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


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#121 xEva

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Posted 17 December 2018 - 05:44 AM

Another paper worth reading: Evolution favours aging in populations with assortative mating and in sexually dimorphic populations, 2018

 

Abstract
Since aging seems omnipresent, many authors regard it as an inevitable consequence of the laws of physics. However, recent research has conclusively shown that some organisms do not age, or at least do not age on a scale comparable with other aging organisms. This begets the question why aging evolved in some organisms yet not in others. Here we present a simulation model of competition between aging and non-aging individuals in a sexually reproducing population. We find that the aging individuals may outcompete the non-aging ones if...


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#122 xEva

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Posted 17 December 2018 - 06:31 AM

oops sorry, here is the free-of-charge link to the full paper: Diversity of ageing across the tree of life, 2014

 

Although it has been predicted that evolution should inevitably lead to increasing mortality and declining fertility with age after maturity, there is great variation among these species, including increasing, constant, decreasing, humped and bowed trajectories for both long- and short-lived species. This diversity challenges theoreticians to develop broader perspectives on the evolution of ageing and empiricists to study the demography of more species.


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#123 QuestforLife

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Posted 17 December 2018 - 09:57 AM

I think there are several objections to programmed aging.

 

(1) The first involves the nature of evolution, which picks the optimal survival strategy for genetic material rather than the individual carrying that material. I don't think this is in question, the question is whether aging is ever selected for specifically, or if it is just one factor among many interrelated ones. Either way, it is clear that aging/longevity is 'evolved' in some sense.

 

(2) The second more fundamental objection is what causes the initialization of aging in a body? We can see stochastic forces are occurring and that at some point the maintenance programs that stop entropy breaking down the body begin to fail. But it's not clear whether this point is simply a consequence of defense mechanisms being overwhelmed, or whether they are being down-regulated due to the evolutionary compromises made in (1). Either way however, clearly the level of the defense mechanisms is set by evolution, so in some sense it is 'programmed' in, even if it is only at the level of engineered obsolescence.

 

(3) The third objection is the practical one. Could hacking this system give us any real gains in lifespan? Opponents of 'programmed' aging say no, because up regulated HSP or mitophagy genes say, will never give us more than CR. So we'll still age, only slower because 'damage' will still be occurring. However we do know that cells can be reprogrammed and youthful gene expression can be fully restored. There is amply evidence of this through telomerase, OSKM, etc. And there are tantalizing hints (atleast to me) that this can be done in an adult animal or human.

 

No doubt I've skimmed over many important points. But I think it's fair to say that people mean different things by 'programmed' aging and that once you accept the evolution of aging, its hard to sustain an objection to some sort of  'program' that is amiable to intervention.


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#124 OP2040

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Posted 17 December 2018 - 02:06 PM

@ QfL,

 

Thanks for articulating some of these objections, maybe it will help clarify the programmed aging position.

 

1. No one would disagree that senescence is somehow based in evolution.  But the central dogma of biology is on it's way out.  It is absolutely not ok anymore to say that only genetic material is the basis for selection.  It's called dogma for a reason.  Group selection is controversial, but I don't see why it should be.  In semelparous animals, aging is definitely specifically selected for, so there are at least some cases where this is true, whether or not it's true for humans.  Although I am not convinced of it yet, I see no reason why humans couldn't have some positive selection for aging as well.  The only difference would be that ours is drawn out over many years as opposed to one dramatic moment. 

 

2.  I like the idea that it could be more like "engineered obsolescence", so I might have to steal that.  The answer here is that we just don't know yet.  I do find it interesting  that the discussion here has moved from silly things like cholesterol and ros to more substantial things like signalling patterns and gene expression.  We now have very strong evidence that things like CR act through signalling and gene expression changes to upregulate repair mechanisms.  I think this points to the idea that repair mechanisms downregulated programmatically.  If it was strictly due to damage, how could they ever be turned back on?

 

3.  We don't have any proof yet for any aging theory if the standard is reversing aging in humans.  It hasn't been proven yet.  However, for animals CR easily fits with a programmed theory.  And as you state, currently  the most exciting potential interventions speak to the fact that damage can be reversed in adult animals.  If damage can be reversed, then game over for any damage theory, as the damage is just downstream symptom.  OSKM reprogramming in particular has been shown to reset a number of other parameters.  Yes, damage, but also all of the other primary hallmarks.  It looks like can potentially set the cellular state to 0, just as happens during reproduction.  Tantalizing to say the least.


