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Is Aging Programmed? Stochastic Damage? "Inherent Instability"?


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#31 Turnbuckle

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Posted 10 December 2018 - 01:11 PM

But if life wasn’t programmed there would be a lot more variability in lifespan as there is in lifestyle.
A car well maintained can last indefinitely, a person not so much.

 

 

I think the analogy fails, as with cars every part can be replaced and the functioning of every part is understood, while with humans only a few parts can be replaced and we've barely come to understand the basics of the mechanism. And in my view there are processes that appear to kill us but in fact have evolved for the opposite reason. Telomere shortening, for instance, looks like the fuse of a cellular self-destruct mechanism (and it is), but hasn't evolved to kill the organism itself. It's evolved to counter cancer and to get rid of old cells that have become dysfunctional due to a more basic cause of aging--epimutations.


Edited by Turnbuckle, 10 December 2018 - 01:15 PM.

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#32 Rocket

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Posted 10 December 2018 - 01:27 PM

Just because the human 'body' is capable of growing healthy and youthful cells does not correlate to the human body being able to maintain the chemistry of existing cells in a youthful state indefinitely. The machinery probably does not exist. Furthermore, because old cells can be reverted to a pluripotent state does not mean that they are identical to 'young' pluripotent cells and will mature into healthy adult cells. Consider the human egg. Look at what happens to birth defect rates when an old egg is fertilized compared to a young egg, yet both are seemingly identical eggs (but they are not identical and hence the rate of birth defects). So if an old fertilized egg does not grow in a human as well as a young fertilized egg, why should old and young pluripotent cells be identical and equal to one another and mature the same?


Edited by Rocket, 10 December 2018 - 01:29 PM.

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#33 OP2040

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Posted 10 December 2018 - 01:33 PM

The cancer vs regeneration trade-off seems to be an enduring mystery and is often thrown into the ring as one of the reasons that aging is an inevitable outcome of forces beyond our control.  We don't have an answer to this when it comes to humans.  But there are enough examples to show that cancer is avoidable in a regenerative state, and I'll provide a few:

1. The many animals that can regenerate entire organs, limbs etc. do not get so much as a teratoma

2. The further back you go in the developmental cycle, and therefore the more regenerative, the more rare is cancer

3. Negligibly senescent animals seem quite immune to it.  There is some evidence that some are immune even with what amounts to dna that looks more like scrambled eggs

 

Clearly, cancer is an aging disease then, so what of it's weird correlation with regenerative processes?  Stem cells look just like cancer cells for example.  Teratomas form with relatively minimal use of OSKM factors.  Many of the things we pursue as regenerative medecines, even herbs, also often come up as loosely correlated with cancer.  I can't count the number of threads where people are pursuing some regenerative therapy idea, and someone throws the C-bomb, the thread collapses into fear and anger.  So this is a real problem.

 

All we can say at this point is that while cancer is not inevitable, tissues that are already vulnerable often due to aging, have this tradeoff problem.  Personally, I attribute 90% of this problem to the collapse of the immune system.  But even that doesn't explain all of it.

 

Once again, I can't resist mentioning the bioelectricity perspective on this.  Levin has been able to stop cancer dead in it's tracks in a couple model animals with bioelectrical interventions.  He defines it as a patterning problem.  Tissues lose their memory of how to grow properly and cancer ensues.  The most intriguing part of this though is that it has little to do with dna damage.  He has proven, at least for frogs and salamanders, that proper patterning can be bioelectrically imposed even when there is extensive dna damage.  In fact, planaria have a genome that is completely messed up for some evolutionary reason that I can't remember at the moment. And yet they have no problem avoiding cancer and reimposing a regenerative pattern over and over again.


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#34 OP2040

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Posted 10 December 2018 - 01:42 PM

Just because the human 'body' is capable of growing healthy and youthful cells does not correlate to the human body being able to maintain the chemistry of existing cells in a youthful state indefinitely. The machinery probably does not exist. Furthermore, because old cells can be reverted to a pluripotent state does not mean that they are identical to 'young' pluripotent cells and will mature into healthy adult cells. Consider the human egg. Look at what happens to birth defect rates when an old egg is fertilized compared to a young egg, yet both are seemingly identical eggs (but they are not identical and hence the rate of birth defects). So if an old fertilized egg does not grow in a human as well as a young fertilized egg, why should old and young pluripotent cells be identical and equal to one another and mature the same?

