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GDF11 abdicates the throne of systemic rejuvenation

stem cells aging gdf11 irina conboy

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#1 corb

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Posted 25 February 2016 - 01:00 AM


GDF11 abdicates the throne of systemic rejuvenation

 

As recently revealed, the key findings on diminished levels of GDF11 with age and of the positive effects of this protein on myogenesis are not reproduced [36, 40–42]. Very importantly, this would not come as a shock if one would read the relevant papers. Based on the science, GDF11 is 90% identical to myostatin, which inhibits (not activates) myogenesis. GDF11 in neurogenesis serves to limit the numbers of neural stem cells [43, 44] and this discrepancy was not cited or discussed in the pro-rejuvenation papers. GDF11 signals through the same receptor as TGF-beta1 and myostatin (more efficiently than myostatin [40] and inhibition (not activation) of this ALK5 receptor has been shown to enhance and rejuvenate myogenesis and also, neurogenesis [6, 37]. The bulk of data questions the anti-aging effects of GDF11, and makes the Cell Metabolism paper important for avoiding years of unproductive research in the wrong directions.
    GDF11 was reported to enhance old muscle repair by attenuating the accumulation of DNA damage in the aged satellite cells [36]; however, a year earlier it was published that old muscle satellite cells do not accumulate DNA damage with age and that DNA damage in muscle stem cells is uncoupled from efficiency of muscle repair and likely represents a physiologically required process of terminal myogenic lineage differentiation [15], [45]. Once again, a key paper in a lesser impact journal questioning main conclusions of a high impact paper was not cited or caught in peer or editorial review.

    In apparent disagreement between two recent studies, GDF11 does [41] and does not [46] reduce hypertrophy of old mouse hearts. Even if there is no direct connection to aging, stem cells or heterochronic parabiosis, ectopic GDF11 may reduce the mass of both young and old hearts [47].
    Age-specific levels of GDF11 are also not without controversy: initially, it was reported that GDF11, but not GDF8/myostatin, declines with age [41]; then more recently it was determined that GDF8/myostatin does decline with age [48], an observation which was also reconfirmed by the original Cell authors, who now combine the two protein names into one, called GFD11/8 [47].

    These controversies may be caused by the fact that antibodies to GDF11 have cross-reactivity with GDF8/myostatin. GDF11 antibody might also simply cross-react with immunoglobulins, which become elevated with age [47, 49]. A very elegant recent paper using a clean myostatin knock-out system demonstrated that GDF11 levels are 500 times less than that of myostatin or activin, thus precluding any competitiveness for the same receptor complexes and arguing against physiological modulation of pSmad2/3 signaling by GDF11 when myostatin, activin or TGF-beta1 are present [48].
    Muscle tissue produces myostatin, so the age-specific decline in myostatin protein may reflect the loss of muscle mass in the old. Consequentially people or mice with physiologically higher muscle mass (particularly in older age) are likely to be healthier, thus exhibiting an indirect link between the levels of myostatin and the health of the heart and other organs. Notably, GDF11 is associated with human colon cancers, which is likely due to the pro-angiogenic properties of GDF11 and most TGF-beta family ligands [50, 51]. Accordingly, Alk1 and Alk5 inhibitors are studied as anti-cancer anti-angiogenic blockers [52, 53].

 

 

Systemic Problems: A perspective on stem cell aging and rejuvenation

http://www.ncbi.nlm....les/PMC4637204/

 

 

Recent high-profile studies report conflicting data on the age-related change in circulating growth/differentiation factor 11 (GDF11) and myostatin as well as the former's influence on muscle regeneration. Both ligands bind and activate ActRIIB receptors with similar affinities and should therefore have similar actions, yet these studies suggest that GDF11 activates muscle regeneration whereas myostatin is well known to inhibit it. They also suggest that circulating GDF11 levels, but not those of myostatin, decline with age. We performed a careful assessment of the ELISA used to quantify circulating myostatin in these studies and determined that assay reagents significantly cross react with each protein, each of which is highly homologous. Circulating myostatin levels decreased with age and estimates of GDF11 levels using myostatin null mice indicate that they were almost 500 times lower than those for myostatin. This suggests that circulating GDF11 has little physiological relevance as it could not outcompete myostatin for ActRIIB binding sites. Together, these results further suggest that the previously reported aging muscle, heart, and brain phenotypes attributed to reduced circulating GDF11 should be reconsidered.