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#125 OP2040

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Posted 17 December 2018 - 02:20 PM

QfL raises one of the most important practical questions for us.  We know that reversal can be done in some animals for various tissues and generically.  We can speculate that it may be the same for humans.  The big question is whether there is a point of no return.  Is there a point at which the youth program cannot be reasserted or the aging program stopped, because of extensive damage?

 

Call me a pollyanna, but my speculative answer to that is no.  And the evidence comes from a number of sources.  Hibernating animals regenerate various organs that look past the point of no return every single year.  Regenerative animals were thought to lose their ability to regenerate due to aging.  However, we can now recapitulate youthful regeneration in an adult animal with various interventions that look a lot like reprogramming. 

 

This is all on an organ level though.  So the even bigger question remains whether systemic damage can go to a point of no return.


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#126 QuestforLife

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Posted 17 December 2018 - 03:46 PM

We can certainly agree that gene expression changes are very important drivers of aging. Of course the argument can always be made that it is stochastic damage that is driving these change, and if so, then restoring gene expression will help but will not restore a cell (or indeed organism) to health and youth.

 

The fact re-elongating telomeres (for example), or transient OSKM expression makes cells indistinguishable from much younger cells does seem to disprove this theory. However it might be that only a subset of cells are being regenerated (and we do in fact know that OSKM re-programming is very low efficiency), and the most damaged cells are instead driven to senescence. This is not necessarily a problem for an animal, so long as the restored cells are numerous enough to replace all the losses, and the losses are not so substantial as to be lethal (through lysis, for example).

 

In regenerating animals the key things to look out for will be: 1. does aging bounce back (regeneration was insufficient to reset the body to a new, younger equilibrium),or 2. Does the animal suffer serious harm or even death (regeneration was too strong, or severe, causing large scale cell death in a significant  portion of cells. And of course, 3. How is the incidence of Cancer effected - does the regeneration of the immune system counter any increased spread of cancerous cells (possibly pre-existing treatment)?



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#127 OP2040

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Posted 17 December 2018 - 04:55 PM

Indeed, cellular rejuvenation does not exactly translate to body rejuvenation.  The tissue environment needs to be treated as a whole to see true rejuvenation. Gene expression is not quite the most upstream target, I think there is something above it.   Nevertheless, it is the most powerful of those things that we have adequate knowledge.

 

All good questions.  The immune system, cancer and ecm are all wild cards.  Does cellular rejuvenation cover these areas, or is something more needed?  I would say yes, but not much more.  Cancer and immune system are the same problem really.  A rejuvenated immune system should prevent cancer.  But there may be a question of timing where the immune system should be rejuvenated, primed and ready before the more systemic cellular rejuvenation.

 

These are all open questions and the only thing we can say is lets get the experiments done so they can be answered. 



#128 OP2040

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Posted 17 December 2018 - 07:41 PM

It's looking more and more like the the genome must be unlocked via epigenetics in order to engage in any type of rejuvenation.  How many powerful interventions have failed in the past because we didn't know how to open up gene expression.  This is going to be huge in terms of translation and getting therapies to actually work in the clinic.

 

This just out today:

https://www.frontier...2018.00874/full

 

 

 

 


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#129 xEva

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Posted 17 December 2018 - 08:44 PM

funny, I was just reading about transcription regulation and chromatin modification genes, following the exceedingly rare cases of developmental program arrests. Remember Brook Greenberg, the girl who never aged? In her and 4 other patients,
 

coding de novo mutations were found in five different genes which fall into similar functional categories of transcription regulation and chromatin modification.  (wiki)

 


Rocket may find this interesting: apparently, cases of developmental  program mishaps are very very rare. All are girls, and there is a unique case in Australia (wiki):

 

Nicky Freeman[18] of Australia (born in 1970), a middle aged man who looks like a preteen boy.

 

[18] Forty-year-old trapped in child's body, The West Australian, 2015

 

University of WA medical genetics professor David Ravine said Mr Freeman's case was extraordinarily rare and he had never come across anything like it in his 22-year career.

 

Take a look at the picture. The wrinkles look appropriate for a 40yo

 

a_260210gennick1_1apon69-1apon6d.jpg?imw


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#130 OP2040

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Posted 17 December 2018 - 09:41 PM

Interesting stuff Eva. If anything these cases are fodder for stochastic damage theories of aging.  In these cases the developmental life history seems to be completely altered, and yet aging itself either speeds up or comes right on time.  It does kind of show that puberty/adulthood is programmed though.

 

Having said that, they are just interesting cases, so it's totally speculative as to how they should be interpreted in terms of aging.  They need to get all their genomes sequenced and see what's up.

