43 replies to this topic

[Santi]

Tributyrin is available at Alibaba.com in purities from 55% to 99% at various prices. Minimum pricing from one of the companies I talked to was $125 for 100ml at 98% purity with a 4 week delivery. As China based companies they don't seem to have a problem sending it to a residential US address like Sigma Aldrich. 

 

 

Does anyone have an idea of the quantity of Tributyrin to take per day sufficient enough to antagonize HDAC3 to upregulate the expression of the gene that encodes Gdf11? 

 

 

 

 

Clinical and pharmacologic study of tributyrin: an oral butyrate prodrug.

Edelman MJ1, Bauer K, Khanwani S, Tait N, Trepel J, Karp J, Nemieboka N, Chung EJ, Van Echo D.

Author information

 

Abstract

PURPOSE:

Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50-100 microM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 microM. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule.

PATIENTS AND METHODS:

Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 h thereafter.

RESULTS:

The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30-74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 microM was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression.

CONCLUSION:

Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing.

Clin Cancer Res. 1998 Mar;4(3):629-34.

 

[zorba990]

Maybe someone here has another source, your price seems quite high....sigma doesnt seem to sell retail
http://www.thedcasit...tyrate.html#six

Edit :aparently sold here
http://tributyrate.c...ion_quality.php

from here.http://spb11.com/order.html

Edited by zorba990, 07 April 2015 - 06:47 PM.

[Avatar of Horus]

This wiki article seems to make it out to suppress nerve and muscle growth in humans.
http://en.m.wikipedia.org/wiki/GDF11
If anyone can explain the contradiction, oh and then float some cash since I'm just about broke (it seems like this vial would be a one day supply), I would give it a try. Stress and illness have just about annihilated me this past year. I'm down to my high school weight and some of that seems to be in the form of edema.

Oops beat to the punch. That's what happens when you wander off in the middle of a post.

 
I can't explain the contradiction. I skimmed over a bunch of articles and I just don't get it. I took developmental biology around 25 years ago and they didn't know about GDF11 back then and I can't get access to a lot of the articles because of pay walls. Also, cognitive decline. There, those are my excuses. Certainly not intellectual laziness. (sarcasm)

So please, someone out there, tell us the mechanism by which GDF11 works to regenerate muscle tissue. Does it stimulate the recruitment of satellite cells (hyperplastic growth)? I can't find anything that states that it does this. I'm just a sorry old housewife now, so feed it to me with a spoon, please.

 

...
One possible explanation to your question, if the effect is on the level of cell signaling, is that in the TGF-beta superfamily, which is rather large, there is a significant number of 'cross-interactions' between its different but related members and receptors, and therefore the effect can be opposite, as it depends on a number of factors, such as the concentrations of the given proteins and antagonists, their receptors and downstream effectors, and the tissue and cellular context. ...

 

 
It seems that with those contemplations we were on the right track:
opposite effect was reported about GDF11 in muscle.
 

Doubts cast on 'rejuvenating' protein
By Jocelyn Kaiser, 19 May 2015 11:00 am
http://news.sciencem...enating-protein
 
A new study questions whether the protein GDF11 explains why young blood renews muscle in old mice.

But work described this week by a team at the Novartis research center challenges GDF11’s rejuvenating powers. ...
The Novartis group does not question that young blood renews old mice. ...
... Some experts were flummoxed by the muscle paper, because GDF11 is a close cousin of myostatin, a well-studied protein that controls muscle growth. Animals and people lacking myostatin develop huge, bulging muscles; too much of it hinders muscle regeneration. How, then, could a very similar protein have the opposite effect?
...
Among the skeptics was David Glass of Novartis Institutes for BioMedical Research in Cambridge, Massachusetts, who helped develop a myostatin-blocking drug for muscular atrophy. ... they found that GDF11 levels actually trend upward with age in rat and human blood and GDF11 mRNA levels rise in rat muscle with age.

The Novartis group also tested GDF11’s effects on muscle regeneration. When they treated a young mouse with GDF11 and damaged its leg muscle with snake venom toxin, a common experiment, they found that muscle regeneration was impaired. “The bottom line is that this molecule [GDF11] seems to be harmful to muscle,” Glass says.

Wagers sticks by her data, noting that her group’s Science paper also found a drop in GDF11 with age using a different antibody that distinguished GDF11 from myostatin. And she says the Glass team’s injury experiment cannot be compared to hers because they used young animals and a dose of GDF11 three times higher. (Glass did this in part because he did not see any effect in old mice at the dose Wagers used.) The signaling pathway in which GDF11 lies “is notoriously dose-sensitive,” and low and high doses can have different or opposite effects, she says. Moreover, she says, the Novartis team’s muscle regeneration test was not comparable to hers—the Harvard team made the injury by freezing tissue, which is less likely than a toxin to kill muscle stem cells needed for regeneration.

