266 replies to this topic

[corb]

Two questions:

 

1) The germline seems to repair its damage, such as AGEs and mitochondrial mutations (with subsequent functional limitations) over millions of years. How does it happen?

 

2) In species with negligible senescence, repair mechanisms seem to be fully adequate?

 

1. Mitochondrial disease in infants.  How do they happen?
   In the case of mtDNA, this paper can give you a perspective how imperfect actual germline "repair" is : http://www.nature.co.../hdy201260a.htm
   
   Autism is a good example. A disease that would not exist if mitochondria were perfectly "repaired" during fertilization.
   
    
2. It's not a good idea to compare humans to clams or protozoa. We live in a different environment, have a different metabolism, eat a completely different diet, have a somewhat different biology, and so on. In fact any research being done on such organisms is mostly useless and has produced no results that can even hint at any therapy that can be translated to mammals, let alone humans.
   
   But to give you an example the forkhead line of genes that is supposed to be the main drive for negligible senescence in clams is already active in humans - and sure enough it does make humans more long lived but definitely not senescence resistant.

Edited by corb, 25 January 2015 - 06:25 PM.

[LeeYa]

 

1. Mitochondrial disease in infants.  How do they happen?
   In the case of mtDNA, this paper can give you a perspective how imperfect actual germline "repair" is : http://www.nature.co.../hdy201260a.htm
   
   Autism is a good example. A disease that would not exist if mitochondria were perfectly "repaired" during fertilization.

 

 

The paper shows, that male fruit flies also can contribute to the mitochondrial pool, at least to some extend. So what?

 

If germline repair would be imperfect per se, our entire existence would be impossible. However, there is no doubt that repair mechanisms can be impaired during the process, and of course you can imagine fatal damage, that can not be repaired.

[xEva]

Wow xEva, you are something else.    You added so much compression noise to the part of the graph you snipped out that it is illegible.  Here it is with less distortion, and including the point at about 27 years that you conveniently excised. 
 
Pentosidine vs age young.GIF
Yes.  I believe this is statistically significant.  It shows EXACTLY what we would expect for AGE accumulation occurring continuously.  The teenagers have more than the children, and the ~27 year old has more than the teens.  Sorry, but 27 is not far enough from 25 to be "irrelevant", no matter how much you say it.   If biological chemistry worked the way you think it does, then you would not see a linear increase.  You would see a flat line that suddenly starts to rise in the mid twenties.  That's not what the data shows.    The rate of increase from teens to mid 20's is completely consistent with the rate seen in the older subjects.
 
If biochem works the way you think it does, and AGEs in people under 25 are getting removed, by what process is this occurring?  The only way I know of to get rid of them is to digest the protein and express a new one.  Do you think that children are constantly remodeling their ECM or their other long-lived tissues?  I don't think there is any evidence to that effect.
 
This hypothesis of yours appears to be based entirely on your visual impression of young adults, and not much else.  Have you ever spent much time around children?  If you have, perhaps you have noticed that their skin is very soft and smooth when they are very young, but it coarsens over time.  A two year old and a twelve year old have different skin, and a 22 year old continues the trend.

 
-?! What compression noise I supposedly added? I only copied the graph you posted into Paint, cut it at 25 and removed the line that linked it to the out of range >25 data. I also scaled up the resulting detail 3 times, because it was too small, which only amplified the noise in your low-res original. You did not post the link to the full text. How many people <25 did they have there? I don't think that those 5 (or 6 with that >25 guy) is enough to make such sweeping conclusions, even if it looked perfect in all respects.

And why do you insist on that >25 person? Just recently you said:
 

It's not all 30 year old plasma.  The donor population is 30 and younger, so it could range down as low as 18.  Personally, I would have cut it off at 25.

And then you stress, that, because you don't know a process by which AGEs can be removed, therefore there is no way it can happen -?? There are a lot of things we don't know. Why, only recently you discovered a lot of new stuff about mitochondria you never knew existed.

And then you talk about babes' skin. I don't want the skin of a 2-year old. It's not practical. The studies of "sun damage" in children that were spoken about here were all snapshots in time (and none posted here showed accumulation). Everyone gets "sun-damaged" after a summer on the beach. But look at the same children in the end of winter, like in high latitudes where I grew up. The sun rises at 11 AM and sets by 3 PM there, so you go to school when it's dark and you return from school when it's dark. The skin recovers from all the "damage" (well, tan, actually) it sustained in summer. That's my experience. But I can see how California kids could be accumulating sun damage, for the simple reason that their skin does not get a break and recover, like ours did.


The ball is really in the accumulation of damage theory court. So far, all you managed to produce in its support is the Czech forensic study, available only as abstract, with data for ~145 people ages 16-95, with unknown number of those <25 -- plus this study, with no link to full text either, of unknown number of people ages 10-85, and about 5 of those <25. My guess, in these 2 papers combined you have maybe a dozen of people <25. Do you really think that's enough? I think that the theory that enjoys such a popular support here should be based on more solid and extensive data than this.

Edited by xEva, 26 January 2015 - 08:18 AM.

[xEva]

Two questions:
 
1) The germline seems to repair its damage, such as AGEs and mitochondrial mutations

(with subsequent functional limitations) over millions of years. How does it happen?
 
2) In species with negligible senescence, repair mechanisms seem to be fully adequate?

Those are very good points. If germline could not repair all the damage, life as we know it would not be possible.

The rare cases when people are born with various mutations, whether they affect mitochondria, like corb brought up, or something else, is irrelevant here. Lots of things can and do go wrong. Most are not viable and aborted. But the vast majority of those who are born, and not just humans, are.. well, normal.

Species with negligible senescence is a perfect example (and I don't know why corb thinks it's about protozoa). Other than hydra, anemones and such, they are mostly birds and reptiles and some mammals -? (whales?) And some of those turtles fecundity increases with age. These animals are subject to the same stresses as the rest of us --mitochondria ROS production, telomeres shortening, apoptosis, etc-- and yet this does not lead to the emergence of senescent phenotype. Why, if basic cellular processes are universally the same? It's gotta be due to their unfailing repair mechanisms.

Edited by xEva, 26 January 2015 - 09:16 AM.

[corb]

 

 

1. Mitochondrial disease in infants.  How do they happen?
   In the case of mtDNA, this paper can give you a perspective how imperfect actual germline "repair" is : http://www.nature.co.../hdy201260a.htm
   
   Autism is a good example. A disease that would not exist if mitochondria were perfectly "repaired" during fertilization.