 

http://www.ncbi.nlm....pubmed/26372181

 

This paper doesn't seem to have circulated on these forums yet as I learned in a recent article in the news section.

 


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#2 to age or not to age

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Posted 25 February 2016 - 03:56 PM

I think Irina Conboy out of Berkeley is more on target.  She has worked with Wagers in the past and explained it all to me. Irina thinks we are only a couple

or years - two or three -away from possible human tests of stem cell reversal. But, she said, all depends on funding.


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#3 Logic

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Posted 25 February 2016 - 05:17 PM

IIRC the GDF11/myostatin question has been answered?

Here IIRC:

Results of my 1.5 years of injecting exogenous GDF11

http://www.longecity...xogenous-gdf11/


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#4 niner

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Posted 25 February 2016 - 09:30 PM

Irina Conboy knows what's up, and people ought to take a look at the paper that corb linked above.  That said, what are we to make of Steve Perry's report?  I don't think he's trying to pimp GDF11; more like he's looking for a way to invest in it.  Placebo effect?  Pretty damn good one, if so.  Lots of questions here...


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#5 corb

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Posted 26 February 2016 - 02:13 AM

I was thinking couple of days back why GDF11 sometimes seems to work.

 

GDF11 binds to the same receptor myostatin does. If you inhibit myostatin you get unnatural levels of muscle growth. These are facts.

Now one experiment has shown that GDF11 is in much lesser quantities than myostatin in mammals. This will have to be reconfirmed but let's take it as true for the time being.

When people were calculating how much GDF11 to supplement in mice (and in big mice) they were looking at myostatin and GDF11 together. And they didn't know that wasn't just GDF11. So the result is they probably injected hundreds of times more GDF11 than there would typically have circulating in the system.

 

So here is my theory - maybe myostatin's ligand is a full agonist, while GDF11's ligand is a partial agonist. They are too close in chemistry for GDF11 to be an inverse agonist (I think). So when they supplemented GDF11 in such quantities they maybe replaced a full agonist with a partial agonist. They got some muscle growth and there's been enough papers posted on here that show correlation between fitness and brain health - I'm ignoring that GDF11 is supposed to have an inhibitory role on brain regeneration for the time being because then the thought experiment becomes too complex for me :happy: - so that's why there was some increase in cognition as well.

 

I'm not a biochemist and chemistry in general was never my strong subject so I'd be surprised if I'm correct. So just to keep the discussion going...


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#6 Rocket

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Posted 26 February 2016 - 02:38 PM

I- I'm ignoring that GDF11 is supposed to have an inhibitory role on brain regeneration for the time being because then the thought experiment becomes too complex for me :happy: - so that's why there was some increase in cognition as well.

 

What?  Wagers found that GDF11 helped the brain.



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#7 corb

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Posted 26 February 2016 - 03:11 PM

 

I- I'm ignoring that GDF11 is supposed to have an inhibitory role on brain regeneration for the time being because then the thought experiment becomes too complex for me :happy: - so that's why there was some increase in cognition as well.

 

What?  Wagers found that GDF11 helped the brain.

 

 

I'm pretty sure I read in one of the papers that it blocks brain regeneration.

This is the problem with GDF11 for every paper that says it does something there's one that say it does the opposite.
 

I'm not sure if it was this one or something else. There's too many GDF11 papers on pubmed now.

 

These data demonstrate GDF11 to be a master regulator of neural stem cell transcription that can suppress cell proliferation and migration by regulating the expression of numerous genes involved in both these processes, and by suppressing transcriptional responses to factors that normally promote proliferation and/or migration.

http://www.ncbi.nlm....les/PMC3820543/


Edited by corb, 26 February 2016 - 03:14 PM.


#8 pone11

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Posted 27 February 2016 - 10:38 PM

I think Irina Conboy out of Berkeley is more on target.  She has worked with Wagers in the past and explained it all to me. Irina thinks we are only a couple

or years - two or three -away from possible human tests of stem cell reversal. But, she said, all depends on funding.

 

Conboy's research on Oxytocin is amazing, and it is beyond frustrating that she has problems getting funding for even more animal research.

 

Oxytocin:

 

1) Has FDA approval for other indications, so once research confirms dosing in humans we might get massive and widespread benefit to humans quickly, without the usual FDA 20 year delay.

 

2) Oxytocin is dirt cheap as an injectible, as it already has widespread applications for humans and animals.

 

3) It is not a proprietary chemical, so those pharmaceutical companies are not going to mess with pricing easily.