 

There's an interesting article/study out there with the title: "Global Heterochromatin Loss.  A Unifying Theory of Aging?"

It's pretty interesting....

 

 


Edited by OP2040, 17 December 2018 - 09:45 PM.


#131 Rocket

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Posted 18 December 2018 - 01:11 AM

funny, I was just reading about transcription regulation and chromatin modification genes, following the exceedingly rare cases of developmental program arrests. Remember Brook Greenberg, the girl who never aged? In her and 4 other patients,


coding de novo mutations were found in five different genes which fall into similar functional categories of transcription regulation and chromatin modification. (wiki)


Rocket may find this interesting: apparently, cases of developmental program mishaps are very very rare. All are girls, and there is a unique case in Australia (wiki):


Nicky Freeman[18] of Australia (born in 1970), a middle aged man who looks like a preteen boy.


[18] Forty-year-old trapped in child's body, The West Australian, 2015


University of WA medical genetics professor David Ravine said Mr Freeman's case was extraordinarily rare and he had never come across anything like it in his 22-year career.


Take a look at the picture. The wrinkles look appropriate for a 40yo


a_260210gennick1_1apon69-1apon6d.jpg?imw


Yes I am familiar with this syndrome. There is a lady in south America trapped in a 2 or 3 year old body.

Its just further evidence that when things go wrong with "programming" they don't lead to people who don't age. This man and the other woman I am referring to are aging right on time even though their bodies are not developing past very early ages.

I sincerely hope this isn't an attempt to prove me wrong because it doesn't. There are NO people alive or dead who never aged because their aging program malfunctioned.... I will say it again, that man and the other woman I know about are aging just like every other living human.

Please don't confuse aging with developing. They are totally different quantities. Just because their bodies stopped growing and developing does in no way mean that their cells have stopped aging. They most assuredly have aging cells... Senescent cells.... Lipofuscin... Glycation... Atherosclerosis... Faltering mitochondria, issues with ELLPs and calcium channels... Failing immune systems, weakening bones, muscle loss... And on and on.

Nature's aging program has never failed in a positive manner, ever. Period.

Why? Because it does not exist. There is no death program. Else why whenit fails does it only shorten life? Why should it never fail and prolong youth and health? It doesn't exist. That man in the picture is aging and dying and losing health right on track.

And by the way, that guy looks 15 years older.

Edited by Rocket, 18 December 2018 - 01:14 AM.


#132 xEva

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Posted 18 December 2018 - 01:44 PM

Rocket, I don't think anyone here confuses aging with development. As for the popular press, they may be excused -- and not in the least due to a limitation in this regard in otherwise super-rich English language. Getting older and to age means both growing up and growing old. And it's had to distinguish the meanings without having to jump hoops. There is a distinction in Slavic languages, say, when siblings are compared, we don't say that one is older. We say senior, which, to me at least, directly translated to English sounds even older (in the decrepit rather than chronological sense).

 

I thought these rare cases are very curious (btw, could not find that Latino woman). Their rarity tells us that problems with the developmental program are generally not compatible with life. It's a miracle these cases survived despite a whole array of health issues. Turns out that Australian guy is also blind. 

 

And you're right, there is no humans with arrested development after reaching maturity, which is what we want. But then what makes other animals so special? Take the naked mole-rat. They don't age, the fecundity of the queen goes up with age, their mortality curve goes down with age overall, and in the last decade remains flat. There is no issues with organs or tissues which would distinguish older individuals from the younger ones. They show no senescence with age, and just drop dead in the very end (I'm still trying to find out why). What gives?

 

Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age, 2017


Edited by xEva, 18 December 2018 - 01:57 PM.


#133 Rocket

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Posted 18 December 2018 - 02:18 PM

Rocket, I don't think anyone here confuses aging with development. As for the popular press, they may be excused -- and not in the least due to a limitation in this regard in otherwise super-rich English language. Getting older and to age means both growing up and growing old. And it's had to distinguish the meanings without having to jump hoops. There is a distinction in Slavic languages, say, when siblings are compared, we don't say that one is older. We say senior, which, to me at least, directly translated to English sounds even older (in the decrepit rather than chronological sense).

 

I thought these rare cases are very curious (btw, could not find that Latino woman). Their rarity tells us that problems with the developmental program are generally not compatible with life. It's a miracle these cases survived despite a whole array of health issues. Turns out that Australian guy is also blind. 