 

 

The paper shows, that male fruit flies also can contribute to the mitochondrial pool, at least to some extend. So what?

 

If germline repair would be imperfect per se, our entire existence would be impossible. However, there is no doubt that repair mechanisms can be impaired during the process, and of course you can imagine fatal damage, that can not be repaired.

 

 

It is imperfect.
That's the biggest misunderstanding you have. And it stems from the same lack of knowledge like xEva's.
Let me explain. When you say damage - you're thinking something that can be seen. Something that can lead to a disease or death.

The thing is - when you go down to the level of a single cell a couple mutations are nothing. DNA is under constant bombardment of intra and extracellular stress factors and it's not rare for a copying error to happen when a gene is damaged.

.

The germline is not perfectly preserved. It doesn't need to be for life to continue. It needs to be viably conserved, but that allows for tremendous wiggle room. Children are born with defects all the time, some are more noticeable than the others and we only say it's a birth defect if it's absolutely noticeable or life threatening to begin with, so it's natural to think that all babies are perfect little angles but the truth can't be further from that.

 

There isn't a perfect DNA repair mechanism in nature (we would not exist if there was but that's a subject for another thread). There isn't a perfect mtDNA repair mechanism in nature. What nature does is it tries to keep gametes away from damage as much as possible (why would it need to do that if it could repair everything perfectly every time?).

 

And now the paper I posted comes into play. You say the germline is perfectly preserved with a perfect mechanism?
Well the paper I posted completely refutes that. Sperm suffers from extreme stresses while moving toward the gamete, it's mitochondria working at a tremendous pace, which allows for a lot of damage to happen to the mitochondria in the process. So the one in a thousand times when mtDNA from a sperm survives in the gamete, means that there is a one in thousand chance (which isn't even that small) of damaged mtDNA to be left in the zygote. And that's just from the sperm's mtDNA.

 

 

 

Two questions:
 
1) The germline seems to repair its damage, such as AGEs and mitochondrial mutations

(with subsequent functional limitations) over millions of years. How does it happen?
 
2) In species with negligible senescence, repair mechanisms seem to be fully adequate?

Those are very good points. If germline could not repair all the damage, life as we know it would not be possible.

The rare cases when people are born with various mutations, whether they affect mitochondria, like corb brought up, or something else, is irrelevant here. Lots of things can and do go wrong. Most are not viable and aborted. But the vast majority of those who are born, and not just humans, are.. well, normal.

Species with negligible senescence is a perfect example (and I don't know why corb thinks it's about protozoa). Other than hydra, anemones and such, they are mostly birds and reptiles and some mammals -? (whales?) And some of those turtles fecundity increases with age. These animals are subject to the same stresses as the rest of us --mitochondria ROS production, telomeres shortening, apoptosis, etc-- and yet this does not lead to the emergence of senescent phenotype. Why, if basic cellular processes are universally the same? It's gotta be due to their unfailing repair mechanisms.

 

 

Negligible senescence is a term used very vaguely in biology.

If an organism can reproduce when it has an old phenotype that's already considered negligible senescence by some biologists.
Interestingly most negligibly senescent organisms that have been found, a lot of them have not been recorded to live longer than humans.
In the case of the whale, the only mammal that has been recorded to live as long (or in that one case longer) than humans is indeed interesting BUT you have to keep in mind whales and humans are completely separate species, hundreds of millions of years of evolutionary branch out in between us. It makes about as much sense to compare us to a whale as it is to compare us to a turtle almost.

[addx]

A while ago opened a thread suggesting that this 'progressive failure' is more of a 'programmed progressive failure' and that ageing is a purposeful mechanism crafted by evolution - manifested exactly as described - by ceasing of repairs. Ceasing of body repairs after maturity increases selection pressure for "smart behavior" that avoids extra body stress. So behavior/nervous system is pressured to evolve smarter behavior tactics. As an organism matures it is infact ready to "take on life". After it starts "taking on life" there's no more (extensive) repairs or such repairs would inherently hide the behavioral lack of fitness which would reduce proper selection.

http://www.longecity...volution/page-1

The point of the thread was pretty much the same. To identify ageing as a purposeful mechanism which should enable us better to find threads of it in the human anatomy. Currently as ageing is considered a sum of random evolutionary failures across the body, there's little coherence in finding the root of it.

 
The idea that better Explanations of Aging can help focus attention on specific mechanisms in the human anatomy is one I like...
 
Still, Aging Explanations, to be taken seriously, need to reference Evidence Nodes (aka, "Threads" in the quotation above) we now know are important. For example, we now know that NF-kB plays a critical role in morbidity and mortality and in many Aging Theories. We now know, in a way we didn't even 5 to 10 years ago, that Epigenetic factors play a role in every major health disorder and in the physical decline of aging. Let's add ROS, Telomeres, and a handful of other things to the list of Threads in the Human Anatomy we already know are important.
 
We know a great deal about the Threads our Explanations must be related to. To imagine that our Explanations don't have to address these and other Already Known "Threads" is a significant step in the wrong direction.

Read the thread, I've applied my logic and found many confirmations easily, the path can surely be followed..

http://www.longecity...e-3#entry654906

Most importantly, I've explained mu and kappa opioid "signalling" as strictly functional in my evolutionary model. And I've yet to find a study which goes against this abstract meaning of their signalling.

Mu opioid signalling handles 'thirst for life', kappa opioid signalling handles 'fear of death' in most any sense or function they have an effect in.

They are not the only ones inolved in those two functions, but they are the chief ones that modulate the response to events that "unstress" or "stress" the body/mind at most any intercell level.

Opioids As Modulators of Cell Death and Survival—Unraveling Mechanisms and Revealing New Indications:
http://pharmrev.aspe...t/56/3/351.full

Mmost of the ageing of humans, as all animals is/should be focused within the nervous system. The nervous system (especially of mammals) obviously has phases of developement which it goes through and then it loses neurogenesis ability in all but two regions of the brain. The phases of nervous system development can be mapped to psychosocial cognitive development and anatomic/bodily development, they all stop once the last piece of the puzzle reaches maturity - and that is - the brain - probably vmPFC, sometime in twenties or so.

Maturing is most definitely and obviously programmed, a very complex cascade and it seems a part(end) of each such maturing program is cease of repairs within whatever the program was building.

Edited by addx, 26 January 2015 - 03:07 PM.

