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Will GDF-11 Cure Aging? (split from NEUMYO-OA trial)


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#151 Bryan_S

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Posted 09 February 2015 - 05:26 PM

Keep in mind they sorted out a particular cell type to make this observation. They are not making a singular distinction that these were the only cells benefiting. This is how they did it: Satellite cells can be isolated by Fluorescence Activated Cell Sorting based on their unique surface marker profile (CD45−Sca-1−CD11b−CXCR4+β1-integrin+), which effectively distinguishes them from non-myogenic cells and more differentiated myoblasts within the muscle. Also remember systemic GDF11 could reverse age-related cardiac hypertrophy and this was not stem cell based. These cells were fully mature cardiac tissue and yet they were brought back to a youthful state. There still remains some very deep questions as to the full range of all tissues affected? Does the protein enable the cell to fix the DNA problems or are the damaged cells just eliminated and heathy satellite cells promoted to replace them. These are early findings and more research needs to be done.

 

Also suggesting something beyond stem cell repair is happening, here is another excerpt. In addition, electron microscopy of uninjured muscle revealed striking improvements of myofibrillar and mitochondrial morphology in aged mice treated with rGDF11 (Fig. 3A). Treated muscles showed reduction of atypical and swollen mitochondria, reduced accumulation of vacuoles, and restoration of regular sarcomeric and interfibrillar mitochondrial patterning (Fig. 3A). Consistent with these ultrastructural improvements, levels of Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis, were increased in the muscle of aged rGDF11-treated mice (Fig. 3B), suggesting that GDF11 may affect mitochondrial dynamics of fission and fusion to generate new mitochondria. Consistent with this notion, in vitro treatment of differentiating cultures of aged satellite cells with rGDF11 yielded increased numbers of multi-nucleated myotubes exhibiting greater mitochondrial content and enhanced mitochondrial function (Fig. S13). Finally, we observed increased basal levels of autophagosome (macroautophagy) markers (assessed as the ratio of autophagic intermediates LC3-II over LC3-I), in the uninjured skeletal muscle of rGDF11-treated aged animals (Fig. 3C). Collectively, these data suggest enhanced autophagy/mitophagy and mitochondrial biogenesis as likely explanations for the cellular remodeling of muscle fibers in rGDF11-treated aged mice.

 

What does this mean, well enhanced mitochondrial function and mitochondrial biogenesis suggests a remodeling and repair of the affected tissues. This suggests something beyond stem cell repair is happening as old tissue is made more functional.

 

http://europepmc.org...cles/pmc4104429


Edited by Bryan_S, 09 February 2015 - 05:27 PM.

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#152 Bryan_S

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Posted 09 February 2015 - 07:39 PM

South Side researcher seeks more crowdfunding to make pets live longer

Mr. Jarvik, a Ph.D. in genetics and a Carnegie Mellon University professor, is interested in GDF11, a protein generated by a gene of the same name that’s generating excitement worldwide, including at the National Institute of Aging.

 

http://www.post-gaze...es/201501290117

 

Professor’s Crowdfunding To Research Age Reversal Of Pets

http://www.focusnews...ationalnews.php


Edited by Bryan_S, 09 February 2015 - 07:41 PM.


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#153 pone11

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Posted 19 February 2015 - 11:23 PM

I spoke to a neurologist today regarding the experiment that Stanford is trying with injecting plasma of young people into old people.   The neurologist said that doing any plasma infusion to an older person is not a zero risk procedure, and one of the possible side effects is kidney failure.   I had limited time with him, and I'm wondering if others here know about plasma infusion side effects and what amounts of plasma are typically required for those to be a substantial risk.

 

The risk I would be more worried about is a blood borne disease (e.g., AIDS).   Sure, they screen for the major viruses, but I'm sure there are many others that they do not screen for.



#154 niner

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Posted 20 February 2015 - 12:10 AM

While I think that occasional infusions of plasma into old people is unlikely to do much good, the kidney failure thing sounds a little overblown.  What would be the mechanism for that?