Wagers says new data from her group will show that “there is a very compelling biological explanation for the apparent discrepancies.” One of her collaborators, Lee, agrees. But Rubin is more cautious: “Obviously, this report has to be taken seriously.” Although the Novartis result does not challenge a second claimed benefit of GDF11, to the brain, “we’re designing a series of experiments to convince ourselves that what we see in the brain is real,” says Rubin, who led that study.

Others say that even if the new finding is correct, it may not contradict at least some of the benefits Wagers and others reported, says molecular biologist Se-Jin Lee of Johns Hopkins University in Baltimore, Maryland, who studies myostatin. He notes that GDF11’s effects in the body are likely complex and haven’t been studied in detail. “There’s still a lot to be sorted out.”

[resveratrol_guy]

We now have 1.5 years of apparently credible human data here. Looks like GDF11 might work more or less as advertised, after all.

[corb]

We now have 1.5 years of apparently credible human data here. Looks like GDF11 might work more or less as advertised, after all.

 

Interesting.

 

The results are in http://diyhpl.us/~br...Backup Data.zip

for whoever wants to see them. Maybe an MD can go through the results and tell us if any of the changes are extraordinary or unexpected.

[HighDesertWizard]

 

This wiki article seems to make it out to suppress nerve and muscle growth in humans.
http://en.m.wikipedia.org/wiki/GDF11
If anyone can explain the contradiction, oh and then float some cash since I'm just about broke (it seems like this vial would be a one day supply), I would give it a try. Stress and illness have just about annihilated me this past year. I'm down to my high school weight and some of that seems to be in the form of edema.

Oops beat to the punch. That's what happens when you wander off in the middle of a post.

 
I can't explain the contradiction. I skimmed over a bunch of articles and I just don't get it. I took developmental biology around 25 years ago and they didn't know about GDF11 back then and I can't get access to a lot of the articles because of pay walls. Also, cognitive decline. There, those are my excuses. Certainly not intellectual laziness. (sarcasm)

So please, someone out there, tell us the mechanism by which GDF11 works to regenerate muscle tissue. Does it stimulate the recruitment of satellite cells (hyperplastic growth)? I can't find anything that states that it does this. I'm just a sorry old housewife now, so feed it to me with a spoon, please.

 

...
One possible explanation to your question, if the effect is on the level of cell signaling, is that in the TGF-beta superfamily, which is rather large, there is a significant number of 'cross-interactions' between its different but related members and receptors, and therefore the effect can be opposite, as it depends on a number of factors, such as the concentrations of the given proteins and antagonists, their receptors and downstream effectors, and the tissue and cellular context. ...

 

 
It seems that with those contemplations we were on the right track:
opposite effect was reported about GDF11 in muscle.
 

Doubts cast on 'rejuvenating' protein
By Jocelyn Kaiser, 19 May 2015 11:00 am
http://news.sciencem...enating-protein
 
A new study questions whether the protein GDF11 explains why young blood renews muscle in old mice.

But work described this week by a team at the Novartis research center challenges GDF11’s rejuvenating powers. ...
The Novartis group does not question that young blood renews old mice. ...
... Some experts were flummoxed by the muscle paper, because GDF11 is a close cousin of myostatin, a well-studied protein that controls muscle growth. Animals and people lacking myostatin develop huge, bulging muscles; too much of it hinders muscle regeneration. How, then, could a very similar protein have the opposite effect?
...
Among the skeptics was David Glass of Novartis Institutes for BioMedical Research in Cambridge, Massachusetts, who helped develop a myostatin-blocking drug for muscular atrophy. ... they found that GDF11 levels actually trend upward with age in rat and human blood and GDF11 mRNA levels rise in rat muscle with age.

The Novartis group also tested GDF11’s effects on muscle regeneration. When they treated a young mouse with GDF11 and damaged its leg muscle with snake venom toxin, a common experiment, they found that muscle regeneration was impaired. “The bottom line is that this molecule [GDF11] seems to be harmful to muscle,” Glass says.

Wagers sticks by her data, noting that her group’s Science paper also found a drop in GDF11 with age using a different antibody that distinguished GDF11 from myostatin. And she says the Glass team’s injury experiment cannot be compared to hers because they used young animals and a dose of GDF11 three times higher. (Glass did this in part because he did not see any effect in old mice at the dose Wagers used.) The signaling pathway in which GDF11 lies “is notoriously dose-sensitive,” and low and high doses can have different or opposite effects, she says. Moreover, she says, the Novartis team’s muscle regeneration test was not comparable to hers—the Harvard team made the injury by freezing tissue, which is less likely than a toxin to kill muscle stem cells needed for regeneration.