 

In a 1:1 comparison, iPSC's and ESC's have been compared and differences are not found, as far as I remember.  But you bring up a good point about old vs. young  eggs and sperm.  There is something about the tissue aging that causes this phenomena, but it may not be the cells in particular.  What happens during embryogenesis is pretty amazing.  One of the things that happens is a lysosomal switch that basically clears the cells of the junk that has built up.  The switch is apparently activated by something as simple as a change in PH balance.  Seems highly translatable, but I haven't seen any further study on it. 

 

As I said in my other post though, it seems as if it is not dna damage that prevents proper regeneration, and I am not convinced it is even cellular as in vitro cell studies never seem to have this problem.  There is something about the tissue milieu that goes awry.  Maybe the ECM prevents proper signaling of some such.



#35 xEva

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Posted 10 December 2018 - 03:34 PM

Living things are not cars and they are alive (unlike a piece of meat that is left to rot), so let's speak biology, please? :)

 

re aging and death for group survival

 

In a changing environment (and limited resources),"a fitter" group is the one that is more genetically diverse. As individuals are replaced, there is a constant influx of novel combinations of traits into the communal genome, and this allows the group to handle a wide variety of current challenges, as well as be ready for whatever may come in the future. And let us not forget that one of the most challenging aspects of any environment are pathogens that keep on evolving even when everything else stays the same.

 

Also, Nature tends to be efficient and it is very costly and inefficient to have a super-organism capable of handling absolutely everything life can throw at it. It's simpler to scatter variations of traits throughout the population, so that no matter what happens, some individuals will have just the right combo to carry the group genome into the future.

 

And now think, what is the simplest way to knock off an organism? Well, it's true that some fall apart promptly after the reproduction. But those that have to linger to take care of the young, are best to decline gradually, and the simplest way to guarantee their demise is to start attenuating the repair pathways. Once this happens and damaged and misfolded proteins begin to accumulate -- there is no telling what kinds of pathologies can develop,  with the same end result for all.

.

So, decline in repair pathways is one programmed aging process. Probably there are others. Epigenetic drift is one for sure and it may have to do with a cell keeping time. I suspect the genome sorta shifts via transposons resulting in different gene clusters becoming accessible for transcription -- something like that.

 

gotta go now, but will post the paper on programmed aging accomplished via a signal traced from germ cells to soma that results decline of a repair pathway.

 


Edited by xEva, 10 December 2018 - 04:10 PM.


#36 QuestforLife

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Posted 10 December 2018 - 04:32 PM

Just because the human 'body' is capable of growing healthy and youthful cells does not correlate to the human body being able to maintain the chemistry of existing cells in a youthful state indefinitely. The machinery probably does not exist. Furthermore, because old cells can be reverted to a pluripotent state does not mean that they are identical to 'young' pluripotent cells and will mature into healthy adult cells. Consider the human egg. Look at what happens to birth defect rates when an old egg is fertilized compared to a young egg, yet both are seemingly identical eggs (but they are not identical and hence the rate of birth defects). So if an old fertilized egg does not grow in a human as well as a young fertilized egg, why should old and young pluripotent cells be identical and equal to one another and mature the same?

 

There is lots of evidence this isn't true. Senescent fibroblasts from a 90 year old have been induced back into a pluripotent state and proliferated to the extent you'd expect a fetal fibroblast culture to.

 

http://genesdev.cshl...25/21/2248.full

 

Aged eggs cells are just that - aged. 

 

Here is another paper I just found that speaks to the point; even a 75 year old with Alzheimer's can produce viable iPSCs. 

 

https://www.scienced...873506116300551

 

That doesn't mean we can do that to an entire organism, but the signs are promising.


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#37 OP2040

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Posted 10 December 2018 - 04:34 PM

Eva good summary of the "Grandmother hypothesis" of disposable soma theory.  I am inclined toward that theory myself.

 

However, the evidence seems to show that there really aren't tradeoffs between growth, reproduction and repair as the theory suggests.  One criticism is the fact that calorie restriction works, and the grandmother hypothesis was proposed to overcome that criticism.  But another one is Michael Rose's experiments with fruit flies.  He bred them to have more than twice the longevity, alongside substantially increased reproduction.  So no inherent trade-off between repair and reproduction.  One thing is for sure, the evidence has been the death knell for antagonistic pleiotropy theories.  But I think disposable soma can be salvaged by saying that it is true under evolutionary conditions of group selection, but the trade-offs are not thermodynamically inherent, and can easily be overcome.

 

Notice that none of these has anything to do with damage.  The evidence shows that lifespan can be increased without addressing damage per se.  Up-regulating repair mechanisms of course relates to damage being a factor in the symptoms of aging that we see, but they are not the cause of aging.  That is an important distinction to make because it means that removing damage will do nothing but slow down the flood of a process that is well on it's way already.  The evidence also bears this out.