[Kalliste]

What a weird debate this is. If aging is actually something that is stopped and only turned on at some point, say after 25 years, I would expect there to be handsome evidence for this effect. Lets see some of that evidence. As it is, I believe aging starts the day you are born and ends the day you die.

[xEva]

That's the biggest misunderstanding you have. And it stems from the same lack of knowledge like xEva's.

Hey corb, you'd do well if you learn to avoid your personal assessments of other people's knowledge and understanding and stick to the topic at hand instead. So far, more often than not, you misinterpreted the data you presented, like when you called a snapshot of AGEs in children an accumulation or when you insisted that comparison of people under 30 to people over 60 proves that damage accumulates in people under 25. And now it turns out that, you are not very familiar with literature on animals with negligible senescence. But that's alright. No one is expected to know everything. One of the great things about a forum like this is that one can learn lots of new stuff in a process of a discussion. What's not alright is to resort to this sort of cheap ad hominems when weaknesses in your arguments are exposed.

And I'm astonished that for you, apparently, the evolution of species is merely the evidence of imperfect damage repair mechanisms. In this view we humans are pathetically damaged mutants of ancient protozoa.

And I probably should have ignored your bringing up mitochondrial mutations in fruit flies as more relevant to human aging than long-lived whales. Though you may find it interesting that increased fecundity with age in some tortoises is a recent discovery, but their 'negligible senescence' was noted long, long ago. Why, in Chinese culture tortoises are ancient symbols of immortality.

So I'm asking you personally, in addition to stop resorting to ad hominems, please stop posting irrelevant stuff -- i.e. genetic diseases and mutations, in fruit flies or in children, are not a topic here.

Edited by xEva, 26 January 2015 - 05:22 PM.

[xEva]

Maturing is most definitely and obviously programmed, a very complex cascade and it seems a part(end) of each such maturing program is cease of repairs within whatever the program was building.

Excellent point. No one can deny that maturing is programmed. It is very tempting to extend this program to aging, at least partially. Though for now, I personally side with antagonistic pleiotropy POW.

[LeeYa]

 

 

It is imperfect.
That's the biggest misunderstanding you have. And it stems from the same lack of knowledge like xEva's.
Let me explain. When you say damage - you're thinking something that can be seen. Something that can lead to a disease or death.

The thing is - when you go down to the level of a single cell a couple mutations are nothing. DNA is under constant bombardment of intra and extracellular stress factors and it's not rare for a copying error to happen when a gene is damaged.

 

 

DNA and mtDNA changes happens from time to time even in the germline and even with full activated repair activity. But nevertheless, there is obviously enough in-built stability to carry on human existence. The half-life of a mitochondrium is 48 hrs, and damaged mitochondria are replaced over and over again. If germline can survive with fully activated repair for millions of years with only minor, funcitonally less important changes, then you could make it at least for a few thousand years, with this amount of repair acitvity.

 

@addx

Maturing is most definitely and obviously programmed, a very complex cascade and it seems a part(end) of each such maturing program is cease of repairs within whatever the program was building.

 

 

 

True! And this (epigenetic!) programm code has to be hacked to regain our repair capacity.

Btw - It is mainly about DNA methylation and acetylation patterns.

Edited by LeeYa, 26 January 2015 - 05:37 PM.

[addx]

What a weird debate this is. If aging is actually something that is stopped and only turned on at some point, say after 25 years, I would expect there to be handsome evidence for this effect. Lets see some of that evidence. As it is, I believe aging starts the day you are born and ends the day you die.

It's a two step process. Maturing is investing, ageing is use of the investement. Literally. The DNA/meme combo that is you represents a "try at life". It has to be built and then it has to be used. Using it shows if it was built well.

Once you mature, you're [ DNA inherited/childhood trained skills combination] is ready to be judged against life. That's phase 2.

That's why there's no indefinite repairs - it would be cheating against this judgement of life and it would not foster any good direction of evolution.

Such an ability would never support evolution of "smarter behavior". Because smart behavior that avoids damage and consequent repair would hardly be selected for. That's why all known immortal animal life is simple, static and plant-like stupid. Too much repair ability and you have an evolutionary dead end not to mention it's hard keeping all those enslaved cells growing but not becoming cancerous

------------

For example, lets say you have fish. How would a female fish choose a partner if the partners success in life wasnt visible in his behavior and state? The fish is rewarded with serotonin for "good work"(finding food lets say), and it makes it act proud, and other fish with less serotonin dont feel so secure and likewas dont act secure, so the successful one gets to "mate" by "scaring" the less succesfull. From a human individualistic perspective, it seems like the "stronger" fish "defeated" the weaker fish, as if a bullying contest went on. But there's no stonger or weaker. Both of them are actually working to advance the fish gene pool. The weaker fish displays its weakness, the stronger display its strongness, they show their cards, they see their state and basicly both of their brains determine the same - the stronger fish shall breed. The species as a whole willfully shows its "strength" via behavior via serotonin levels etc. It's infact a form of communication on an organization level higher than individual.

Imagine you've been given a car to test. Your brother as well. The gene pool told you two to take them out for a race and return the winner so the gene pool can make more of the winners. You go out and drive your car the best you can, you want to prove yours is the best, because that's the only way to the truth, by giving it all you got. In the end you might lose, and show your car to be a lesser car than the one given to your brother.

That's evolution.

Now imagine that there's 10000s of fathers(species/gene pools/groups) each having such sons racing cars they make for them. The fathers are competing who will make the best car(specie). How far do you think your father would get in that race of species if his two sons didn't want to end the race and show their father which car is better? How many adaptations could the father make to the cars if the sons ran the race forever and never returned with their cars and results to the father? Zero. Your fathers cars would not evolve at all. If you make the races short, your father could have plently meaningfull info about the cars each day.

For humans, the "father" is infact embedded genetically and "memetically" in our brains. We can't procreate without others finding it useful somehow, we can't replicate knowledge without others judging it useful somehow. So all of us are both judges and players to each other and we also have a vague time limit for the game.

[xEva]

What a weird debate this is. If aging is actually something that is stopped and only turned on at some point, say after 25 years, I would expect there to be handsome evidence for this effect. Lets see some of that evidence. As it is, I believe aging starts the day you are born and ends the day you die.

No one says that "aging is actually something that is stopped and only turned on at some point". My observation is that accumulation of damage, that is the hallmark of aging, does not start until after 25 -- in most people and, in some, not after 35 or so. Where is the evidence to the contrary?