Wagers says new data from her group will show that “there is a very compelling biological explanation for the apparent discrepancies.” One of her collaborators, Lee, agrees. But Rubin is more cautious: “Obviously, this report has to be taken seriously.” Although the Novartis result does not challenge a second claimed benefit of GDF11, to the brain, “we’re designing a series of experiments to convince ourselves that what we see in the brain is real,” says Rubin, who led that study.

Others say that even if the new finding is correct, it may not contradict at least some of the benefits Wagers and others reported, says molecular biologist Se-Jin Lee of Johns Hopkins University in Baltimore, Maryland, who studies myostatin. He notes that GDF11’s effects in the body are likely complex and haven’t been studied in detail. “There’s still a lot to be sorted out.”

 

 

Yes, but, the Wagers team has come back with a formal reply for the Glass Novartis Institute Team...

 

A study summary is here... Antiaging protein is the real deal, Harvard team claims

 

The Wagers team published study abstract is here...  Circulating Growth Differentiation Factor 11/8 Levels Decline with Age

[pone11]

The latest major GDF11 research was just released, from Mayo Clinic in Cell Metabolism June 2016, and the title is "Quantification of GDF11 and Myostatin in Human Aging and Cardiovascular Disease".

 

Some key parts of that study:

 

"Previous studies exploring the relationship of GDF11 to aging

have been contradictory. Thus, we utilized our quantitative LCMS/

MS assay to measure serum protein levels in 70 women

and 70 men, age 21–93. GDF11 levels did not statistically differ

as a function of age or sex (Figure 1B). MSTN levels were highest

in men in their 20s and statistically declined throughout subsequent

decades (p < 0.05) (Figure 1C). Female MSTN levels did

not change as a function of age (Figure 1C). Consistent with

our previous study (Bergen et al., 2015), young women had lower

circulating MSTN levels than young men (Figure 1C). As methods

used in several previous studies were unable to distinguish

GDF11 from MSTN, we also report combined GDF11 and

MSTN levels. GDF11 + MSTN levels declined in men (p <

0.05), but not women, throughout aging, in register with MSTN

levels (Figure 1D). When data from both sexes were combined,

we did not observe statistically significant differences in circulating

GDF11 + MSTN levels throughout aging (Figure 1E).

Notably, GDF11 represented, on average, 15.5% and 11.2% of

composite GDF11 + MSTN values for women and men, respectively.

Thus, GDF11 levels are not altered in women or men as a

function of age, and previous observations of age-dependent

decreases in GDF11 levels likely reflect changes in MSTN levels."

 

 

And regarding pathologies associated with high GDF11:

 

"We next interrogated potential associations between GDF11 and

MSTN levels and baseline comorbid conditions. Increased circulatingGDF11was

identified in a greater proportion of study participants

with diabetes (p = 0.019). 46% of individuals with high

GDF11 had diabetes, in contrast to only 14% with low levels.

Elevated GDF11 was also associated with a history of previous

cardiac conditions (p = 0.021),with a significant relationship drawn

with previous coronary artery bypass (p = 0.041). Participants with

the highest GDF11 levels at surgery had significantly higher New

YorkHeart Association (NYHA) class ranking than thosewith lower

GDF11 levels (p = 0.042) and were uniquely categorized as high

risk based on a mean Society of Thoracic Surgeons (STS) predicted

risk of mortality score greater than 8% (Thourani et al.,

2015) (p = 0.044) (Table 1). Critically,we did not identify differences

in aortic stenosis severity or related cardiac dysfunction, as

measuredbyejectionfraction,meangradient, aortic valve velocity,

valve area, valve area index, or left ventricular mass index, as a

function of circulatingGDF11 concentration (Table S5). In contrast

to GDF11, we were unable to draw any statistically significant

associations between MSTN and comorbid conditions, NYHA

classification, or mortality risk (Table 2)."

 

 

GDF11 is associated with frailty while aging:

 

"Frailty is a strong predictor of poor post-operative outcomes, yet

biomarkers of frailty have not been forthcoming. Accordingly,

we tested whether circulating GDF11 and MSTN protein levels

areassociatedwithfrailty statususingCardiovascularHealthStudy

(CHS) criteria, specified by unintentional weight loss, grip strength,

endurance,gait speed,andphysical activity (Friedetal., 2001).Participantswho

reported lowenergy and endurance had significantly

higher levels of circulating GDF11 than thosewho reported normal

energy (p < 0.001). A trend toward increased plasma GDF11 concentrations

was observed in individuals demonstrating unintentional

weight loss (p = 0.064) and low activity (p = 0.066), relative

to peers reporting no weight loss and normal activity (Figure 2B).