 

Also, this doesn't necessarily show that aging is programmed.  It most obviously shows that there is a selection shadow that developed due to strong group selection pressures during evolution.  Whether one wants to call that programmed or not I guess is almost a personal preference. 

 

At least this puts us well past that time in history when curmudgeons could say that aging is built into the system so tightly that you cannot do anything about it.  Unfortunately, no less a luminary than Leonard Hayflick subscribes to such a dismal theory.  But I think psychology plays a larger role in these debates than we would like to imagine.  Older folks probably prefer the idea that aging and death are inevitable since it seems any regenerative medicine would be too late for them.  What they don't know is that some day these technologies will be so powerful that there will be a technology of resurrection as well.  But that's another thread.



#38 QuestforLife

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Posted 10 December 2018 - 04:37 PM

Once again, I can't resist mentioning the bioelectricity perspective on this.  Levin has been able to stop cancer dead in it's tracks in a couple model animals with bioelectrical interventions.  He defines it as a patterning problem.  Tissues lose their memory of how to grow properly and cancer ensues.  The most intriguing part of this though is that it has little to do with dna damage.  He has proven, at least for frogs and salamanders, that proper patterning can be bioelectrically imposed even when there is extensive dna damage.  In fact, planaria have a genome that is completely messed up for some evolutionary reason that I can't remember at the moment. And yet they have no problem avoiding cancer and reimposing a regenerative pattern over and over again.

 

I totally agree that tissue exerts higher (than cell) levels of control and cancer can be thwarted this way - after not all mutations involving oncogenes lead to a cancerous cell, and some cancerous cells have no mutations. But I think the key here is the epigenetic control exercised by the cell in question. This can be knocked about, but so long as it returns to baseline we're okay. But cells lose this control over gene expression with age and can no longer withstand the slings and arrows of outrageous misfortune (i.e. entropy). 



#39 OP2040

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Posted 10 December 2018 - 05:28 PM

For the life of me I can't find the reference.  But I think I've read somewhere that things like dna breaks themselves do not increase with age, rather they accumulate due to the lack of repair capacity.  Either way, it is DNA repair capacity that is very closely correlated with species longevity. 

 

Calorie restriction mechanisms (because fuxx c.r. itself) are a great mechanism to target this pathway, and they are the most proven of all anti-aging interventions.  If we had even more direct and powerful dna repair interventions I would expect even better results.

 

Reading the wiki article on dna damage, there is a great snippet on how epigenetics plays a role in silencing gene expression.  Apparently, it is normal and expected for methylation to occur and silence gene expression while a dna repair is happening.  It is supposed to be reversed after the repair is done, but this doesn't always happen and hence the buildup of silenced genes that also contribute to aging. 

 

So here we see that epigentics is a tool we are not yet using that could be a game changer.  Many of the interventions kinda sorta work, and work less the older the person is.  A big part of this is the gene silencing.  We may find that reversing that silenced gene expression as a pre-requisite to a useful intervention will make any intervention all the more powerful.  And in fact, there may be interventions that we don't really get why they don't work, but they will ultimately work if the gene expression channels are accessible.  The various stem cell therapies come to mind as an example of this.  Stem cells cannot do their job in a microenvironment chock full of silenced repair genes.

 

 

Endogenous, naturally occurring DNA damages are frequent, and in humans include an average of about 10,000 oxidative damages per day and 50 double-strand DNA breaks per cell cycle [see DNA damage (naturally occurring)].

 

Several reviews[122][123][124] summarize evidence that the methylation enzyme DNMT1 is recruited to sites of oxidative DNA damage. Recruitment of DNMT1 leads to DNA methylation at the promoters of genes to inhibit transcription during repair. In addition, the 2018 review[122] describes recruitment of DNMT1 during repair of DNA double-strand breaks. DNMT1 localization results in increased DNA methylation near the site of recombinational repair, associated with altered expression of the repaired gene. In general, repair-associated hyper-methylated promoters are restored to their former methylation level after DNA repair is complete. However, these reviews also indicate that transient recruitment of epigenetic modifiers can occasionally result in subsequent stable epigenetic alterations and gene silencing after DNA repair has been completed.


There may be some relationship between the epigenetic clock and epigenetic alterations accumulating after DNA repair. Both unrepaired DNA damage accumulated with age and accumulated methylation of CpG islands would silence genes in which they occur, interfere with protein expression, and contribute to the aging phenotype.