 

I also feel we are right on the edge of major discoveries to extend the period of youthful vigor - if not lifespan - in humans, and again it is incomprehensible that foundations are not funding the required additional research.



#9 pone11

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Posted 27 February 2016 - 11:17 PM

I was thinking couple of days back why GDF11 sometimes seems to work.

 

GDF11 binds to the same receptor myostatin does. If you inhibit myostatin you get unnatural levels of muscle growth. These are facts.

Now one experiment has shown that GDF11 is in much lesser quantities than myostatin in mammals. This will have to be reconfirmed but let's take it as true for the time being.

When people were calculating how much GDF11 to supplement in mice (and in big mice) they were looking at myostatin and GDF11 together. And they didn't know that wasn't just GDF11. So the result is they probably injected hundreds of times more GDF11 than there would typically have circulating in the system.

 

So here is my theory - maybe myostatin's ligand is a full agonist, while GDF11's ligand is a partial agonist. They are too close in chemistry for GDF11 to be an inverse agonist (I think). So when they supplemented GDF11 in such quantities they maybe replaced a full agonist with a partial agonist. They got some muscle growth and there's been enough papers posted on here that show correlation between fitness and brain health - I'm ignoring that GDF11 is supposed to have an inhibitory role on brain regeneration for the time being because then the thought experiment becomes too complex for me :happy: - so that's why there was some increase in cognition as well.

 

I'm not a biochemist and chemistry in general was never my strong subject so I'd be surprised if I'm correct. So just to keep the discussion going...

 

That's a nice hypothesis.   Is it shown that myostatin levels go up with age, and if yes does anyone have suggestions about why this happens?

 

If your hypothesis is true, then one might get the same or better results from a myostatin antagonist, rather than a less efficient proxy (e.g., GDF-11).



#10 corb

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Posted 28 February 2016 - 03:26 AM

 

That's a nice hypothesis.   Is it shown that myostatin levels go up with age, and if yes does anyone have suggestions about why this happens?

 

If your hypothesis is true, then one might get the same or better results from a myostatin antagonist, rather than a less efficient proxy (e.g., GDF-11).

 

 

Myostatin inhibitors are in human trials for muscle dystrophies right now. I think the best results to come so far are from Folistatin - which generally inhibits tgf beta pathways.

 

 

Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal.

 

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age. Exploring the hypothesis that youthful calibration of key signaling pathways may enhance regeneration of multiple old tissues, we found that systemically attenuating TGF-β signaling with a single drug simultaneously enhanced neurogenesis and muscle regeneration in the same old mice, findings further substantiated via genetic perturbations. At the levels of cellular mechanism, our results establish that the age-specific increase in TGF-β1 in the stem cell niches of aged hippocampus involves microglia and that such an increase is pro-inflammatory both in brain and muscle, as assayed by the elevated expression of β2 microglobulin (B2M), a component of MHC class I molecules. These findings suggest that at high levels typical of aged tissues, TGF-β1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-β1 signaling normalized B2M to young levels in both studied tissues.

http://www.ncbi.nlm....pubmed/26003168

 

 

Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice.

 

Sarcopenia, or skeletal muscle atrophy, is a debilitating comorbidity of many physiological and pathophysiological processes, including normal aging. There are no approved therapies for sarcopenia, but the antihypertrophic myokine myostatin is a potential therapeutic target. Here, we show that treatment of young and old mice with an anti-myostatin antibody (ATA 842) for 4 wk increased muscle mass and muscle strength in both groups. Furthermore, ATA 842 treatment also increased insulin-stimulated whole body glucose metabolism in old mice, which could be attributed to increased insulin-stimulated skeletal muscle glucose uptake as measured by a hyperinsulinemic-euglycemic clamp. Taken together, these studies provide support for pharmacological inhibition of myostatin as a potential therapeutic approach for age-related sarcopenia and metabolic disease.

http://www.ncbi.nlm....pubmed/26858428



#11 Steve H

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Posted 29 March 2016 - 11:59 PM

Conboy is right. And what causes tgf beta1 to rise? Two things spring to mind. Senescent cell sasp and glucosepane cross links. Glucosepane has been shown to significantly increase tgf beta levels and its progression is linear looking at the papers I have.

Senolytics to clear senescent cells is the target my lab group is going for and ideally followed up as a second study senolytics plus stem cell therapy.