 

And you're right, there is no humans with arrested development after reaching maturity, which is what we want. But then what makes other animals so special? Take the naked mole-rat. They don't age, the fecundity of the queen goes up with age, their mortality curve goes down with age overall, and in the last decade remains flat. There is no issues with organs or tissues which would distinguish older individuals from the younger ones. They show no senescence with age, and just drop dead in the very end (I'm still trying to find out why). What gives?

 

Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age, 2017

 

If I ever sound curt or being short and rude, its because I'm at work and trying to type out an argument in a minute or two and don't have time for niceties. :)

 

I appreciate these odd cases. They are very curious. But they are called Larsons's syndrome (spell) and from reading the cause is a lack of IGF1 while they are developing.

 

The naked mole rat is a curiousity. BUT...... But they only live to be 30 years old in good health. Humans live to be 60(?) in good health. Sure other rodents don't live as log but maybe the genome and cellular pathways (here goes my bio ignorance talking) of the NMR is similar to the human genome and pathways and... Presto!! Long lived rodents. 

 

I am a broken record, I know it. Why does the human ageing program ever fail to the detriment of human life? Why does it never fail in a positive way and maintain youthful cells through the 70 80s 90s 100s??? If such a program existed, it mus fail both ways: Negatively and Positively. But we see ONLY negative failings.

 

Therefore there is a lack of evidence for a ageing or death program for it only fails negatively when probability says it must fail negatively and positively.

 

Prove yourself wrong! When I was in ungraduate school, I read a lot of Feynam. People don't try to prove themselves wrong. 

 

The easiest person to fool is yourself.

 

"We are trying to prove ourselves wrong as quickly as possible, because only in that way can we find progress."

 

Don't get hung up a theory because you fell in love with it. Get hung up on experimental evidence. Shut up and calculate.


Edited by Rocket, 18 December 2018 - 02:19 PM.

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#134 Oakman

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Posted 18 December 2018 - 03:23 PM

Rocket, I don't think anyone here confuses aging with development. As for the popular press, they may be excused -- and not in the least due to a limitation in this regard in otherwise super-rich English language. Getting older and to age means both growing up and growing old. And it's had to distinguish the meanings without having to jump hoops. There is a distinction in Slavic languages, say, when siblings are compared, we don't say that one is older. We say senior, which, to me at least, directly translated to English sounds even older (in the decrepit rather than chronological sense).

 

I thought these rare cases are very curious (btw, could not find that Latino woman). Their rarity tells us that problems with the developmental program are generally not compatible with life. It's a miracle these cases survived despite a whole array of health issues. Turns out that Australian guy is also blind. 

 

And you're right, there is no humans with arrested development after reaching maturity, which is what we want. But then what makes other animals so special? Take the naked mole-rat. They don't age, the fecundity of the queen goes up with age, their mortality curve goes down with age overall, and in the last decade remains flat. There is no issues with organs or tissues which would distinguish older individuals from the younger ones. They show no senescence with age, and just drop dead in the very end (I'm still trying to find out why). What gives?

 

Naked mole-rat mortality rates defy Gompertzian laws by not increasing with age, 2017

 

The naked mole rat is certainly the exception that seems to put some strongly held beliefs in question. Namely, that aging and death are part of the same process. If a mole rat can live and reproduce, lacks evidence of senescence and female menopause, then potentially these processes are exposed as unrelated. With other species, these processes are blurred together so as to confuse us as to their true nature.

 

Does this not lead to the likelihood that death is on the clock (tick, tick, drop dead), whereas aging is dependent of other extrinsic and intrinsic factors that are manifest differently by species?


Edited by Oakman, 18 December 2018 - 03:24 PM.

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#135 OP2040

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Posted 18 December 2018 - 03:44 PM

The naked mole rat is certainly the exception that seems to put some strongly held beliefs in question. Namely, that aging and death are part of the same process. If a mole rat can live and reproduce, lacks evidence of senescence and female menopause, then potentially these processes are exposed as unrelated. With other species, these processes are blurred together so as to confuse us as to their true nature.

 

Does this not lead to the likelihood that death is on the clock (tick, tick, drop dead), whereas aging is dependent of other extrinsic and intrinsic factors that are manifest differently by species?

 

That's a very good point Oakman and it brings with it a whole new possible perspective.   I am curious why there aren't any 100 year old NMR.  The definition of negligible senescence is that mortality rate does not increase from year to year.  In the wild, it would make sense that no NMR would make it to 100.  But in the lab, we should have one by now.  Or is this just a historical phenomenon because we haven't had NMR in labs for 100 years yet.  What do NMR die of if not age-related disease?  This would be a huge clue as to what constitutes a purely death (but not aging) program.  Is this all just scientific hype in the sense that yes NMR do not age for most of their lifespan, but then do actually age just before death.  But this is emphatically not what the study proving they are n.s. says.  It says that the rate of dying is random (not increased) at all ages.  It's very confusing to say the least.