That would be great if you could post some data in support of your belief. If you care to read the discussion above, niner posted 2 studies with very iffy cohorts and no full text available to examine the data in question. There gotta be something better in support of your belief than this. The study should show accumulation of damage in children and young adults, not mere presence as a snapshot in time. That's the point of this thread, that damage does occur all the time, it's an integral part of metabolism, and that damage is effectively repaired in young people. That's how youth is defined.

I also recall you talking about skin cancer above as the proof of damage accumulation in children. To my knowledge, skin cancer is very rare in children but more common in old adults. This sort of 'info' as well as various disease states and mutations are irrelevant to this discussion.

[addx]

Maturing is most definitely and obviously programmed, a very complex cascade and it seems a part(end) of each such maturing program is cease of repairs within whatever the program was building.

Excellent point. No one can deny that maturing is programmed. It is very tempting to extend this program to aging, at least partially. Though for now, I personally side with antagonistic pleiotropy POW.

It is tempting, follow the opioids. Read the studies and my description of opioid functions...

Opioids govern neuronal stem cell proliferation and differentiation as an "evolutionary response" to events (events being the damage or i'd rather simply say experience). Opioids cause stem cells to proliferate (mu-opioid like heroin or morphine) or to differentiate (become less stem cells and more true neurones, this is kappa-opioid action, only salvia divinorum and menthol have this effect, menthol doesnt cross the blood brain barrier).

A muscle that is used (and pained) to help a lion hunt a dear gets proliferated by opioids as a secondary effect of the pain-analgesia provided to the aching muscle. A synapse scheme that helps the lion hunt a dear down gets proliferated by mu opioids in the same way by pleasure-analgesia as complementary to the muscle it worked. A synapse scheme that responds to being attacked by a bear gets differentiated (not so much proliferated) via kappa opioids as a secondary effect of its fear-analgesia. Differentiation causes overreacting neurones (typical for fear-learning-adaptation - kappa opioid). Proliferation causes more neurones for more "brain resolution" to be awarded to some "life gaining - positive process" (mu opioid/heroin). More neurones = less overreacting individual neurones.

As you mature, opioid mu and kappa receptors modulate the growth and differentiate your brain in accordance to your use of it and the success at use. Same goes for muscles.

As you pass maturing point opioids can not effect "brain development" as much since its protein cascade has switched off neuronal growth by some other means... but some of their effects remain.
Overdifferentiating stem cells into neurones and "further" causes their premature death through overexertion. Kappa opioids receptors (visceral pain and fear processing) are literaly age(or stress/damage) markers! They also correlate with women, they have more and they have more visceraly.


From what I've understood, it is paramount to find triggers that "handle" various stem cell populations. As one can see, opioids are functionally used to adapt the growth direction of the brain during maturing and they do this by affecting stem cells! They are the prime candidate to consider as a thread on to pull to show the cascade.

IMO most of the ageing of the animal and human body will if not sourced, at least be reflected by the nervous system (which is why kappa opioid receptors are a marker for ageing). So, if we uncover how ageing works through the nervous system, I think we're on top of it.

Edited by addx, 26 January 2015 - 06:19 PM.

[LeeYa]

@addx

 

I'm not sure if a single superordinated aging promotor really exists, but If so, the hypothalamus would be the first candidate.

 

Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH

http://www.nature.co...ature12143.html

 

However, aging perfectly works for evolution and consequently, reversal of biological aging is against evolution if we don't take over our own evolutionary process.

 

 

 

What a weird debate this is. If aging is actually something that is stopped and only turned on at some point, say after 25 years, I would expect there to be handsome evidence for this effect. Lets see some of that evidence. As it is, I believe aging starts the day you are born and ends the day you die.

 

It depends on your definition of aging. If you consider it as:

 

biological aging (also spelled biological ageing) is the gradual deterioration of function characteristic of most complex lifeforms, arguably found in all biological kingdoms, that on the level of the organism increases mortality after maturation.

http://en.wikipedia....wiki/Senescence

 

and take a look at human mortality data, then I would conclude that aging starts in the early twenties, or that your aging definition is different.

 

 

http://www.senescenc...definition.html

 

 

I can understand your argument. But, if we define the developement program as part of the aging process, fighting the aging process finally will result in a "peter pan like" state... How young you would like to be?

 

Edited by LeeYa, 26 January 2015 - 07:54 PM.

[niner]

 

You added so much compression noise to the part of the graph you snipped out that it is illegible.

 
-?! What compression noise I supposedly added? I only copied the graph you posted into Paint, cut it at 25 and removed the line that linked it to the out of range >25 data. I also scaled up the resulting detail 3 times, because it was too small, which only amplified the noise in your low-res original. You did not post the link to the full text. How many people <25 did they have there? I don't think that those 5 (or 6 with that >25 guy) is enough to make such sweeping conclusions, even if it looked perfect in all respects.

 

I didn't go back to the original for the enlargement I posted.  I took that from the previous posted image, so you must be the one who added the noise.   I didn't want to post a link to sci-hub, because it's a little "under the radar" if you know what I mean, but the original can be found there.  I have to run ATM, so I'll reply to the rest later if I survive the impending "blizzard of historic proportion".

[corb]

True! And this (epigenetic!) programm code has to be hacked to regain our repair capacity.

Btw - It is mainly about DNA methylation and acetylation patterns.

 

How does demethylation happen?

It happens when DNA is repaired - the whole portion of DNA is gone and then rebuilt so naturally the methyl group is gone as well, but the DNA repair doesn't add it back.

Another way it happens is when a methyl group gets oxidized.

And we go full circle, back to wear and tear.

 

That's the problem with genetics even when deleterious effects can be traced back to mechanisms being down regulated, it still doesn't explain why the mechanism was down regulated to begin with until you consider direct damage.

Cellular senescence is also important, it is a very strong drive for change in the chromatin structure.

 

No one argues that epigenetics play a big role in disease. They probably play a big role in aging as well. But there is no proof they are the main cause.

[APBT]

I second that, no full access, and the abstract does not say anything about accumulation of AGEs in that young group.

 

http://www.longecity...e-4#entry709124

 

 

FULL TEXT:  Plasma advanced glycation end products are decreased in obese children compared with lean controls

Attached Files

•  Plasma advanced glycation end products are decreased in obese.pdf   103.19KB   4 downloads

Edited by APBT, 26 January 2015 - 10:07 PM.