We also have access to glucosepane and are seeking a skilled biochemist with a lab interested in breaking it. We can even arrange for glucosepane to be sent out to another lab if someone is willing and able to do the work.
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#12 Steve H

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Posted 30 March 2016 - 12:09 AM

We know that tgf beta originates also in the hippocampus via microglia. So is glycation or sasp causing these changes? We know that if inflammation is reduced by alk5 inhibiting stem cells rejuvenate and gives us some clue of what benefits happen if AGE is cleaved. I know the conboys and I think they are right on the money. Tgf beta1 is the bad actor and is implicated in various age related problems. It's certainly not the only problem aging causes but I suspect it's role is substantial
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#13 pone11

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Posted 02 June 2016 - 10:45 AM

 

 

I- I'm ignoring that GDF11 is supposed to have an inhibitory role on brain regeneration for the time being because then the thought experiment becomes too complex for me :happy: - so that's why there was some increase in cognition as well.

 

What?  Wagers found that GDF11 helped the brain.

 

 

I'm pretty sure I read in one of the papers that it blocks brain regeneration.

This is the problem with GDF11 for every paper that says it does something there's one that say it does the opposite.
 

I'm not sure if it was this one or something else. There's too many GDF11 papers on pubmed now.

 

 

I believe the brain regeneration paper you are thinking of might be this one:

http://ac.els-cdn.co...951542cc14d905a

 

The main problem I see with the competing groups at the moment is that they are disputing how to actually measure GDF11 as distinct from myostatin.

 

The other problem appears to be dosing.  Some of these studies are using massive overdoses, with the possibility that this allows GDF11 to bind to other receptors and create undesired effects.


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#14 corb

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Posted 02 June 2016 - 03:16 PM

 

I believe the brain regeneration paper you are thinking of might be this one:

http://ac.els-cdn.co...951542cc14d905a

 

The main problem I see with the competing groups at the moment is that they are disputing how to actually measure GDF11 as distinct from myostatin.

 

The other problem appears to be dosing.  Some of these studies are using massive overdoses, with the possibility that this allows GDF11 to bind to other receptors and create undesired effects.

 

 

Even the Walker group went back and renamed what they measured as - GDF11/GDF8 at some point as I said in the begining, so it's not a difference of opinion. It's rather a realization of inconsistency.

A group months later posted a paper saying they had perfected a way of measuring the two separately. A conclusive answer will come eventually, but so far every other big group to try the GDF11 supplementation has been incapable of replicating the results, and in fact even the Walker group has been posting some results which quite honestly make the whole thing quite questionable - the mice in their experiments seem to be losing weight instead of gaining it, this is not really consistent with muscle regeneration, this is why GDF11 research has moved from sarcopenia to heart disease as a focus as far as I know.


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#15 corb

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Posted 16 June 2016 - 08:54 PM

Now we have some new information so we can move the conversation forward.

According to the recently posted articles in the bionews section GDF11 does not, in fact, decrease with age.

 

In the original papers that started all the hype it was noted that GDF11 regenerates muscles and brains in old animals.

Canonically GDF11 and Myostatin generally inhibit cell proliferation. Not the other way around.

Obviously this is a paradox.

Something which even a couple of weeks after the original paper was published was pointed out in a critique response publication by another lab - on these forums and elsewhere that response was ignored. In some cases otherworldly explanations of this inconsistency were made up by certain blogs (I'm not going to point fingers).

 

The strongest argument for the supplementation of GDF11 was the assumption it decreases with age. That argument is now - pretty much confirmed for false.

 

Unfortunately that does not completely disqualify the original paper - even though as I've pointed out (time after time), no one besides the original group has really been capable of reaffirming it experimentally so far. I'd loved if this could be laid to rest finally so the lucky few possessing a sizable disposable income on these forums could use their money for better things - there are quite a few active crowdfunding projects you can take part in at this moment instead of self experimenting with dubious compounds.


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#16 pone11

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Posted 19 June 2016 - 04:58 AM

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?
 

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#17 corb

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Posted 19 June 2016 - 05:06 PM

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?

 

Some studies note GDF11 injection has negative effects in animals. I've already posted some in different threads:

 

http://www.ncbi.nlm....pubmed/27303621

http://www.ncbi.nlm....pubmed/27034276

 

Some fail to note any significant effect:

 

http://www.ncbi.nlm....pubmed/27139744

 

Some note GDF11 as indicative of disease (on top of the ones in the Mayo clinic article):

 

http://www.ncbi.nlm....pubmed/26932855

 

All of these papers are from the last 30-60 days. That's a large quantity of negative arguments in a very (for the scale of medical research)  short time.