 


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#40 HighDesertWizard

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Posted 10 December 2018 - 06:13 PM

< SNIP >

 

Calorie restriction mechanisms (because fuxx c.r. itself) are a great mechanism to target this pathway, and they are the most proven of all anti-aging interventions.  If we had even more direct and powerful dna repair interventions I would expect even better results.

 

< SNIP >

 

The statement highlighted in red above is false.

 

The most proven anti-aging intervention is The Inflammatory Reflex.

 

A 2014 clinical study was stopped after two years because too many more study participants were surviving who were taking an Inflammatory Reflex Agonist than those who weren't.

 

Gi4gJwch.png

 

 

 

Holding beliefs that have been falsified slows personal learning and progress. Proactive promotion of False Beliefs to others slows progress even more because more people will tend to get caught up in the false belief.

 

Perhaps I'm wrong.

 

If you can point to a robust study in humans showing that calorie restriction has that kind of pro-longevity potency, I'll gladly retract my criticism.

 

If you can't, please stop making statements that slow progress by promoting Beliefs that are easily shown to be False, like I just showed.

 

Cheers!


Edited by HighDesertWizard, 10 December 2018 - 06:15 PM.

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#41 OP2040

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Posted 10 December 2018 - 06:37 PM

HDW,

The study you posted is highly specific to one disease, it is not an aging study.  When I say that calorie restriction is the most tested, it is using the following presumptions:

1. Specifically for Aging (either median or max lifespan)

2. Number of replicated studies

3. It does not need to be in humans since aging studies in humans aren't even a thing yet.

 

Even specifically for alzheimer's it's not even that interesting of a study.  The cholinergic hypothesis has been around forever now, and as far as I can tell Alzheimer's is still going strong.  It is targeting the disease as it manifests in it's very late stages, and therefore offers nothing in terms of a complete cure that an age reversal intervention would offer.

 


Edited by OP2040, 10 December 2018 - 06:41 PM.

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#42 Mind

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Posted 10 December 2018 - 06:47 PM

Just chiming in to congratulate the LongeCity community for "keeping it civil". This is one of the more scientific and civil forums on the Internet. I have seen other discussions in other places about the Programmed vs. Damage theories of aging explode into name calling and bitterness. Not productive.

 

Glad to see people here hashing it out in a mostly civil manner. Like most things in life and science, the theory of aging is probably not a black or white issue, but shades of grey. I am glad to see so many different angles presented in this thread.


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#43 OP2040

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Posted 10 December 2018 - 07:00 PM

It occurs to me that even if we were to take the flawed car metaphor seriously, it still wouldn't work as most people conceive of the damage theory.  Lets say a car is falling apart due to aging.  What good would simply removing damage do? Absolutely nothing.  Mechanics would be needed and that represents highly active repair mechanisms.  Some might object that this is still supports a damage-based theory.   But in practice most people from the damage camp seem to think that clearing damage will do something, when in fact it's been proven do no nothing, with the notable but explainable exception of senolytics. 


Edited by OP2040, 10 December 2018 - 07:01 PM.


#44 Mind

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Posted 10 December 2018 - 07:36 PM

It occurs to me that even if we were to take the flawed car metaphor seriously, it still wouldn't work as most people conceive of the damage theory.  Lets say a car is falling apart due to aging.  What good would simply removing damage do? Absolutely nothing.  Mechanics would be needed and that represents highly active repair mechanisms.  Some might object that this is still supports a damage-based theory.   But in practice most people from the damage camp seem to think that clearing damage will do something, when in fact it's been proven do no nothing, with the notable but explainable exception of senolytics. 

 

I guess the counter-argument/analogy would be that it is a car has self-repair mechanisms and the damage degrades the natural self-repair, thus removing the damage would allow the self-repair to operate optimally and prevent aging. I know it is not a perfect analogy, nothing is, but that is the way I would think about it in a damage theory framework.



#45 Rocket

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Posted 10 December 2018 - 08:22 PM

To take the "flawed" vehicle analogy further... Repairing an aging car is a losing battle. What good is it to replace the struts and brakes when the car is slowly oxidizing into rust? Eventually all the repairing in the world won't fix it as the vehicle corrodes away. It's more efficient to buy a new one (and recycle the old back into its constituent components), much like its easier for nature to pass on our DNA into a new body than it is to fight a losing battle and try to maintain youth indefinitely.


Edited by Rocket, 10 December 2018 - 08:25 PM.