#155 pone11

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Posted 20 February 2015 - 12:57 AM

While I think that occasional infusions of plasma into old people is unlikely to do much good, the kidney failure thing sounds a little overblown.  What would be the mechanism for that?

 

It might be acute renal failure from AHTR, as described here:

http://www.merckmanu...ransfusion.html

 

But honestly most of the reactions on that page I just do not understand.



#156 niner

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Posted 20 February 2015 - 01:57 AM

 

While I think that occasional infusions of plasma into old people is unlikely to do much good, the kidney failure thing sounds a little overblown.  What would be the mechanism for that?

 

It might be acute renal failure from AHTR, as described here:

http://www.merckmanu...ransfusion.html

 

 

I don't think it's that, because AHTR is an immune reaction to antigens on donor erythrocytes, but plasma doesn't have erythrocytes.  Maybe if there were some weird antibodies in the donor plasma, or other troublesome antigens, then you could have a problem, but fundamentally I think a plasma infusion (assuming it's non-infectious) would be pretty safe.   I don't expect it will do much for these people, but neither do I worry that it will hurt them.


Edited by niner, 20 February 2015 - 01:58 AM.


#157 Bryan_S

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Posted 20 February 2015 - 05:50 AM

 

Follow the Somalogics link above, data may already be out there as many are asking these very same questions, if we knew what youthful levels were we'd have a better handle and know what to shoot for.

 

I looked at the Somalogics site, and didn't see anything about work with Wagers, but the assay (which is very cool, btw) works between the range of  1 uM to 25 fM.   So I guess that gives you a range (8 orders of magnitude...)  GDF11 is 25 kDa, so if you inject 500 ug into an approximate 5 liter blood volume, you get:

 

500e-6 g (mol/25,000g)  / 5 liter = 4 nM.   So this is at least in the range of the assay.

 

This is NOT an actual blood level.  It's a wild approximation based on HED sorcery and lots of assumptions.  It's probably off by at least a factor of ten, if not more.  I'm sure that someone knows the level in youthful human blood, we just need to find that, then figure out how to determine our own blood levels...  (technology needed... Maybe the Somalogics assay would work.  It would probably cost more than the GDF11, if the 400 USD/g price is for real (which seems unlikely).

 

 

I never thanked you for these insightful comments. I do think the full array young blood factors would be superior to GDF11 alone but obtaining it would require some ghoulish endeavor to achieve and maintain long term. 

 

Remember our previous conversation about making it, well we aren't the only ones to propose this.

http://holographicga...al-old-age.html

 

So realistically how complicated is it to produce GDF11 from a mammalian expression system in high enough quantities to be of use?  Yea I'm thinking mammalian. I know everyone else is using Escherichia coli at the moment but what about the proper glycosylation and protein folding, which the mammalian expression systems are known for. Plus Escherichia coli produces endotoxins which have to be removed.

 

As I've mentioned previously I've located some readily available GDF-11 plasmids. The mammalian lipid reagents for plasmid transfection are also readily available. Can something like this be cultured and purified at home or is this total nonsense?



#158 niner

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Posted 20 February 2015 - 10:42 PM

My sense of it is that it is very difficult and would require a lot of equipment that the average kitchen doesn't have.   The holographic galaxy guy is either a super genius who doesn't communicate well or comically clueless.  I lean toward the latter...



#159 pone11

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Posted 21 February 2015 - 12:01 AM

My sense of it is that it is very difficult and would require a lot of equipment that the average kitchen doesn't have.   The holographic galaxy guy is either a super genius who doesn't communicate well or comically clueless.  I lean toward the latter...

 

Like everything in science, the holographic galaxy guy should prove his own claims, not leave them as an exercise for the reader.   Let's see him mass produce GDF11 using the technique he describes, then separate out the GDF11 and provide some lab measurements of his home brew.

 

I personally hate sites like this.  They string together facts to create the appearance of knowledge when in fact they are just building an open ended hypothesis and offering no proof that it can actually be accomplished.   


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#160 pone11

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Posted 21 February 2015 - 08:56 AM

Well, this is not a very positive study for this thread:

http://www.ncbi.nlm....les/PMC4215333/

 

Old mice injected once a week with plasma from young mice do NOT live longer.