#18 pone11

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Posted 20 June 2016 - 12:22 AM

 

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?

 

Some studies note GDF11 injection has negative effects in animals. I've already posted some in different threads:

 

http://www.ncbi.nlm....pubmed/27303621

http://www.ncbi.nlm....pubmed/27034276

 

Some fail to note any significant effect:

 

http://www.ncbi.nlm....pubmed/27139744

 

Some note GDF11 as indicative of disease (on top of the ones in the Mayo clinic article):

 

http://www.ncbi.nlm....pubmed/26932855

 

All of these papers are from the last 30-60 days. That's a large quantity of negative arguments in a very (for the scale of medical research)  short time.

 

 

Right, but Mayo shines against all of these because they came up with a new and highly accurate method of testing.  All those other studies you are referencing were based on a less accurate method and people could have dismissed those with the claim that they failed to measure GDF11 alone, accurately.



#19 tunt01

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Posted 20 June 2016 - 02:23 AM

 

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?

 

 

Thank you for posting this Mayo study.

 

While I share your skepticism about whatever is left to Wagers' et al. claims re: GDF11, I would not be surprised if we eventually found that GDF11 was elevated in certain of these disease states (diabetes, kidney disease) because it is a growth factor in trying to stimulate a response to a disease state.  

 

In T2D, insulin rises but is ultimately unsuccessful in removing glucose from circulation due to insulin resistance.  I think GDF-11 might be rising because it is part of a process where the body is trying to respond to the disease and stimulate organ/tissue differentiation.  I'm pretty sure GDF-11 stimulates pancreas (pdx-1) differentiation.  

 

Therefore, injecting GDF-11 may not lead to an adverse pathology in the absence of any underlying disease and it isn't a causative factor.

 

It will be interesting to see what happens with GDF-11 over the next couple years as they figure out exactly what it is doing.  I would bet it has some utility in certain circumstances.


Edited by prophets, 20 June 2016 - 02:37 AM.

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#20 corb

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Posted 20 June 2016 - 03:06 AM

 

 

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?

 

Some studies note GDF11 injection has negative effects in animals. I've already posted some in different threads:

 

http://www.ncbi.nlm....pubmed/27303621

http://www.ncbi.nlm....pubmed/27034276

 

Some fail to note any significant effect:

 

http://www.ncbi.nlm....pubmed/27139744

 

Some note GDF11 as indicative of disease (on top of the ones in the Mayo clinic article):

 

http://www.ncbi.nlm....pubmed/26932855

 

All of these papers are from the last 30-60 days. That's a large quantity of negative arguments in a very (for the scale of medical research)  short time.

 

 

Right, but Mayo shines against all of these because they came up with a new and highly accurate method of testing.  All those other studies you are referencing were based on a less accurate method and people could have dismissed those with the claim that they failed to measure GDF11 alone, accurately.

 

 

It's true measuring it properly is important.

But at the same time it's not really applicable to the papers I posted.
In 2 of the papers in that post the labs injected mice with recombinant GDF11 - the same thing Wager's lab did.
The mice did not get better. They even got worse.

Since the original argument was injecting GDF11 is a panacea ... well, it's not.
Maybe it can do something positive in a very specific circumstance.

After rereading the first 2 papers, I see they injured the mice in a very specific manner, even in those papers it was noted GDF11 did nothing if the mice were not injured. So maybe it helps with healing. Or maybe the combination of the way they were injured and GDF11 is important - I think they froze their legs or something similar. Maybe GDF11 helps with frostbite? Who knows.

 

There's so many things that irk me when it comes to this research - for instance - a lot of properties of GDF11 observed were only observed in vitro. No one bothered to reconfirm them in a live animal, but in a lot of papers they were taken as factual. And unfortunately I think created and unrealistic expectation about GDF11, and it doesn't' seem like GDF11 will be able to meet the expectations.


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#21 pone11

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Posted 20 June 2016 - 09:11 AM

 

 

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?

 

 

Thank you for posting this Mayo study.

 

While I share your skepticism about whatever is left to Wagers' et al. claims re: GDF11, I would not be surprised if we eventually found that GDF11 was elevated in certain of these disease states (diabetes, kidney disease) because it is a growth factor in trying to stimulate a response to a disease state.  