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#46 OP2040

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Posted 10 December 2018 - 09:21 PM

Repairing an aging car is fairly easy, and they can be repaired indefinitely.  It is only out of economic convenience and technological innovation that we prefer to buy new at some point rather than repair.  It doesn't really matter if it's an inconvenience in terms of economics or evolution.  All that matters now is whether it's an inconvenience to the conscious entities that now exist and would like to do something about it.  Decline is not inevitable, which is the only point that matters if decide we want to change it.

 

However, it is interesting that in order to save the car repair analogy, you have to bring humans back into the equation as an anti-entropic force.  Aging cannot be due to entropy because the earth/universe is an open system and living systems are built to exploit that.  There is absolutely no reason why a living thing should not be able to repair indefinitely, and we have ample evidence to conclude that both the germline and some animals have the potential to go on indefinitely.

 

The car repair analogy brings up another interesting idea, that of Theseus' ship.  When we do get our indefinite lifespans, I have always said that identity will replace death as our main existential concern.  Mastering life and biology brings out all kinds of identity issues.  After all, having life is no guarantee you will be a remotely similar person in 1,000 years.  Personally, I'm looking forward to that part, but some people are so attached to who they think they are it might cause some serious psych problems.  Anyway, that's another thread.

 

 

 



#47 OP2040

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Posted 10 December 2018 - 09:52 PM

The first article is pretty old but I can't believe it slipped by me.  Isn't it amazing, btw, that we think of 2015 as "old" when it comes to these things.  I think we're living through a revolution that we may not even see because we're in it.  The second one, in the same vein, is a study proposing a "genetic switch" theory of aging.  I rather like that term and pretty much sums up how I think it works. 

 

https://www.eurekale...u-sfo072015.php

 

https://www.ncbi.nlm...pubmed/28797825



#48 OP2040

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Posted 10 December 2018 - 10:06 PM

I just discovered a new scenario in which biological tissue can be brought back from the brink and regenerate.  Apparently, hibernating bears (and presumably other hibernating animals) have completely devastated kidneys when they wake up to the point at which a human would be on dialysis.  And yet "something happens" and "bam" fresh, high functioning kidneys for another season.  And this must happen every year of a bears life.  So if we simply list all of the various regenerative scenario that we know to exist, the list is getting quite extensive:

1. n,.s. animals

2. part regeneration after injury (salamanders, etc.)

3. germline regeneration before reproduction

4. regeneration of the organs of hibernating animals

5. regeneration of brain and memory! in metamorphic species.

6. re-expressing ONE gene, FOXN1 will get you a spanking new thymus.

7. etc. etc. etc.

 

As the evidence piles up, it appears more and more like tissue renewal is really quite an easy trick.  And it seems more and more likely that it is relatively rare only because it was selected against (or aging selected for), not at all because it is difficult or impossible.

 

Sorry for posting so much, I just love this topic.  It's like a mystery wrapped inside a riddle, and covered in secret sauce lol

 

 



#49 xEva

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Posted 10 December 2018 - 11:25 PM

Here is the paper that showed that onset of aging is programmed: Repression of the heat shock response is a programmed event at the onset of reproduction, 2015.

 

Some key quotes:

 

We found that multiple stress responses become transcriptionally repressed on the first day of adulthood, resulting in animals that are much more susceptible to environmental stress.

 

By focusing on the HSR, we found that transcriptional repression occurs within a 4 hour window and coincides with the onset of egg-laying, suggesting that interplay between the germ line and the soma results in active remodeling of stress responses once animals are committed to reproduce.

 

Using a combination of genetic and biochemical approaches we found that the global repression of stress responses is controlled by signals from germ line stem cells through [a specific molecule] indicating that stress response collapse represents an active down-regulation of protective pathways at the onset of reproduction.

 

We found that the inducibility of the HSR is reduced by 60-70% between 8 and 12 hours into the first day of adulthood and coincides with the onset of egg-laying. This suggests that repression of the HSR represents an actively controlled transcriptional re-tuning that marks the onset of reproductive maturity and could represent an early molecular event in the aging process.

 

Our data suggest that stress response pathways are not gradually and progressively dysregulated as a consequence of stochastic damage with age but are instead rapidly and precisely repressed as animals commit to reproduction.


Edited by xEva, 10 December 2018 - 11:38 PM.

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#50 xEva

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Posted 11 December 2018 - 12:58 AM

Eva good summary of the "Grandmother hypothesis" of disposable soma theory.  I am inclined toward that theory myself.