 

The study could be criticized because they only inject plasma once a week, whereas parabiosis is guaranteeing the appropriate components are available to the old mouse at all times.   The response to that might be that if reversing aging requires an old person to get a plasma infusion every single day, then the idea just is not workable.   There would be significant risk of blood borne infections and side effects getting 365 plasma infusions a year.  Moreover, where are you ever going to find that much donor blood?

 

If humans react like mice did, the Stanford blood plasma study with alzheimer's patients will not reach a good endpoint.   Those patients are being infused once a week.

 

Daily GDF11 injections - later to be supplemented with other anti-aging proteins / peptides as they are discovered - appears to be the only approach that would hold any hope to scale to constant use.

 


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#161 markymark

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Posted 21 February 2015 - 02:02 PM

Hello all,

I hope that this is not redundant, or off topic. Here is something about GDF-11 levels in humans.

http://content.onlin...7/07804.pdf.gif

 

The reseachers found, that high levels of GDF-11 were associated with lower prevalence of left ventriclar hypertrophy (LVH). Sadly they do not provide GDF-11 serum levels in healthy and old patients with heart disease. It was a poster presented at the ACC.14

 

There is also a paper in pubmed

http://www.ncbi.nlm....pubmed/25260834

regs

MM

 

 

 

 

 

 


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#162 Bryan_S

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Posted 22 February 2015 - 05:46 PM

Thanks markymark  :-D

 

prone11 "Well, this is not a very positive study for this thread:

http://www.ncbi.nlm....les/PMC4215333/"

 

That is downright disappointing. Amy Wagers Phd has already criticized the Wyss-Coray study saying it could set back the whole field of study if they fail. This adds weight that they may already be on that road.


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#163 pone11

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Posted 22 February 2015 - 08:16 PM

Thanks markymark  :-D

 

prone11 "Well, this is not a very positive study for this thread:

http://www.ncbi.nlm....les/PMC4215333/"

 

That is downright disappointing. Amy Wagers Phd has already criticized the Wyss-Coray study saying it could set back the whole field of study if they fail. This adds weight that they may already be on that road.

 

At the same time, we know that Amy's studies show that daily GDF-11 injections work nearly as well as parabiosis.   So phase 2 of the Wyss-Coray study should be daily GDF11 injections in humans, and that study I predict is going to produce some shocking good results.



#164 Bryan_S

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Posted 23 February 2015 - 12:18 AM

 

Thanks markymark  :-D

 

prone11 "Well, this is not a very positive study for this thread:

http://www.ncbi.nlm....les/PMC4215333/"

 

That is downright disappointing. Amy Wagers Phd has already criticized the Wyss-Coray study saying it could set back the whole field of study if they fail. This adds weight that they may already be on that road.

 

At the same time, we know that Amy's studies show that daily GDF-11 injections work nearly as well as parabiosis.   So phase 2 of the Wyss-Coray study should be daily GDF11 injections in humans, and that study I predict is going to produce some shocking good results.

 

 

This was a rush to gain the glory and future funding, plain and simple. The money to fund these endeavors is highly speculative to begin with. Wyss-Coray didn't plan to take that path and include GDF11. We've all ready learned how exorbitantly expensive lab quantities of the protein are. If his subjects show no cognitive improvements from the plasma the news won't add any momentum and likely seed doubt.

 

We'll keep our fingers crossed but a once a week plasma injection appears to be inadequate from your post.

 

Oh, good find by the way! This opens the door for someone to give it a shot but I believe its going to be a soup to nuts organization that can produce a trial like this because of the costs. Maybe Wyss-Coray can get one of the labs to produce the stuff on campus?  



#165 niner

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Posted 23 February 2015 - 03:06 AM

At the same time, we know that Amy's studies show that daily GDF-11 injections work nearly as well as parabiosis.   So phase 2 of the Wyss-Coray study should be daily GDF11 injections in humans, and that study I predict is going to produce some shocking good results.