 

In T2D, insulin rises but is ultimately unsuccessful in removing glucose from circulation due to insulin resistance.  I think GDF-11 might be rising because it is part of a process where the body is trying to respond to the disease and stimulate organ/tissue differentiation.  I'm pretty sure GDF-11 stimulates pancreas (pdx-1) differentiation.  

 

Therefore, injecting GDF-11 may not lead to an adverse pathology in the absence of any underlying disease and it isn't a causative factor.

 

It will be interesting to see what happens with GDF-11 over the next couple years as they figure out exactly what it is doing.  I would bet it has some utility in certain circumstances.

 

 

The Mayo study did find a relationship to diabetes, and I did quote that:

 

"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."
 
Your description of T2D is not quite correct.  Insulin resistance refers to the fact that high levels of insulin shut off lipolysis, but fail to shut off glucose production by the liver.  Insulin is primarily a signaling hormone to other hormones and processes, such as gluconeogenesis.  The liver fails to respond.   So the person with T2D fails to burn off their fat, while continuing to produce high levels of glucose.
 
An interesting fact is that cells do not require insulin to absorb glucose.  There are other pathways for glucose to get into a cell, and studies record that T2D patients with high glucose levels actually absorb *more* glucose than regular non-T2D patients.  The primary pathology of type 2 diabetes is that insulin fails as a signal to turn off production of glucose in the liver from glycogen and from gluconeogenesis.
 
Not that any of this matters to a GDF11 discussion....


#22 pone11

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Posted 20 June 2016 - 09:18 AM

 

 

 

Right, but Mayo shines against all of these because they came up with a new and highly accurate method of testing.  All those other studies you are referencing were based on a less accurate method and people could have dismissed those with the claim that they failed to measure GDF11 alone, accurately.

 

 

 

It's true measuring it properly is important.

But at the same time it's not really applicable to the papers I posted.
In 2 of the papers in that post the labs injected mice with recombinant GDF11 - the same thing Wager's lab did.
The mice did not get better. They even got worse.

Since the original argument was injecting GDF11 is a panacea ... well, it's not.
Maybe it can do something positive in a very specific circumstance.

After rereading the first 2 papers, I see they injured the mice in a very specific manner, even in those papers it was noted GDF11 did nothing if the mice were not injured. So maybe it helps with healing. Or maybe the combination of the way they were injured and GDF11 is important - I think they froze their legs or something similar. Maybe GDF11 helps with frostbite? Who knows.

 

 

Hey, you might be onto something there.   Steve Perry, who is taking GDF11, reports much higher levels of cardiovascular exercise.  What if the mechanism of action for GDF11 is that it speeds *recovery* from the injury to muscle caused by exercise?   That would then allow a person to recover from each exercise event quicker, and possibly it would spur improvements in strength and exercise fitness because you had better-repaired muscles each time you exercised and could, therefore, exercise more strenuously.   That creates a virtuous cycle of improving fitness.  Most of the benefits actually come from the exercise itself, and GDF11 just accelerates healing between exercise events.   

 

You saw the section on injury in the original Wagers study as well as the follow-up Harvard study?

 

The exercise / injury / repair hypothesis aside, how would we explain the neurogenesis that the Wagers team claimed to see in the mice?    Maybe that is a byproduct of improved fitness as well?



#23 corb

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Posted 20 June 2016 - 10:19 PM

The exercise / injury / repair hypothesis aside, how would we explain the neurogenesis that the Wagers team claimed to see in the mice?    Maybe that is a byproduct of improved fitness as well?

 

There is research in direct contradiction:

http://www.ncbi.nlm....pubmed/21852401

http://www.ncbi.nlm....pubmed/19297409

 

The paragraph from the Conboy paper I started the thread with has some words about it:

 

 

GDF11 in neurogenesis serves to limit the numbers of neural stem cells [43, 44] and this discrepancy was not cited or discussed in the pro-rejuvenation papers. GDF11 signals through the same receptor as TGF-beta1 and myostatin (more efficiently than myostatin [40] and inhibition (not activation) of this ALK5 receptor has been shown to enhance and rejuvenate myogenesis and also, neurogenesis [6, 37]. The bulk of data questions the anti-aging effects of GDF11, and makes the Cell Metabolism paper important for avoiding years of unproductive research in the wrong directions.

http://www.ncbi.nlm....les/PMC4637204/

 

As long as the contradictions remain unresolved I really prefer not to bother myself with too much conjecture.

And by the way the paper that implied neurogenesis is improved was one of the in vitro only experiments, so fitness would've made no difference considering they had a petri dish of cells instead of a complete animal.