 

However, the evidence seems to show that there really aren't tradeoffs between growth, reproduction and repair as the theory suggests.  One criticism is the fact that calorie restriction works, and the grandmother hypothesis was proposed to overcome that criticism.  But another one is Michael Rose's experiments with fruit flies.  He bred them to have more than twice the longevity, alongside substantially increased reproduction.  So no inherent trade-off between repair and reproduction.  One thing is for sure, the evidence has been the death knell for antagonistic pleiotropy theories.  But I think disposable soma can be salvaged by saying that it is true under evolutionary conditions of group selection, but the trade-offs are not thermodynamically inherent, and can easily be overcome.

 

Notice that none of these has anything to do with damage.  The evidence shows that lifespan can be increased without addressing damage per se.  Up-regulating repair mechanisms of course relates to damage being a factor in the symptoms of aging that we see, but they are not the cause of aging.  That is an important distinction to make because it means that removing damage will do nothing but slow down the flood of a process that is well on it's way already.  The evidence also bears this out.

 

Also, this doesn't necessarily show that aging is programmed.  It most obviously shows that there is a selection shadow that developed due to strong group selection pressures during evolution.  Whether one wants to call that programmed or not I guess is almost a personal preference. 

 

At least this puts us well past that time in history when curmudgeons could say that aging is built into the system so tightly that you cannot do anything about it.  Unfortunately, no less a luminary than Leonard Hayflick subscribes to such a dismal theory.  But I think psychology plays a larger role in these debates than we would like to imagine.  Older folks probably prefer the idea that aging and death are inevitable since it seems any regenerative medicine would be too late for them.  What they don't know is that some day these technologies will be so powerful that there will be a technology of resurrection as well.  But that's another thread.

 

I'm afraid, despite some superficial similarities, my take has nothing to do with "Grandmother hypothesis," nor is it rooted in the disposable soma theory.  Let me try to make myself clear.

 

To simplify, assume that the amount of resources is irrelevant. Say, food is abundant, always. But the habitat is limited (space) Then again, never forget about evolving pathogens.

 

 

What I'm saying is that a 'fit' germ line is the one which is genetically rich, flexible and malleable.

 

I'm sure you'll agree that there is no other way to satisfy this requirement except by influx of novel individuals into the group.

 

 In the conditions of limited space, a population cannot grow indefinitely => therefore Mother Nature must ensure that less novel individuals (to avoid saying 'old') must be weeded out so that novel individuals can take their place.

 

In other words, individual's death is the price for everlasting genetic flexibility and renewal of the group as a whole.

 

 

How exactly this weeding out is accomplished is irrelevant. We know of many different strategies that evolved in the life history of each species. Humans happen to age slowly. Salmon fall apart right after spawning. Animals with negligible senescence, succumb in the very end. The point is, all must die BECAUSE: individuals cannot change their genome -- they cannot renew or modify it.

 

 

Again: all individuals within a group must die to ensure that the group genome remains flexible and diverse and that it continues to evolve, or change. Otherwise the group will not last that long. This is such an important requirement that Mother Nature could not leave it drifting. Aging and death are  ensured in our developmental  program as part of our life history. This is the bad news.

 

 

The good news is that we have already discovered ways of modifying our genomes in situ and there surely will be more to come. This means that we satisfy this most important Nature's requirement for an indefinite lifespan.

 

 

 

PS btw, we refer to the same seminal 2015 paper.


Edited by xEva, 11 December 2018 - 01:13 AM.

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#51 QuestforLife

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Posted 11 December 2018 - 09:08 AM

Here is the paper that showed that onset of aging is programmed: Repression of the heat shock response is a programmed event at the onset of reproduction, 2015.

 

Our data suggest that stress response pathways are not gradually and progressively dysregulated as a consequence of stochastic damage with age but are instead rapidly and precisely repressed as animals commit to reproduction.

 

Yes xEva, evolution certainly favors turning the HSP response down in adulthood. I'm sure animal populations in the wild do better because of this, otherwise it wouldn't happen, but there is not enough evidence to say for sure that this is due to the inducement of faster aging (and pop turnover) or a tradeoff with some other fundamental attribute.

 

For example it might well be that it is very important to grow to adulthood without any errors in protein folding, but once you're grown the growth and repair pathways can afford to be sloppier but faster, perhaps, and this offers survival advantages?


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#52 Rocket

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Posted 11 December 2018 - 01:51 PM

Perhaps it would be helpful if the terminology was defined. What is mean by "programmed" and what is the "clock" by which events are triggered to occur. A framework of these fundamentals should be defined, else discussions can lead to erroneous and useless tangents.

 

What is the programming? How does the programming unfold? In every computer there is clock and a microprocessor in which instructions are carried out. By what biological method are instructions stored and then carried out in an organism? Who or what coded the instruction set into living organisms?