 

Is that in the works already?  i.e., do you know that they are planning on doing GDF-11 injections, or are you just saying that it would be a good idea?  I think it would be a good idea, although it's a much bigger hurdle to get that through the Institutional Review Board, compared to plasma.  It's a question of "safety" for the otherwise-doomed patients.



#166 pone11

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Posted 23 February 2015 - 04:49 AM

 

At the same time, we know that Amy's studies show that daily GDF-11 injections work nearly as well as parabiosis.   So phase 2 of the Wyss-Coray study should be daily GDF11 injections in humans, and that study I predict is going to produce some shocking good results.

 

Is that in the works already?  i.e., do you know that they are planning on doing GDF-11 injections, or are you just saying that it would be a good idea?  I think it would be a good idea, although it's a much bigger hurdle to get that through the Institutional Review Board, compared to plasma.  It's a question of "safety" for the otherwise-doomed patients.

 

 

Good point.  I was suggesting it would be an obvious thing to try next, if weekly plasma injections fail.  Ironically, plasma is probably much more dangerous than purified GDF11, but I agree with you that a review board may see plasma as a known quantity, whereas GDF11 may be seen as a pure unknown.   Someone has to cross that hurdle and start using GDF11 on humans, or we are going to run in circles around this for a decade.



#167 serp777

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Posted 23 February 2015 - 07:25 AM

Could GDF11 help prevent cancer because there is a strong link between aging and cancer? Could this also potentially protect damage to cardiac cells or liver cells over time? How safe would it theoretically be long term?



#168 pone11

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Posted 23 February 2015 - 10:37 PM

Could GDF11 help prevent cancer because there is a strong link between aging and cancer? Could this also potentially protect damage to cardiac cells or liver cells over time? How safe would it theoretically be long term?

 

That's the main question - will GDF11 increase the incidence of cancer - and it is currently not answered.   There are not even long term safety studies in mice receiving GDF11 daily.   And there are no studies in humans receiving GDF11 at all, at least not to my knowledge.



#169 pleb

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Posted 23 February 2015 - 10:52 PM

I can't see it increasing cancer as its a hormone found naturally in our blood that decreases with age. Just one of about 400 floating around in there.
As long as it's not over done regarding the amount taken I can't see a problem.
I can't see it increasing cancer as its a hormone found naturally in our blood that decreases with age. Just one of about 400 floating around in there.
As long as it's not over done regarding the amount taken I can't see a problem.
Sorry for the double post my kindled playing up. Again

#170 pone11

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Posted 23 February 2015 - 11:25 PM

I can't see it increasing cancer as its a hormone found naturally in our blood that decreases with age. Just one of about 400 floating around in there.
As long as it's not over done regarding the amount taken I can't see a problem.
Sorry for the double post my kindled playing up. Again

 

Right, but the response might be that GDF11 seems to activate growth of stem cells.  That is what explains growth of neurons, repair to cardiac tissue, etc.   

 

I also do not think it will cause cancer, but this is a risk and needs to be verified.



#171 Bryan_S

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Posted 24 February 2015 - 01:41 AM

Could GDF11 help prevent cancer because there is a strong link between aging and cancer? Could this also potentially protect damage to cardiac cells or liver cells over time? How safe would it theoretically be long term?

 

You guys are picking up on an earlier post: http://www.longecity.org/forum/topic/73209-will-gdf-11-cure-aging-split-from-neumyo-oa-trial/page-5#entry712649

 

​From a DNA repair standpoint I can see your interest. Cancers are believed to be the result of DNA mutations. I just read an article outlining the problem with this repair process this morning. 'DNA spellchecker' means that our genes aren't all equally likely to mutate.

 

 

Its a bit early to draw this conclusion but if GDF11 initiates stem cell DNA repair as this Wagers study referenced http://europepmc.org/articles/pmc4104429 there might be something to your notion.

 

But keep in mind as the article about the DNA spell checker suggests, some areas of the genome are not checked well enough. They also didn't suggest there was an answer to this problem. I'm absolutely sure Amy Wagers lab has tabled this question based on their earlier findings suggesting repair. I'm sure from their perspective it's on the to-do list but there has been nothing published that remotely suggests they will be performing the tests to answer this question.