 

 


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#24 corb

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Posted 27 June 2016 - 10:41 PM

 

Differential Binding Activity of TGF-β Family Proteins to Select TGF-β Receptors.

 

Growth differentiation factor-11 (GDF11) and Myostatin (MSTN) are highly related TGF-β ligands with 89% amino acid sequence homology. They have different biological activities and diverse tissue distribution patterns. However, the activities of these ligands are indistinguishable in in vitro assays. SMAD 2/3 signaling has been identified as the canonical pathway for GDF11 and MSTN, However, it remains unclear which receptor heterodimer and which antagonists preferentially mediate and regulate signaling. In this study, we investigated the initiation and regulation of GDF11 and MSTN signaling at the receptor level using a novel receptor dimerization detection technology (PathHunter®, DRX). We utilized the dimerization platform to link early receptor binding events to intracellular downstream signaling. This approach was instrumental in revealing differential receptor binding-activity within the TGF-β family. We verified the ActR2b/ALK5 heterodimer as the predominant receptor for GDF11- and MSTN-induced SMAD 2/3 signaling. We also showed ALK7 specifically mediates Activin-B signaling. We verified Follistatin as a potent antagonist to neutralize both SMAD2/3 signaling and receptor dimerization. More remarkably, we showed that the two related antagonists, GASP1 and GASP2 differentially regulate GDF11 (and MSTN) signaling. GASP1 blocks both receptor dimerization and downstream signaling. However, GASP2 blocks only downstream signaling without interference with receptor dimerization. Our data strongly suggest that physical binding of GDF11 (and MSTN) to both ActR2b and ALK5 receptors is required for initiation of signaling.

 

The American Society for Pharmacology and Experimental Therapeutics.

 

http://www.ncbi.nlm....pubmed/27340210

 

So two things we can get out of this:

  1. Parish very much has inhibited both Myostatin and GDF11 with her Follistatin gene therapy - we know for sure now. Of course we have to consider the transfection rate of AVV and then consider how much Follistatin you actually need to be producing to inhibit Myostatin fully, so probably she's not REALLY inhibiting them as such but just throwing in a tiny spanner... well, that's for another thread.
  2. Circulating GDF11 might compete with Myostatin for binding sites if it's supplemented a couple hundred times above the norm - which isn't hard to do in a mouse - and is significantly harder in anything bigger.

Don't quote me on the second one, ask a biochemist instead.
Anyway if stopping Myostatin from binding is the point, Follistatin does that better. You still need to take a significant amount of the stuff as far as I've heard though, so not a significantly cheaper or easier to get option.



#25 corb

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Posted 06 July 2016 - 10:14 AM

I went through the Steve Perry thread and he's posed an interesting question - is mature GDF11 or latent GDF11 what is being measured in the different papers.

 

 

However, we are not yet able to determine
the relative proportions of either latent versus mature GDF11
or MSTN, or unbound versus bound (to propeptide, GASP1,
FLRG, or other binding proteins) mature GDF11 or MSTN.
Indeed, additional methodological advances that resolve these
limitations will yield important insights into the abundance and

regulation of these fascinating proteins. An additional contributor
to the inconsistent conclusions about GDF11’s role in aging may
be the experimental contexts (e.g., species, models, doses of re-
combinant protein) in which it has been studied. These issues
have been discussed exhaustively elsewhere (Egerman et al.,
2015; Harper et al., 2016; McNally, 2016; Walker et al., 2016).

 

It seems they measure both combined, unless I'm misreading the paper. They wouldn't be talking about proportions otherwise - still it's a good thing to send Mayo an email, I might do it myself.
If it's combined amount for certain, then possibly it could grow as a combined quantity while the mature and bound separately go down.
I'm not sure by what logic simply injecting extra would force it to mature and bind in that case.
Let alone why injecting just the "right" amount would be important, considering you'd already have extra circulating around.

 

So yeah. I'm not sure how long it could take for me to get a reply if I do send them an email, I'm not a part of an institution ... I guess I could say I'm a journalist, but anyone with a blog does that nowadays, I doubt it'll hasten the reply significantly.

 

Anyway the wording in the paper makes it seem like they measure it combined, best answer you can get for now

 

edit: To be clear, this is from the Mayo Clinic paper. Also after a quick check it seems the research lead is very much focused on GDF11/GDF8 research, so you could say he knows his stuff. I decided I will definitely send him an email, since Myostatin is his focus of research there's a greater chance I'll get a reply.