[APBT]

FULL TEXT:  Tendon and Ligament Biochemistry and Pathology

 

Attached Files

•  Tendon and Ligament Biochemistry and Pathology.pdf   591.6KB   4 downloads

[addx]

@addx

 

I'm not sure if a single superordinated aging promotor really exists, but If so, the hypothalamus would be the first candidate.

 

 

 

Im not saying that there's just one.

 

I'm saying kappa and mu opioid mechanisms modulate responsive/adaptive changes to neuronal growth/differentiation rate before maturity, they trigger adaptive changes to synaptic schemas during lifetime, they trigger adaptive muscle changes during lifetime, trigger skin tissue adaptive changes and even sperm adaptive changes all in response to experience, maybe more..

 

Maturing is guided by a complex cascade of cells diffentiating, producing proteins which cause futher and different differentiation, tissues producing "counter tissues". An insect can duplicate only gene in the HOX region and it might cause him a fully functional set of wings or legs, meaning one gene duplication in the base "segment" region of DNA will have the muscle and nervous system genes fully work on the extra set, connect it to the brain and the brain even adjust to using them. So, the process of producing the body as a connected set of tissues is very "fractalish" and complex as can be imagined from that example.

 

Adaptive changes in response to "active life experience" however seem to be neatly modulated mostly by opioidergic effects. Opioidergic effects are affected by a different number of cofactors and depending on which cell culture.

 

Kappa opioid activation has different effects depending p38 mapk activation which is a major stress pathway (as proposed fear-analgesia - effects on synaptic schemas) - https://hopecenter.wustl.edu/?p=3460

 

http://www.ncbi.nlm....pubmed/10807318

 

MAP kinase pathways activated by stress: the p38 MAPK pathway.

 

Abstract

A stress-activated serine/threonine protein kinase, p38 mitogen-activated protein kinase (p38 MAPK), belongs to the MAP kinase superfamily. Diverse extracellular stimuli, including ultraviolet light, irradiation, heat shock, high osmotic stress, proinflammatory cytokines and certain mitogens, trigger a stress-regulated protein kinase cascade culminating in activation of p38 MAPK through phosphorylation on a TGY motif within the kinase activation loop. p38 MAPK appears to play a major role in apoptosis, cytokine production, transcriptional regulation, and cytoskeletal reorganization, and has been causally implicated in sepsis, ischemic heart disease, arthritis, human immunodeficiency virus infection, and Alzheimer's disease. The availability of specific inhibitors helps to clarify the role that p38 MAPK plays in these processes, and may ultimately offer therapeutic benefit for certain critically ill patients

 

 

Arrestin-mediated activation of p38 MAPK: molecular mechanisms and behavioral consequences.

 

Abstract

Studies of kappa opioid receptor signaling mechanisms during the last decade have demonstrated that agonist activation of the receptor results in Gβγ-dependent signaling and distinct arrestin-dependent signaling events. Gβγ-dependent signaling results in ion channel regulation causing neuronal inhibition, inhibition of transmitter release, and subsequent analgesic responses. In contrast, arrestin-dependent signaling events result inp38 MAPK activation and subsequent dysphoric and proaddictive behavioral responses. Resolution of these two branches of signaling cascades has enabled strategies designed to identify pathway-selective drugs that may have unique therapeutic utilities.

 

http://www.ncbi.nlm....pubmed/24292835

 

 

Possible role of dynorphins in Alzheimer's disease and age-related cognitive deficits.

Ménard C1, Herzog H, Schwarzer C, Quirion R.

Author information

 

Abstract

BACKGROUND/AIMS:

Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with cognitive deficits in rodents. Elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease (AD) patients, and prodynorphin (PDYN) gene polymorphisms might be linked to cognitive function in the elderly. Activation of κ-opioid receptors by dynorphins has been associated with stress-related memory impairments. Interestingly, these peptides can also modulate glutamate neurotransmission and may affect synaptic plasticity underlying memory formation. N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazol-propionate (AMPA) ionotropic glutamate receptor levels generally decrease with aging, and their function is impaired in AD.

METHODS:

Here, we compared the impact of aging on ionotropic glutamate receptor levels in the hippocampal formation of wild-type (WT) and Pdyn knock-out (KO) mice.

RESULTS:

We observed a significant reduction in GluR1 and GluR2 AMPA receptor subunits in the hippocampal formation of 18- to 25-month-old WT mice in comparison with 6-month-old mice. Conversely, the GluR1 protein level was maintained in old Pdyn KO mice, and the NMDA NR2B subunit level was increased by 42% when compared to old WT animals.

CONCLUSIONS:

These results suggest that elevated dynorphin expression occurring during aging and AD may mediate cognitive deficits by altering the glutamatergic system integrity.

http://www.ncbi.nlm....pubmed/23970097

 

 

 

The κ opioid system regulates endothelial cell differentiation and pathfinding in vascular development.

http://www.ncbi.nlm....pubmed/21460241

 

 

 

Prodynorphin knockout mice demonstrate diminished age-associated impairment in spatial water maze performance.

Nguyen XV1, Masse J, Kumar A, Vijitruth R, Kulik C, Liu M, Choi DY, Foster TC, Usynin I, Bakalkin G, Bing G.

Author information

 

Abstract

Dynorphins, endogenous kappa-opioid agonists widely expressed in the central nervous system, have been reported to increase following diverse pathophysiological processes, including excitotoxicity, chronic inflammation, and traumatic injury. These peptides have been implicated in cognitive impairment, especially that associated with aging. To determine whether absence of dynorphin confers any beneficial effect on spatial learning and memory, knockout mice lacking the coding exons of the gene encoding its precursor prodynorphin (Pdyn) were tested in a water maze task. Learning and memory assessment using a 3-day water maze protocol demonstrated that aged Pdyn knockout mice (13-17 months) perform comparatively better than similarly aged wild-type (WT) mice, based on acquisition and retention probe trial indices. There was no genotype effect on performance in the cued version of the swim task nor on average swim speed, suggesting the observed genotype effects are likely attributable to differences in cognitive rather than motor function. Young (3-6 months) mice performed significantly better than aged mice, but in young mice, no genotype difference was observed. To investigate the relationship between aging and brain dynorphin expression in mice, we examined dynorphin peptide levels at varying ages in hippocampus and frontal cortex of WT 129SvEv mice. Quantitative radioimmunoassay demonstrated that dynorphin A levels in frontal cortex, but not hippocampus, of 12- and 24-month mice were significantly elevated compared to 3-month mice. Although the underlying mechanisms have yet to be elucidated, the results suggest that chronic increases in endogenous dynorphin expression with age, especially in frontal cortex, may adversely affect learning and memory.

http://www.ncbi.nlm....pubmed/15922052

 

 

Sorry if this seems like spam, but opioids yield a lot of nice results when used with cell death differentiation proliferation, stem cell control etc. In addition to all that they already do. And when you think about it analgesia is a trigger for changes. Ok, I'll numb it up for now, but changes need to be made for it to be ready better later, or triaged/severed. 