Edited by Bryan_S, 24 February 2015 - 01:53 AM.


#172 niner

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Posted 24 February 2015 - 02:08 AM

I can't see it increasing cancer as its a hormone found naturally in our blood that decreases with age. Just one of about 400 floating around in there.
As long as it's not over done regarding the amount taken I can't see a problem.

 

A lot of pro-growth factors that decrease as we age are being down-regulated so that we are not as susceptible to the cancer that is more likely as we age.  If we start jacking them back up again without understanding exactly what they're doing, we might be asking for trouble.


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#173 Alpharius

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Posted 24 February 2015 - 06:42 PM

 

 

A lot of pro-growth factors that decrease as we age are being down-regulated so that we are not as susceptible to the cancer that is more likely as we age.  If we start jacking them back up again without understanding exactly what they're doing, we might be asking for trouble.

 

 

 

Assuming that our body does downregulate some factors with high age in order to protect us from cancer would also implicate, that the evolution has somehow selected this mechanisms to care about cancer in high age. But this seems unlikely, as our ancestors were not living that long, that any kind of evolutionary selection in this direction could take place. I do not really share this opinion. Do you have any references or theories which support this?


Edited by Alpharius, 24 February 2015 - 06:44 PM.

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#174 pone11

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Posted 24 February 2015 - 08:15 PM

 

 

 

A lot of pro-growth factors that decrease as we age are being down-regulated so that we are not as susceptible to the cancer that is more likely as we age.  If we start jacking them back up again without understanding exactly what they're doing, we might be asking for trouble.

 

 

 

Assuming that our body does downregulate some factors with high age in order to protect us from cancer would also implicate, that the evolution has somehow selected this mechanisms to care about cancer in high age. But this seems unlikely, as our ancestors were not living that long, that any kind of evolutionary selection in this direction could take place. I do not really share this opinion. Do you have any references or theories which support this?

 

That's a good point regarding natural selection having no influence on an animal's tendency to get cancer once they are well past a breeding age.   In fact - if we are examining society prior to organized groups going back maybe 60K years - you could even argue that natural selection might favor killing off humans that are into "old age" because that will increase the productive breeding of younger people who are more likely to successfully raise a child in very harsh conditions.   At worst, natural selection would probably be neutral, not protective of the aging person.

 

The counter argument might be that within the last 60K years when organized human groups formed, there was an evolutionary value in keeping older people alive, for their wisdom and experience.   The problem with that argument is that long-lasting evolutionary changes take about one million years to stick:

http://phys.org/news...lion-years.html

 

They still need to test whether daily GDF11 injections increases risk of cancer.

 

As pure hypothesis, I think it is more likely that with age there is a simple wearing down of metabolism, which then produces less of many critical proteins, peptides, and enzymes.   Some of these - like GDF11 - are responsible for promoting tissue replacement from stem cells.  With less stem cell turnover, the overall balance of tissues becomes more aged, less efficient, and this then starts the organism on a downward cycle of aging.


Edited by pone11, 24 February 2015 - 08:16 PM.


#175 niner

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Posted 25 February 2015 - 02:37 PM

 

A lot of pro-growth factors that decrease as we age are being down-regulated so that we are not as susceptible to the cancer that is more likely as we age.  If we start jacking them back up again without understanding exactly what they're doing, we might be asking for trouble.

 

Assuming that our body does downregulate some factors with high age in order to protect us from cancer would also implicate, that the evolution has somehow selected this mechanisms to care about cancer in high age. But this seems unlikely, as our ancestors were not living that long, that any kind of evolutionary selection in this direction could take place. I do not really share this opinion. Do you have any references or theories which support this?

 

I would agree if "high age" meant 65, but not if "high age" means 35.  The "grandmother hypothesis" says that having grandparents around to help care for children increases their likelihood of survival.  I think that this is quite likely.  It's a common misconception that our ancestors had uniformly short lifespans.  That isn't the case.  They had very high childhood mortality, but if they survived early childhood, they could attain ages that were not dramatically less than is typical today.  It's just that today, almost everyone survives childhood.

