouse. That led to a question: “If blood from younger mouse rejuvenated the older mouse, what was it in the blood that did it?” Further work has landed on GDF11 as the rejuvenating protein, but the experimental path to this protein has been fraught with false starts, bumps, and wrong turns. New work by a team of Harvard University scientists hopes to set the record straight on GDF11.
Work by Harvard stem cell biologist Amy Wagers, cardiologist Richard Lee and the members of their laboratories and their collaborators have discovered that the blood concentrations of GDF11 drop in mice as they age. Such a finding is a correlation, which might be suggestive, but it fall short of proving that GDF11 is an anti-aging protein. However, Wagers and Lee and their colleagues also showed that when older mice are injected with GDF11, the protein partially reverses the thickening of the heart that comes with age. Wagers and her team also showed in two papers that were published in the journal Science that administration of GDF11 can rejuvenate the muscles and brains of older mice.
Wagers’ findings, however, received some push-back in May, 2015. According to Jocelyn Kaiser, writing at the Science web site, David Glass, who works at the Novartis Institutes for Biomedical Research in Cambridge, Massachusetts, and his colleagues have made use of an antibody that specifically binds to GDF11 to detect the protein and measure its concentration in the blood and tissues. Experiments with the anti-GDF11 antibody revealed that blood levels of GDF11 increase as rats and people get older. Also, in the hands of Glass and his team, injected GDF11 protein inhibited muscle regeneration in young mice. Furthermore, work from Steven Houser’s group at Temple University in Philadelphia, Pennsylvania, has shown that injections of GDF11 do not decrease the age-related thickening of the hearts of older mice. Now we have a genuine scientific controversy: so who’s right?
Wagers and Lee have concluded that the specific assay Novartis used to detect GDF11 and a related protein (GDF8 or myostatin) did not work properly. In their own experiments, the combined efforts of the Wagers and Lee teams showed that the main protein detected by the antibody test designed and used by the Glass group is immunoglobulin (antibodies). The levels of antibody proteins in the blood are known to rise in the blood as people get older. As a control, when the Wagers and Lee group used the Novartis-designed test to measure the proteins levels of laboratory mice that do not possess the gene that encodes antibodies, the blood of those mice tested negative. According to Jocelyn Kaiser, these data were published in a paper that appeared in the journal Circulation Research.
Wagers summarized the results of her and Lee’s laboratories, “They actually had very consistent findings to ours with respect to the blood levels of GDF11/8 with the antibody we all used.” However, according to Wagers, “their interpretation was confused by this case of mistaken identity.” To corroborate your point, Wagers cited a recently published study by scientists from the University of California, San Francisco, who found that GDF11/8 blood levels decline as people age, and are low in heart disease patients. These results support the hypothesis that GDF11 has antiaging activity.
The Harvard team’s paper also examined the results from the Houser laboratory. According to Wagers, Houser and his colleagues utilized commercially purchased GDF11, and this source of protein can vary in activity and levels. Wagers noted that it “wasn’t something that affected us early on, but we figured out it was an issue. The variability of commercially purchased GDF11 might explain why Houser and his colleagues were unable to see any results from injected GDF11. Houser and his team were quite careful to make sure that they injected the same dose of GDF11 as the Wagers and Lee. However, Wagers pointed out that if only a fraction of the protein was as active as the protein used by Wagers and Lee, then it is likely that Houser and his group actually used a lower effective dose than the Harvard group. Lee has also noted that he and his group have data that suggests that the GDF11 dose they used was actually higher than they initially thought.
Wagers and others also showed that daily injections of GDF11 can shrink heart muscle in both old and new mice, and, incredibly, the mice also lost weight. “We don’t have much insight into that right now, but we’re looking into it,” Wagers says. Wagers suspects that GDF11 only works within a particular therapeutic concentration, outside of which is will not work and above which it might cause side effects that are harmful.
What does the competition think? Houser thinks that Wager and Lee are probably correct that at least one of the assays used by the Novartis team to measure GDF11 detected immunoglobulin. However, both Houser David Glass have pointed out that the Novartis team used a different GDF11 detection assay whose accuracy was not challenged by the work in this new paper.
Houser remains sanguine about finding molecules that can delay aging. “I’m going to be 65 in a couple months. I’d love to have something that improves my heart, brain, and muscle function,” said Houser. “I think the field is going to figure this out and this is another piece of the puzzle.”
The jury is still out when it comes to GDF11, but Wagers and Lee have made a positive contribution to a robust and thrillingly interesting scientific discussion.
2012pharmaceutical
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