[niner]

Two questions:

 

1) The germline seems to repair its damage, such as AGEs and mitochondrial mutations (with subsequent functional limitations) over millions of years. How does it happen?

 

2) In species with negligible senescence, repair mechanisms seem to be fully adequate?

 

Great questions.

The germline is composed of single cells.  They are well-protected and don't reproduce frequently.  (reduces nuclear mutations)  There is no extracellular matrix that gets glycated without adequate repair mechanisms, as occurs in much of the body.  Any glycation that might occur in the germline cell can be handled via autophagy.   Very importantly, the germ cells do not perform Oxidative Phosphorylation, so they don't generate ROS.  This reduces damage significantly.  I suppose they are not exposed to a large quantity of oxidized cholesterol and other indigestible junk, so their lysosomes are adequate for the time period from conception to reproduction.

 

I like this question a lot, because it points out the difference between a cell and the entire organism.  Most cells maintain themselves well and some can be thought of as "immortal".  Organisms, on the other hand, are far more complicated and have a lot more systems that can malfunction or be damaged.    This question points toward some things that are probably important in aging; specifically, the mitochondria.  Mitochondrial OxPhos is shut off in germ / stem cells, but not in somatic cells.  Somatic cells acquire oxidative damage from OxPhos, but germ/stem cells do not.

 

As for species with negligible senescence, repair mechanisms are presumably adequate, although there are no vertebrates with multi-thousand year lifespans that I know of.

[niner]

And then you stress, that, because you don't know a process by which AGEs can be removed, therefore there is no way it can happen -?? There are a lot of things we don't know. Why, only recently you discovered a lot of new stuff about mitochondria you never knew existed.

 
So your hypothesis rests on a repair mechanism for AGE crosslinks that No One Knows About, and that stops working at the age of 25?  That sounds like Unicorn territory.  Your hypothesis is inconsistent with the relatively small amount of published data that we have, which shows increasing amounts of crosslinks at young ages.
 

And then you talk about babes' skin. I don't want the skin of a 2-year old. It's not practical. The studies of "sun damage" in children that were spoken about here were all snapshots in time (and none posted here showed accumulation). Everyone gets "sun-damaged" after a summer on the beach. But look at the same children in the end of winter, like in high latitudes where I grew up. The sun rises at 11 AM and sets by 3 PM there, so you go to school when it's dark and you return from school when it's dark. The skin recovers from all the "damage" (well, tan, actually) it sustained in summer. That's my experience. But I can see how California kids could be accumulating sun damage, for the simple reason that their skin does not get a break and recover, like ours did.

The point isn't about 2 year old skin being optimal, I'm just pointing out that there is a constant coarsening of skin, if you examine it closely, which is not consistent with your hypothesis of perfect damage repair in the young.
 

The ball is really in the accumulation of damage theory court. So far, all you managed to produce in its support is the Czech forensic study, available only as abstract, with data for ~145 people ages 16-95, with unknown number of those <25 -- plus this study, with no link to full text either, of unknown number of people ages 10-85, and about 5 of those <25. My guess, in these 2 papers combined you have maybe a dozen of people <25. Do you really think that's enough? I think that the theory that enjoys such a popular support here should be based on more solid and extensive data than this.

Why is the ball in my court? So far, I'm the only one who has provided any data at all. Where's your proof that damage repair is perfect until 25? It's just an idea you cooked up based on limited visual observations, and has no plausible mechanism of action. I think that if you expect to overturn current biological understanding, you are going to need at least a shred of evidence. Certainly more that none whatsoever.

[Danail Bulgaria]

Based on the AGES, or not, the repair mechanisms at macroscopic level, fail down with the age. In all clinical medical books for traumatology is written, that broken bones in old people heal slower than in young people. Same in skin wounds.

[xEva]

You added so much compression noise to the part of the graph you snipped out that it is illegible.

 
-?! What compression noise I supposedly added? I only copied the graph you posted into Paint, cut it at 25 and removed the line that linked it to the out of range >25 data. I also scaled up the resulting detail 3 times, because it was too small, which only amplified the noise in your low-res original. You did not post the link to the full text. How many people <25 did they have there? I don't think that those 5 (or 6 with that >25 guy) is enough to make such sweeping conclusions, even if it looked perfect in all respects.

 
I didn't go back to the original for the enlargement I posted.  I took that from the previous posted image, so you must be the one who added the noise.   I didn't want to post a link to sci-hub, because it's a little "under the radar" if you know what I mean, but the original can be found there.  I have to run ATM, so I'll reply to the rest later if I survive the impending "blizzard of historic proportion".

 
How strange that you insist that I "added the noise". Why would I do that? I'm not the one desperately defending the SENS assertion that damage accumulates "even starting before we're born".

Here is the graph again, along with accompanied graph, which you conveniently omitted, from the full text (thanks APBT ). So I was right, there were exactly 5 people under 25 and one ~27. The second graph has only 2 people <25 (the second looks exactly 25) and, as you can see, it shows decline of pentosidine with age for those two, which, however, proves nothing, just like the first graph proves nothing, 'cause the sample size is just too small.
 

 penta25.png   12.1KB   2 downloads -  penta100.png   57.03KB   2 downloads

 

The ball is really in the accumulation of damage theory court. So far, all you managed to produce in its support is the Czech forensic study, available only as abstract, with data for ~145 people ages 16-95, with unknown number of those <25 -- plus this study, with no link to full text either, of unknown number of people ages 10-85, and about 5 of those <25. My guess, in these 2 papers combined you have maybe a dozen of people <25. Do you really think that's enough? I think that the theory that enjoys such popular support here should be based on more solid and extensive data than this.