 

When complex multicellular life first evolved, cancer was perhaps the biggest threat it faced.  We have evolved a LOT of mechanisms to keep uncontrolled growth in check.  While some of them are in place at the beginning of life, others appear to start around the time that development ends, perhaps at the age of 25 in humans.   The down-regulation of pro-growth factors in the face of ever-increasing risk of cancer is consistent with this.


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#176 niner

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Posted 25 February 2015 - 02:52 PM

That's a good point regarding natural selection having no influence on an animal's tendency to get cancer once they are well past a breeding age.   In fact - if we are examining society prior to organized groups going back maybe 60K years - you could even argue that natural selection might favor killing off humans that are into "old age" because that will increase the productive breeding of younger people who are more likely to successfully raise a child in very harsh conditions.   At worst, natural selection would probably be neutral, not protective of the aging person.

 

The counter argument might be that within the last 60K years when organized human groups formed, there was an evolutionary value in keeping older people alive, for their wisdom and experience.   The problem with that argument is that long-lasting evolutionary changes take about one million years to stick:

http://phys.org/news...lion-years.html

 

Evolutionary anthropologists would side with the counter argument.  Here's a review of the grandmother hypothesis.  The idea that killing off older people would be beneficial to the group would only apply under conditions of severe food scarcity.  While that undoubtedly occurred in many cases, it's not taking into account the value of a non-breeding pair of hands, not to mention the knowledge repository of the older cohort.  These effects probably evolved over millions of years, not just in the last 60K.



#177 Bryan_S

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Posted 25 February 2015 - 04:12 PM

 

Evolutionary anthropologists would side with the counter argument.  Here's a review of the grandmother hypothesis.  The idea that killing off older people would be beneficial to the group would only apply under conditions of severe food scarcity.  While that undoubtedly occurred in many cases, it's not taking into account the value of a non-breeding pair of hands, not to mention the knowledge repository of the older cohort.  These effects probably evolved over millions of years, not just in the last 60K.

 

 

I remember reading something to that affect. Grandparents were useful in helping to teach and raise the young, this added to the continuing success of the community.



#178 pleb

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Posted 26 February 2015 - 08:53 AM

I agree that growth factors need to be checked because of the possible increase in the cancer risk but like many things it is only a possibility that it will increase risk despite research including giving kids anywhere between 4 and 8 times the normal levels solidly for two years because of lack of growth a study in 2006 showed no increase in cancer rates amongst this group compared to the norm. Although a possible increase in risk.

I'm not sure what one would call dying at a younger age years ago. For quite some time now the age of our ancestors and death rates for the average have not used the traditional methods. Science has given historians and others the ability to not only detect how old they were when they died but also if they died from disease.
Hundreds of bones from early middle age grave sites have been studied both here and in Europe. The average age in Anglo Saxon sites from 400 ad up to 1000 ad give and average lifespan for adults of 36.2 years. 65 graves recently opened and examined gave the oldest dying at 45.
By 1500 average life span was 42. These are from bones teeth etc from adults who did not die from any life threatening disease.
We actually have written records giving ages and dates of births and deaths of various people going back well over a thousand years the averages given ignore the high infant mortality rate which in Anglo Saxon times was 1 in 3 at birth and only 1 in 10 reaching the age of 21.
The kings of Scotland and England in 1500 reached the ages of 48 and 52 the king of England had 16 children only one lived to adulthood.

#179 markymark

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Posted 27 February 2015 - 08:20 AM

Here is an interesting talk about GDF-11 and sarcopenia from 2014... 18 mins long

https://www.youtube...._uCe3tNv0#t=514



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#180 Bryan_S

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Posted 02 March 2015 - 05:46 PM

Young Blood Fights Effects Of Aging In Old Bodies Forbes/Wolfe Emerging Tech Report 2/24/2015

 

http://www.forbes.co...-in-old-bodies/

 

 

 

How We Age

From DNA damage to cellular miscommunication, aging is a mysterious and multifarious process.

By The Scientist Staff | March 1, 2015

http://www.the-scien...tle/How-We-Age/


Edited by Bryan_S, 02 March 2015 - 05:56 PM.





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