Similarly, individuals with slow gait (p = 0.150) and weak grip

strength (p = 0.163) appeared to possess higher GDF11 levels

than counterparts with normal gait and appropriate grip strength,

although these associations did not reach statistical significance.

Using the presence of three ormore CHS criteria as an operational

frailtydefinition,we comparedGDF11 concentrationsbetween frail

and non-frail study participants. Mean GDF11 levels increased by

21%as a function of frailty (p = 0.002) (Figure 2C). Unlike GDF11,

MSTN levels were not associated with frailty status (Table 2). To

evaluate whether the relationship between GDF11 and frailty remained

after adjusting for potential confounding demographic

and comorbidity characteristics, we applied a multivariable model

using a penalized stepwise logistic regression approach for variable

selection. After variable adjustment, GDF11 was still significantly

related to frailty (p = 0.003) (Table S6)."

 

 

This Mayo study uses the first really accurate technique for measuring GDF11 and GDF8 separately and precisely.  

 

This was not a good study for the pro GDF11 camp.  This Mayo study doesn't prove that if you inject GDF11 that you will get all of these disease conditions.   This study doesn't even really prove that injecting GDF11 will increase your risk of these other conditions.   But this Mayo study should really make you question that injecting GDF11 is a fountain of youth that will reverse any of your tissue aging.   And who wants to be the guy on the block with the highest level of GDF11 circulating in your blood when this study is saying that those people all have terrible diseases and frailty as they age?

 

[maximum411]

Thanks for the update! Interesting and unexpected results

[ceridwen]

There must be something else in plasma that gives the good results then. Clearly it is not GDF11. However plasma has been rejuvenating mice so possibly a different GDF or it could be a combination of everything in plasma but GDF11 seems to be doing the opposite of what we want.

[pone11]

There must be something else in plasma that gives the good results then. Clearly it is not GDF11. However plasma has been rejuvenating mice so possibly a different GDF or it could be a combination of everything in plasma but GDF11 seems to be doing the opposite of what we want.

 

It might be GDF11 is doing something very non obvious.   One of the ideas I wanted to explore with Steve Perry here is whether GDF11 simply makes you *feel* better and as a result you do high amounts of cardiovascular exercise.   Perhaps the exercise itself accounts for the improvements that are seen in muscle?   GDF11 by itself may hinder muscle growth, but this effect might be overwhelmed by the very positive effect of significant additional exercise levels.

 

Unfortunately, it feels to me like there is some real subtlety here, and the science just isn't there yet.   I am very disappointed.  I wanted this to be a no-brainer and a straight forward fountain of youth.

[pone11]

There must be something else in plasma that gives the good results then. Clearly it is not GDF11. However plasma has been rejuvenating mice so possibly a different GDF or it could be a combination of everything in plasma but GDF11 seems to be doing the opposite of what we want.

 

I keep coming back to Oxytocin.   Irina Conboy's research on this clearly shows some rejuvenation, and what is very important is that oxytocin has FDA approval and is cheap!

 

Conboy's attack on GDF11 is a very well thought out and researched paper:

http://www.ncbi.nlm....PMC4637204/#R40

 

I really like the work of this researcher (and her husband) and wish they would get more financing.

[Hebbeh]

 

There must be something else in plasma that gives the good results then. Clearly it is not GDF11. However plasma has been rejuvenating mice so possibly a different GDF or it could be a combination of everything in plasma but GDF11 seems to be doing the opposite of what we want.

 

I keep coming back to Oxytocin.   Irina Conboy's research on this clearly shows some rejuvenation, and what is very important is that oxytocin has FDA approval and is cheap!

 

Conboy's attack on GDF11 is a very well thought out and researched paper:

http://www.ncbi.nlm....PMC4637204/#R40

 

I really like the work of this researcher (and her husband) and wish they would get more financing.

 

 

Perhaps it's just the abundance of stem cells in the young blood.

[ortcloud]

Well here it is years later and it turns out Steve perry has hundreds of people reporting success on GDF11.

Its a shame the early research was conflicting as I feel like I really missed out all of these years taking it

based on early research that showed it wasnt helpful.

 

I suspect alot of people in here made up their mind a long time ago on this and will never consider taking it, which is a shame.

 

Anybody else feel regret?

 

I am going to start on this right away.

[DJSwarm]

Here is a more current (Oct 2019) study: https://onlinelibrar...1111/acel.13038

Thanks to "guest" for the find.