 

 


Edited by Rocket, 11 December 2018 - 01:56 PM.

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#53 OP2040

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Posted 11 December 2018 - 02:30 PM

The key takeaway of the study that Eva and I posted is that the HSP response collapses immediately at a specific time around reproductive age.  Yes it is only one system, but it's a very important one.  By any rational criteria, that looks like programming.  Of course, there are many animals that have a similar semelparous collapse that is even more dramatic.  And one might argue that these species are quite different from humans.  Do repair systems collapse in humans?  If there's one thing I've learned reading a lot of studies, it's that almost everything that constitutes the "infrastructure" (genes/proteins/etc.) is highly conserved among almost all species.  So the main differences arise through differences in gene expression.  We have all the same genes that a salamander has to rebuild a limb, but they are turned off and inaccessible.  In terms of proteostasis collapse, it could be that the difference arises because our HSP system is only partially turned off.  Many of the things that are turned off in a trigger-like manner in semelparous animals may only be turned off partially in us, thus providing a more drawn out collapse. 

 

Proteostasis is one of the least talked about primary hallmarks, so maybe this is something we've been missing. 



#54 HighDesertWizard

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Posted 11 December 2018 - 02:36 PM

The key takeaway of the study that Eva and I posted is that the HSP response collapses immediately at a specific time around reproductive age.  Yes it is only one system, but it's a very important one.  By any rational criteria, that looks like programming.  Of course, there are many animals that have a similar semelparous collapse that is even more dramatic.  And one might argue that these species are quite different from humans.  Do repair systems collapse in humans?  If there's one thing I've learned reading a lot of studies, it's that almost everything that constitutes the "infrastructure" (genes/proteins/etc.) is highly conserved among almost all species.  So the main differences arise through differences in gene expression.  We have all the same genes that a salamander has to rebuild a limb, but they are turned off and inaccessible.  In terms of proteostasis collapse, it could be that the difference arises because our HSP system is only partially turned off.  Many of the things that are turned off in a trigger-like manner in semelparous animals may only be turned off partially in us, thus providing a more drawn out collapse. 

 

Proteostasis is one of the least talked about primary hallmarks, so maybe this is something we've been missing. 

 

 

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#55 OP2040

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Posted 11 December 2018 - 02:50 PM

Perhaps it would be helpful if the terminology was defined. What is mean by "programmed" and what is the "clock" by which events are triggered to occur. A framework of these fundamentals should be defined, else discussions can lead to erroneous and useless tangents.

 

What is the programming? How does the programming unfold? In every computer there is clock and a microprocessor in which instructions are carried out. By what biological method are instructions stored and then carried out in an organism? Who or what coded the instruction set into living organisms?

 

Fair enough.  A program should be characterized as a code/algorithm that translates into some action.  There is a reason we have always called it the genetic code. 

 

I don't think any of that is controversial.  I am trying to figure out why it is controversial when it is applied to aging, but not in other circumstances.  Clearly, the genetic code unpacks, translates and acts at a specific time to produce what we call "puberty", and other life stages too.  I don't see why it has to be so different for aging.

 

The only argument I can think of for why this would not apply to aging is the "selection shadow".  Living, reproducing animals have never lived a long time, therefore evolution has not selected for the same youthful gene expression in old age.

 

So here we have what may be the actual controversy.  Life is clearly built from code.  But does aging represent a collapse of the code, or is there an active code that promotes aging.  The evidence seems to indicate the former.  I prefer to still call this programmed aging, since it is clear that the solution is in the programming.  But others may intuitively object because they notice that aging actually looks like there is no efficient code running the show.  They are correct as far as that goes, and so the question gets broken down into a semantic or stylistic argument. 

 

As for damage theories, they are correct to the extent that after the youth code stops translating, damage is most of what we see and scientifically evaluate.  However, my objection has always been that trying to rectify damage to fix this problem will only result in a game of whack-a-mole.  If we want to get to the true source of aging and fix it, then we need to turn back on youthful gene expression. 

 

The CR scenario seems to do exactly that to a limited extent.  Youthful gene expression is turned up to ensure that a population will not collapse, or that an individual still has a chance of reproducing even during hard times.  That's why CR  induces the expression many youthful gene expressions.  We see autophagy ramped up, but almost all the other repair systems are ramped up as well. 



#56 OP2040

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Posted 11 December 2018 - 03:08 PM

Perhaps it would be helpful if the terminology was defined. What is mean by "programmed" and what is the "clock" by which events are triggered to occur. A framework of these fundamentals should be defined, else discussions can lead to erroneous and useless tangents.

