GDF11

[BrianMDelaney]

From Al Pater:

 

http://www.the-scientist.com/?articles.view/articleNo/43006/title/Studies-Conflict-on-Regenerative-Molecule/

 

Arg.... Finding a "magic pill" is not easy!

 

Brian

[Guest saul]

Hi Brian!

 

I'm more interested in an "Off-Topic" post that was posted by Michael Rae in the old CR List (he was reporting as the Scince Writer for Aubrey's group).

 

The post discussed the "feel good" homone Oxytocin.  A Berkeley study hinted that, at lease in the strain of rodent tested, supplementing oxytocin to youthful levels in aged rodents restored their age reduced muscles to near youthful levels.

 

I looked up the original paper of the Berkely professors that had made the study -- and found that my Endocrinologist, Dr. Steven Wittlin, head of Endocrinology at Strong Memorial Hospital (the hospital of the University of Rochester), was interested in the same paper, and was trying to organize a study to test the effects of oxytocin on muscle reguvenation in aged subjects.

 

I indicated my interest in such a study -- but unfortunately, Prof. Wittlin was unable to get the Gerontologists at UR to join him, so the study will not be made.

 

I volunteered to be in a case study -- but Dr. Wittlin said such a study was potentially dangerous.  My wife, a Nurse Practioner specialised in Gastroenterology, agrees.

 

Oh well -- it would be great if someone reading this Forum was able and capable to make such a study -- I'd be very interested in participating.

 

  -- Saul 

[Michael R]

Another non-replication of the GDF-11 reports:

 

Circ Res. 2015 Sep 17. pii: CIRCRESAHA.115.307527. [Epub ahead of print]

GDF11 Does Not Rescue Aging-Related Pathological Hypertrophy.
Smith SC¹, Zhang X¹, Zhang X¹, Gross P¹, Starosta T¹, Mohsin S¹, Franti M², Gupta P², Hayes D², Myzithras M², Kahn J², Tanner J², Weldon SM², Khalil A², Guo X³, Sabri A³, Chen X¹, MacDonnell S², Houser SR⁴.

... A recent study showed that reduced GDF11 blood levels with aging was associated with pathological cardiac hypertrophy (PCH), and restoring GDF11 to normal levels in old mice rescued PCH. ... [in this new study,] 24-month-old C57BL/6 mice were given a daily injection of either recombinant ® GDF11 at 0.1mg/kg or vehicle for 28 days. ...

rGDF11 levels were significantly increased but there was no significant effect on either heart weight (HW) or body weight (BW). HW/BW ratios of old mice were not different from 8 or 12 week-old animals, and the PCH marker ANP was not different in young versus old mice. Ejection fraction, internal ventricular dimension, and septal wall thickness were not significantly different between rGDF11 and vehicle treated animals at baseline and remained unchanged at 1, 2 and 4 weeks of treatment. There was no difference in myocyte cross-sectional area rGDF11 versus vehicle-treated old animals. In vitro studies using phenylephrine-treated neonatal rat ventricular myocytes (NRVM), to explore the putative anti-hypertrophic effects of GDF11, showed that GDF11 did not reduce NRVM hypertrophy, but instead induced hypertrophy.

CONCLUSIONS: Our studies show that there is no age-related PCH in disease free 24-month-old C57BL/6 mice and that restoring GDF11 in old mice has no effect on cardiac structure or function.

PMID: 26383970

If they're right, the previous report was, at minimum, based on abnormal, sickly mice with something wrong with their hearts; GDF-11 may reverse this aberrant hypertrophy, but (in this report) there's no evidence that it improves the log of a "normally"-aging mouse.

[BrianMDelaney]

Damn! But there are still many substances to be tested to see what might be causative in the heterochronic parabiosis study results.

 

- Brian

[Saul]

Hi Michael!

 

My question was about Oxytocin -- is GDF11 another name for Oxytocin?

 

  -- Saul

[Michael R]

Hi Michael!

 

My question was about Oxytocin -- is GDF11 another name for Oxytocin?

 

  -- Saul

 

No -- use wikipedia ;) .

[Saul]

Hi Michael!

 

I didn't think so -- but, I'm still very curious about oxytocin as a possible beneficial agent -- the full text of the Berkeley research suggested that the answer might be affirmative.   And I've seen an article in Science News suggesting a possible benefit for bone health, as well.