Why is the ball in my court? So far, I'm the only one who has provided any data at all. Where's your proof that damage repair is perfect until 25? It's just an idea you cooked up based on limited visual observations, and has no plausible mechanism of action. I think that if you expect to overturn current biological understanding, you are going to need at least a shred of evidence. Certainly more that none whatsoever.

lol Can one prove a negative? You have not provided any valid data. 7 samples, with 2 of them showing decline is hardly any proof. I assume something similar goes on with the Czech forensic study. But seriously, is that all you could dig up in support of this SENS assertion?

And pray who else actually supports this "current biological understanding", besides de Grey? I have not heard anyone else, in the modern times, asserting this very, very old idea, which probably sounded reasonable 150-200 years ago, when it was born -- or should I say cooked up?

There is plenty of data showing accumulation of damage with advancing age. There is nothing --it turns out!-- to show that damage accumulates in children and young adults. How did de Grey come up with it, based on what data? It looks like just another old, unexamined assumption.

[niner]

I didn't go back to the original for the enlargement I posted.  I took that from the previous posted image, so you must be the one who added the noise.   I didn't want to post a link to sci-hub, because it's a little "under the radar" if you know what I mean, but the original can be found there.  I have to run ATM, so I'll reply to the rest later if I survive the impending "blizzard of historic proportion".

 
How strange that you insist that I "added the noise". Why would I do that? I'm not the one desperately defending the SENS assertion that damage accumulates "even starting before we're born".

Here is the graph again, along with accompanied graph, which you conveniently omitted, from the full text (thanks APBT ). So I was right, there were exactly 5 people under 25 and one ~27. The second graph has only 2 people <25 (the second looks exactly 25) and, as you can see, it shows decline of pentosidine with age for those two, which, however, proves nothing, just like the first graph proves nothing, 'cause the sample size is just too small.
 

penta25.png - penta100.png

I don't think you did it out of malice, you just made a mistake. Kind of like you did with the second graph-- That plot is for a tissue where the collagen turns over regularly, and as a result, does not show the linear increase of AGE damage shown by the tendon in the first graph. This is readily apparent in that the crosslink percentage in older people is also quite random. The second plot is thus irrelevant to this discussion, since we already know that proteins that are rapidly turned over don't accumulate AGEs. THAT is the body's "repair mechanism", such as it is.
 

The ball is really in the accumulation of damage theory court. So far, all you managed to produce in its support is the Czech forensic study, available only as abstract, with data for ~145 people ages 16-95, with unknown number of those <25 -- plus this study, with no link to full text either, of unknown number of people ages 10-85, and about 5 of those <25. My guess, in these 2 papers combined you have maybe a dozen of people <25. Do you really think that's enough? I think that the theory that enjoys such popular support here should be based on more solid and extensive data than this.

Why is the ball in my court? So far, I'm the only one who has provided any data at all. Where's your proof that damage repair is perfect until 25? It's just an idea you cooked up based on limited visual observations, and has no plausible mechanism of action. I think that if you expect to overturn current biological understanding, you are going to need at least a shred of evidence. Certainly more that none whatsoever.

lol Can one prove a negative? You have not provided any valid data. 7 samples, with 2 of them showing decline is hardly any proof. I assume something similar goes on with the Czech forensic study. But seriously, is that all you could dig up in support of this SENS assertion?

And pray who else actually supports this "current biological understanding", besides de Grey? I have not heard anyone else, in the modern times, asserting this very, very old idea, which probably sounded reasonable 150-200 years ago, when it was born -- or should I say cooked up?

There is plenty of data showing accumulation of damage with advancing age. There is nothing --it turns out!-- to show that damage accumulates in children and young adults. How did de Grey come up with it, based on what data? It looks like just another old, unexamined assumption.

You can try to demonstrate that AGEs in long-lived proteins don't accumulate until people are over 25, but then they start accumulating linearly. That is your hypothesis, right? All you have to do is get appropriate collagen samples from people under 25. Because young children are growing in size, they are constantly adding new collagen, diluting the AGE percentage, so that should help. However, all data in long lived proteins that I'm aware of says you're wrong. You should also come up with a mechanism for AGE repair that fails at the age of 25. The mechanism for accumulation of AGEs, the Maillard reaction, is very well understood at a molecular level. There is simply no doubt that AGEs accumulate in proteins. That is science over a century old that has been replicated countless times.

I could probably find more data in support of my point if I was willing to look for it, but how much more time do I want to put into this project of refuting an idea that ignores basic science and has no evidence to back it up? Not much.

And for godsake, you should learn a little bit about the theory that you denigrate on the internet so you don't look like a person who knows nothing about science. Go to pubmed and enter "Vlassara H". That would be a start.

[xEva]

Thanks APBT for posting the full text of the study of AGEs in children. They had 18 obese kids, ages 5-18, and 18 lean controls, ages 4-17. Unfortunately, the data is presented 'in bulk' for each group.
 

So your hypothesis rests on a repair mechanism for AGE crosslinks that No One Knows About, and that stops working at the age of 25?  That sounds like Unicorn territory. Your hypothesis is inconsistent with the relatively small amount of published data that we have, which shows increasing amounts of crosslinks at young ages.

Where is that "relatively small data"?

And regarding that No One Knows About part, just not to go too far, this is what that irrelevant for this discussion study of AGEs in young obese children has to say:

Except for AGEs formed primarily on plasma proteins, circulating AGEs also represent AGE peptides released by extracellular proteolysis from tissue-immobilized AGEs and free adducts, resulting from proteolytic degradation of intracellular proteins. Food intake represents an additional source of plasma AGEs, as AGEs are also produced during thermal processing of foods (8) and are partially absorbed into circulation (9).
The kidney plays a pivotal role in the disposal of AGEs, particularly the low molecular weight AGEs. AGE adducts and peptides are filtered by the glomeruli, and a part is reabsorbed and degraded by proximal tubular cells (47,48). In type 2 diabetes, patients with GRF 130 ml/min/1.73m2 show significantly lower plasma low-molecular weight (LMW) AGEs than those with normal renal function (49), suggesting that hyperfiltration is associated with enhanced disposal of AGE-modified LMW proteins.

So it looks like extracellular proteolysis releases AGEs into the circulation, following which they are filtered out by kidneys. How about that?


 

The point isn't about 2 year old skin being optimal, I'm just pointing out that there is a constant coarsening of skin, if you examine it closely, which is not consistent with your hypothesis of perfect damage repair in the young.