Edited by corb, 06 July 2016 - 10:37 AM.

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#26 corb

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Posted 06 July 2016 - 04:03 PM

And the answer :

 

the post-translational modifications to myostatin and where they occur are complex and, in part, poorly understood. At this time, we are measuring GDF11 (and distinguishing it from GDF8) by monitoring peptides in the mature region. We do not know if this has been “released” or not from the latent complex. At this stage, best to refer to it as combined or ‘total’ GDF11.
Best-
Nathan LeBrasseur

 



#27 to age or not to age

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Posted 06 July 2016 - 06:32 PM

Personally, having interviewed Irina Conboy (and her partner Michael Conboy) at length on video this past October, I think the discussion (or a separate new one) should concentrate on her work.  I have been remiss and not posted video excerpts,  but her brilliance, insight, and ability to draw disparate ideas together - her method is to do " in biblio" research - leads her to effectively cut to the chase.  She is  sophisticated and thinks it is now a matter of the administration and dosage of a couple substances.  Conboy is ready to put up. And, with regard to Wagers, with whom she worked at Stanford , Irina was politic but quite convinced Wagers had gotten certain things wrong. 

In terms off funding, she explained the morass of NIH funding, as a number of other scientists have told me.  To wit: the methodology of  funding is simply flawed, and the fact that NIH budgets have basically flatlined is an outrage which causes scientists to play the funding game and waste time rather than do research.  


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#28 corb

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Posted 06 July 2016 - 07:49 PM

I am quite aware of her work which is why I started the thread to begin with.
She's developing a drug which reinvigorates old stem cells by blocking TGF beta proteins.

GDF11 and GDF8 are part of this family of proteins, that is why I've been skeptical of GDF11 supplementation, both blocking and supplementing can't have the same effect ;).
Granted the majority of the literature is in favour of blocking rather than supplementing as well, so I didn't base my opinion solely on Conboy's work of course. That would be hypocrisy.


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#29 pone11

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Posted 15 July 2016 - 01:20 AM

Personally, having interviewed Irina Conboy (and her partner Michael Conboy) at length on video this past October, I think the discussion (or a separate new one) should concentrate on her work.  I have been remiss and not posted video excerpts,  but her brilliance, insight, and ability to draw disparate ideas together - her method is to do " in biblio" research - leads her to effectively cut to the chase.  She is  sophisticated and thinks it is now a matter of the administration and dosage of a couple substances.  Conboy is ready to put up. And, with regard to Wagers, with whom she worked at Stanford , Irina was politic but quite convinced Wagers had gotten certain things wrong. 

In terms off funding, she explained the morass of NIH funding, as a number of other scientists have told me.  To wit: the methodology of  funding is simply flawed, and the fact that NIH budgets have basically flatlined is an outrage which causes scientists to play the funding game and waste time rather than do research.  

 

Why didn't you put up the video on Youtube?


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#30 alc

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Posted 15 July 2016 - 07:26 AM

Personally, having interviewed Irina Conboy (and her partner Michael Conboy) at length on video this past October, I think the discussion (or a separate new one) should concentrate on her work.  I have been remiss and not posted video excerpts,  but her brilliance, insight, and ability to draw disparate ideas together - her method is to do " in biblio" research - leads her to effectively cut to the chase.  She is  sophisticated and thinks it is now a matter of the administration and dosage of a couple substances.  Conboy is ready to put up. And, with regard to Wagers, with whom she worked at Stanford , Irina was politic but quite convinced Wagers had gotten certain things wrong. 

In terms off funding, she explained the morass of NIH funding, as a number of other scientists have told me.  To wit: the methodology of  funding is simply flawed, and the fact that NIH budgets have basically flatlined is an outrage which causes scientists to play the funding game and waste time rather than do research.  

 

I wish things are tested sooner (that is why we need trials that are focused just on rejuvenation technology). I suggested 

to Lifespan team to have Conboys (and other researchers) create projects there.

I'm sure most of us will donate small sums to clarify things, instead of keep arguing.

It is just bad that in 2016 potential work that can lead to rejuvenation (even if it is just partial) sit

there waiting for funding. I follow their work (and Rando's) for years now, hoping some person with

lots of money will donate to her work.

 

Her team ("Futicon") is on Palo Alto Prize.

 

http://paloaltoprize.com/team/futicon/

 

they use Oxytocin
 







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