 

What is the programming? How does the programming unfold? In every computer there is clock and a microprocessor in which instructions are carried out. By what biological method are instructions stored and then carried out in an organism? Who or what coded the instruction set into living organisms?

 

As for the "clock", that is a good question, and I have no problem saying that we just don't know.  If I had to guess, my bias would be back to "life history" events, just like as demonstrated in the c. elegans study.  One element of the aging program there is initiated by a specific life event, namely reproductive maturity.  This makes a lot of sense.  As for the specific molecular triggers, I'm not sure if they cover that.  In humans it could be hormones.  Reproductive age is a great candidate for the time of aging initiation in all reproductive species.  Given the huge cascade of biological events that happens at puberty it may take some time to narrow down the most potent triggers. And after all, there is a robust correlation between lifespan and age of puberty.

 

Here's a good review of it, a little dated:

https://www.ncbi.nlm...les/PMC3509060/


Edited by OP2040, 11 December 2018 - 03:21 PM.


#57 Rocket

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Posted 11 December 2018 - 03:30 PM

The hormonal clock is interesting, but again, what is the clock that registers it is time for puberty to begin and begin flooding the body with sex hormones? What is the "clock" driving puberty?

 

What I am driving at through asking questions is that there is no program controlling ageing. There is a cascade of chemical events that occurs as a body matures from infancy through adulthood. While it may appear programmed because it appears to happen on a schedule (puberty around 12), there is no schedule. the body matures, the cells that produce sex chemicals mature and develop over the years until the sex hormones increase. 

 

There is no clock. There is no instruction set. (to carry the programming terminology to it's logical conclusion). There is however a developing and growing human body and some chemicals get turned off during the growth process because the cells die or cease to function. Other cells mature and develop and begin to excrete adult hormones like T and E. 

 

Are there genes that can be activated that would extend life (today)? Sure. But 75,000 years ago, why would nature evolve an organism as complicated as a human to thrive until 100 when life expectancy was 25 or 30 years due to disease, injury, dental health, being eaten by a saber tooth tiger, freezing to death? Hell, I am sure before homosapiens arrived, that the life expectancy of what we evolved from was not even 25 years old. It's a miracle that we live with these genes into our 100s, albiet in a frail and weak state of being.

 

As Richard Feynam liked to say when people wanted to debate the nature of quantum mechanics, "Shut up and calculate." In other words, don't waste time pondering what cannot be known. Spend your time doing the science and solving real problems. I think that is relevant to ageing. Whereas some people see "programming", others see a cascade of physical events that leads to other events without programming involved. What it the correct theory? Who cares. Shut up and solve the problems one by one.


Edited by Rocket, 11 December 2018 - 03:37 PM.

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#58 QuestforLife

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Posted 11 December 2018 - 03:54 PM

The key takeaway of the study that Eva and I posted is that the HSP response collapses immediately at a specific time around reproductive age.  Yes it is only one system, but it's a very important one.  By any rational criteria, that looks like programming. 

 

Absolutely, this is a programmed change, just as the body's development from embryo to adult is finely programmed. What is in question is whether or not aging is programmed, and although HSPR shutdown contributes to aging it does not mean this is its programmed purpose.


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#59 OP2040

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Posted 11 December 2018 - 04:01 PM

I absolutely support the "shut up and calculate"  idea, which for aging means many more experiments than are currently done.

 

However, theory does matter because it drives where the money goes and how effective the outcome is.  Almost the entire research community is currently built to study "damages".  It hasn't gotten us very far.  So there is the question of funding for aging, and for alternative views of aging. 

 

I respectfully disagree with how you characterize development.  It certainly looks exquisitely timed to me.  Although we don't know the mechanics of it yet, surely there is some plan involved, and not just random inertia as you seem to be implying. 

 

There is certainly a clock somewhere.  We know there is a circadian clock, and no one would object to that.  In evolutionary terms, there doesn't need to be a physical clock like a CMOS, the clock exists due to a particular set of genetic instructions resulting from natural selection.

 

 

 


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#60 OP2040

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Posted 11 December 2018 - 04:20 PM

Absolutely, this is a programmed change, just as the body's development from embryo to adult is finely programmed. What is in question is whether or not aging is programmed, and although HSPR shutdown contributes to aging it does not mean this is its programmed purpose.

 

I think I agree on this.  Basically, there is a developmental program, but aging constitutes the ending of that program.  Nevertheless, it is important to recognize that restoring youthful gene expression (program) is still the best way to try to defeat aging.  And that removing damages will do next to nothing if youthful gene expression is not restored. 






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