 

Why does a question about Oxytocin engender a response about an entirely different substance?

 

??

 

  -- Saul

[Michael R]

Heh? The subject of the thread is "GDF11," and the first post is from Brian, and is about GDF-11. Yes, you had asked a side-question about oxytocin; did you assume that every post after that would be about it?

[AlPater]

Oh boy.

 

http://www.the-scientist.com//?articles.view/articleNo/44305/title/New-Data-Attempt-to-Resolve-Protein-Dispute/

 

The Scientist » News & Opinion » Daily News
New Data Attempt to Resolve Protein Dispute

 

The latest analysis on GDF11, a proposed antiaging protein, blames discrepancies in the literature on misreported doses and misinterpretation.

 

By Kerry Grens | October 22, 2015

 

A protein called growth differentiation factor 11 (GDF11) has been at the center of a tug of war: some scientists have provided evidence that it declines with age, and that returning GDF11 to youthful levels can fix a heart problem in mice. Yet others have found no such relationship, and one group published evidence this year that GDF11 actually increases with age.

 

To figure out why there have been discrepancies in the data, Richard Lee of Harvard Medical School and his colleagues—the team that found GDF11 dropped with age—scrutinized a conflicting study and found the likely explanation to be a case of mistaken identity. Rather than measuring levels of GDF11, Lee’s group found, the other researchers were likely measuring immunoglobulin light chain. “It’s a misinterpretation,” Lee told The Scientist.

 

Novartis Research Institutes, which led the study that found GDF11 levels rising with age, did not respond to requests for comment. Lee told The Scientist he had pointed out the error to the Novartis team over the summer, but has not heard back.

 

This week (October 21), the Harvard group showed in Circulation Research that an antibody against GDF11 used in Western blot analyses also recognizes immunoglobulin, and that eliminating immunoglobulin from the assay wipes out the band. Mass spectra of the band also indicated that the signal came from immunoglobulin.

 

Steven Houser of Temple University School of Medicine, who was not involved in either study, says Lee’s data in support of a misinterpretation by Novartis are strong. “It looks like the Novartis group misidentified a band as GDF11,” he said. But he added that questions about GDF11’s effects on the heart are still unresolved.

 

Last month, Houser’s team reported evidence conflicting with Lee’s data on cardiac hypertrophy, or thickening of the heart muscle. Lee’s team had found that giving older mice a boost in GDF11 levels fixed their cardiac hypertrophy. Houser’s group, on the other hand, found no effect.

 

According to the Lee group’s latest paper, the difference might be due to variability in the concentration of GDF11. Originally, Lee’s team—as subsequently replicated by Houser’s—used a concentration of 0.1 mg/kg, but it turns out that the manufacturer had sent the Lee group variable concentrations. Now, the Harvard researchers have reported, a concentration of 0.5 mg/kg is the effective dose.

 

“They think the dose was higher than they realized. That’s troubling, to be honest,” Hauser told The Scientist. “If they knew the dose to be reported was not the right dose, there are ways to inform the field.”

 

Lee agreed there is still much to be learned about GDF11, and this latest study does not put questions about its activity to bed. “I think a lot of this is, early on in the field the reagents aren’t perfect, the assays aren’t perfect, so people get results that look like they’re opposing each other. . . . We need better assays, we need more science, we really just need to do more work.”

 

T. Poggioli et al., “Circulating growth fifferentiation factor 11/8 levels decline with age,” Circulation Research, doi:10.1161/CIRCRESAHA.115.307521, 2015.

 

Tags

 

Western blot, regeneration, physiology, heart, cardiomyocyte and aging

Circulating Growth Differentiation Factor 11/8 Levels Decline with Age.
Poggioli T, Vujic A, Yang P, Macias-Trevino C, Uygur AN, Loffredo FS, Pancoast JR, Cho M, Goldstein J, Tandias RM, Gonzalez E, Walker RG, Thompson TB, Wagers AJ, Fong YW, Lee RT.
Circ Res. 2015 Oct 21. pii: CIRCRESAHA.115.307521. [Epub ahead of print]
PMID: 26489925

 

Abstract

 

RATIONALE:

 

Growth differentiation factor 11 (GDF11) and 8 (GDF8) are members of the TGF-β superfamily sharing

89% protein sequence homology. We have previously shown that circulating GDF11 levels decrease with age in mice. However, a recent study by Egerman et al. reported that GDF11/8 levels increase with age in mouse serum.