That's a good point you bring up. Does coarsening of skin always represent damage? By agreeing that 2 year old skin may not be optimal, don't you imply that at least some of this "coarsening" is functional? And if so, how does this affect your definition of "molecular damage"?

Edited by xEva, 28 January 2015 - 01:24 AM.

[xEva]

You can try to demonstrate that AGEs in long-lived proteins don't accumulate until people are over 25, but then they start accumulating linearly. That is your hypothesis, right? All you have to do is get appropriate collagen samples from people under 25. Because young children are growing in size, they are constantly adding new collagen, diluting the AGE percentage, so that should help. However, all data in long lived proteins that I'm aware of says you're wrong.

Where is that data?

 

I could probably find more data in support of my point if I was willing to look for it, but how much more time do I want to put into this project of refuting an idea that ignores basic science and has no evidence to back it up? Not much.

That's really too bad
 

And for godsake, you should learn a little bit about the theory that you denigrate on the internet so you don't look like a person who knows nothing about science. Go to pubmed and enter "Vlassara H". That would be a start.

Another ad hominem   not a good sign  
 
And I just looked at Helen Vlassara. There are 188 publications, all dealing with pathology of AGEs in sick adults >25, mostly elderly, and diabetic children. Relevance?

Edited by xEva, 28 January 2015 - 01:31 AM.

[niner]

So your hypothesis rests on a repair mechanism for AGE crosslinks that No One Knows About, and that stops working at the age of 25?  That sounds like Unicorn territory. Your hypothesis is inconsistent with the relatively small amount of published data that we have, which shows increasing amounts of crosslinks at young ages.

Where is that "relatively small data"?

And regarding that No One Knows About part, just not to go too far, this is what that irrelevant for this discussion study of AGEs in young obese children has to say:

Except for AGEs formed primarily on plasma proteins, circulating AGEs also represent AGE peptides released by extracellular proteolysis from tissue-immobilized AGEs and free adducts, resulting from proteolytic degradation of intracellular proteins. Food intake represents an additional source of plasma AGEs, as AGEs are also produced during thermal processing of foods (8) and are partially absorbed into circulation (9).
The kidney plays a pivotal role in the disposal of AGEs, particularly the low molecular weight AGEs. AGE adducts and peptides are filtered by the glomeruli, and a part is reabsorbed and degraded by proximal tubular cells (47,48). In type 2 diabetes, patients with GRF 130 ml/min/1.73m2 show significantly lower plasma low-molecular weight (LMW) AGEs than those with normal renal function (49), suggesting that hyperfiltration is associated with enhanced disposal of AGE-modified LMW proteins.

So it looks like extracellular proteolysis releases AGEs into the circulation, following which they are filtered out by kidneys. How about that?

Some of that data is posted in this thread. There's probably a lot more in the literature.

Proteolysis described here is how tissues that get turned over are repaired. That kind of tissue isn't the problem. You still have to explain how very slow turnover parts of the ECM get repaired in people under 25, but not older.
 

The point isn't about 2 year old skin being optimal, I'm just pointing out that there is a constant coarsening of skin, if you examine it closely, which is not consistent with your hypothesis of perfect damage repair in the young.

That's a good point you bring up. Does coarsening of skin always represent damage? By agreeing that 2 year old skin may not be optimal, don't you imply that at least some of this "coarsening" is functional? And if so, how does this affect your definition of "molecular damage"?

I just brought it up as a critique of the idea that damage repair in the young is perfect, and that no damage is accrued. The change between a 2 year old and a 12 year old may well be mostly a functional change; for example, I think the skin gets thicker. They've not had much time to acquire AGE crosslinks, particularly since a significant amount of their collagen was more recently laid down. The changes between 12 and 22 may have more to do with damage. None of this changes my definition of molecular damage, as I don't think that the damage is beneficial in the young.

[niner]

 

You can try to demonstrate that AGEs in long-lived proteins don't accumulate until people are over 25, but then they start accumulating linearly. That is your hypothesis, right? All you have to do is get appropriate collagen samples from people under 25. Because young children are growing in size, they are constantly adding new collagen, diluting the AGE percentage, so that should help. However, all data in long lived proteins that I'm aware of says you're wrong.

Where is that data?

You said that you couldn't prove a negative, and I'm telling you how to do it. It's not an unprovable negative, it's a matter of seeing how much AGE crosslinking is there as a function of chronological age in the young. All you have to do is repeat the tendon measurements posted above, with more data in the young range. It will probably be necessary for you to acquire a grant in order to fund this experiment, but it's not impossible.
 

 

And for godsake, you should learn a little bit about the theory that you denigrate on the internet so you don't look like a person who knows nothing about science. Go to pubmed and enter "Vlassara H". That would be a start.

Another ad hominem   not a good sign  
 
And I just looked at Helen Vlassara. There are 188 publications, all dealing with pathology of AGEs in sick adults >25, mostly elderly, and diabetic children. Relevance?

 

This is the third time you've accused people of ad hominem in this thread, but you've ad hommed countless times in the same space, certainly by the standards you hold others to, or in some cases worse. I don't think anyone has called you a "moron", but that's what you did to someone else. You have every right to complain if you think that you're being treated unfairly, but if you want to complain, you should really clean up your own act.

Sorry, the Vlassara reference was terrible. I realized it was wrong not too long after I posted it, but couldn't get back in time to correct it. Here's a review, although most of it is about soluble AGEs, it has a section of bone, muscle, and tendon that is more applicable.

[LeeYa]

Based on what I've read so far, collagen turnover is the main route for AGE clearance in the extracellular matrix.

 

Bradytophic tissues such as a tendon should carry more AGEs because of a less frequent turnover, even in a 20 year old person. But if repair mechanisms remain constant, there should be an equilibirum and not an accumulation?

 

Tendon collagen replacement is constitutionally slow, but it is done by the body and can be accelerated, if  exogenous injury occurs. Why not pushing collagen replacement? The repair mechanisms could do more for us, if they are stimulated adequately.

 

To my knowledge, the only tissue without collagen replacement is the eye lens. Are there other connecitve tissues that can not be adressed by endogenous repair?

Edited by LeeYa, 28 January 2015 - 07:56 AM.

[Kalliste]

I guess time will tell us about that LeeYa. As it is, I do not believe that kind of messing about with metabolism is not likely to produce meaningful results. It will be costly and take a long time and in the end we don't know if it will pay of. That is why people ask for repair-approaches.