 

OBJECTIVE:

 

Here we clarify the direction of change of circulating GDF11/8 levels with age and investigate effects of GDF11 administration on the murine heart.

 

METHODS AND RESULTS:

 

We validated our previous finding that circulating levels of GDF11/8 decline with age in mice, rats, horses and sheep. Furthermore, we showed by Western analysis that the apparent age-dependent increase in GDF11 levels, as reported by Egerman et al., is due to cross-reactivity of the anti-GDF11 antibody with immunoglobulin, which is known to increase with age. GDF11 administration in mice rapidly activated SMAD2 and SMAD3 signaling in myocardium in vivo and decreased cardiac mass in both young (2 month old) and old (22 month old) mice in a dose dependent manner after only nine days.

 

CONCLUSIONS:

 

Our study confirms an age-dependent decline in serum GDF11/8 levels in multiple mammalian species and that exogenous GDF11 rapidly activates SMAD signaling and reduces cardiomyocyte size. Unraveling the molecular basis for the age-dependent decline in GDF11/8 could yield insight into age-dependent cardiac pathologies.

 

KEYWORDS:

 

Cardiac signaling; GDF11/8; TGF-β; aging; growth factors and cytokines; signaling pathways

[AlPater]

More contradiction was reported:

 

 

http://www.the-scientist.com/?articles.view/articleNo/45718/title/Latest-on-Disputed--Youthful--Protein/&utm_campaign=NEWSLETTER_TS_The-Scientist-Daily_2016&utm_source=hs_email&utm_medium=email&utm_content=28004315&_hsenc=p2ANqtz-8fCE9_mREzo_YVjWEqI6aMCoK2YvIstPoixur2j3ffzg12InBDnYVq1SU0VJGwj-uNBMYCKZSe8xz0mba0_iubeh7k4Q&_hsmi=28004316/

 

The Scientist » The Nutshell Latest on Disputed “Youthful” Protein

Studies reach conflicting conclusions on GDF11 as a rejuvenating factor.

By Kerry Grens | April 4, 2016 

 

WIKIPEDIA, RAMA

 

Growth differentiation factor 11 (GDF11) has been hailed an anti-aging protein, capable of spinning back the clock on aged mouse heart and muscle. But a few studies have found evidence to the contrary. Most recently, researchers reported in Aging Cell last month (March 28) that GDF11 did not improve muscle function of older animals as had been observed by others.

 

“We have been unable to confirm the reported activity of GDF11,” the team from GlaxoSmithKline and Five Prime Therapeutics wrote in its report. In particular, the researchers were unable to replicate the results of a 2014 study from Amy Wagers and Richard Lee of Harvard University and colleagues.

 

The GlaxoSmithKline group treated skeletal muscle satellite cells from older mice with GDF11, but did not see increased activity as Wagers and Lee had reported. Administering the protein to young mice resulted in a reduction of lean mass as well, the team noted.

 

These latest results fall more in line with a 2015 study from the Novartis Institutes for Biomedical Research than with those reported by the Harvard team. But Lee and collaborators later produced evidence that the discrepancy between their results and the Novartis findings was due to reagents. “I think a lot of this is, early on in the field the reagents aren’t perfect, the assays aren’t perfect, so people get results that look like they’re opposing each other,” Lee told The Scientist in October 2015. “We need better assays, we need more science, we really just need to do more work.”

 

Indeed, the debate over GDF11’s role in aging is far from settled. In a pair of commentaries in the April issue of Circulation Research, the Lee/Wagers group and a separate team, led by Steven Houser of Temple University, laid out the evidence for GDF11’s functions and attempt to explain the discrepancies between different labs’ results. Given the lack of consensus, the Houser team urged caution regarding translational research efforts. “The data from the Lee/Wagers groups, and the associated media coverage, have given hope to aged individuals with cardiac, skeletal muscle, and central nervous system dysfunction,” Houser and colleagues wrote. “However, there is now sufficient concern about these data and we hope that any proposed rGDF11 clinical trials will do no harm.”

 

Tags

regeneration, myostatin, muscle, heart, gdf11, controversy and aging