#136 OP2040

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Posted 18 December 2018 - 03:50 PM

An unsatisfying but very scientific answer from the the guru of NMR research himself:

 

 

"We really don't know what's killing them at this point," Buffenstein said.

 

I mean, it's amazing even if it were just not aging until the last minute.  For us that means 80 year olds romping and downhill skiing like they did in their 20s.  I'd take that any day.  But something doesn't add up here when it comes to NMR coffin-dodgers....



#137 QuestforLife

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Posted 18 December 2018 - 04:39 PM

Perhaps Naked Mole rats have an instrinsic mortality that is relatively high (such that they don't live as long as humans). We do know that their mortality does not appear to increase with age.

But this begs the question why we don't see extreme outliers in NMR populations, who are very old. So perhaps they do age, we just haven't been able to detect it yet.



#138 Oakman

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Posted 18 December 2018 - 04:48 PM

An unsatisfying but very scientific answer from the the guru of NMR research himself:

 

 

I mean, it's amazing even if it were just not aging until the last minute.  For us that means 80 year olds romping and downhill skiing like they did in their 20s.  I'd take that any day.  But something doesn't add up here when it comes to NMR coffin-dodgers....

 

Very unscientific, but as a kid, I always thought each animal simply has a different sized 'life-time battery' in them, that just discharged and when it's gone - so are they. Of course, that was before rechargeable batteries like today (Just kidding)!


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#139 OP2040

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Posted 18 December 2018 - 04:49 PM

Three possibilities.  They age but we can't detect.  Their aging is limited to the very last and finite part of life.  They really do not age at all, even at the end, and we just haven't studied long enough to see the outliers.

 

Btw, I think it makes sense that we would never see aged animals in the wild even if for whatever reason they didn't age.  There are just way too many ways to die in the wild.  Microbes and predators would take care of the vast majority of any non-aging animal.

 

How long have we been breeding NMR for is a good question.  It would have to be since the 70s in order to see a 50 year old one, and I'm not sure that it has been that long, at least not on the scale it's done today.



#140 OP2040

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Posted 18 December 2018 - 05:41 PM

Meanwhile, the epigenetic "wins" just keep on rolling in...  This isn't directly related to the thread, except for the fact that epigenetics explains aging far better than anything else at the moment. 

 

https://www.telegrap...g-proving-four/

 

And if it can be characterized that efficiently (100%) then it should be able to be reversed that efficiently, unless the marks are nothing more than recording devices and nothing more.

 

Combine this with the HPV vaccine and it's looking like cervical cancer is on it's way out and will be the first cancer that we completely eradicate, with Australia taking the lead.  Awesome, awesome awesome!


Edited by OP2040, 18 December 2018 - 05:45 PM.


#141 xEva

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Posted 18 December 2018 - 06:30 PM

Three possibilities.  They age but we can't detect.  Their aging is limited to the very last and finite part of life.  They really do not age at all, even at the end, and we just haven't studied long enough to see the outliers.

 

aging of cells and tissues is straightforward to detect, so it's not it.

I suspect there could be more than one way Nature could ensure an individual's death. One is the familiar aging which leads to diminished fitness. This is a malleable process, which gets suspended when the conditions for reproduction are not right (say, food scarcity). And it can be modulated 'artificially' by upregulating some 'house keeping' genes / cellular repair pathways.

 

And then there seems another one. Could be some sort of a tick tack clock that runs out -?

 

In the case of the NMR, it could be something as simple as telomere attrition in some key organ cells. Telomere attrition is what limits the number of clones a euglena can produce. It must conjugate to reset its telomere length, but after that it's no longer the same individual.

 

But what if there is a 'final switch' in the epigenetic clock? We know that, as it ticks. it turns some genes on and others off. What if there is a final switch that shuts off the transcription of some essential genes-?  Does not even have to be running in all cells, but in some key endocrine organ. (hey! don't shoot, it's just an idea).



#142 OP2040

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Posted 18 December 2018 - 07:01 PM

But what if there is a 'final switch' in the epigenetic clock? We know that, as it ticks. it turns some genes on and others off. What if there is a final switch that shuts off the transcription of some essential genes-?  Does not even have to be running in all cells, but in some key endocrine organ. (hey! don't shoot, it's just an idea).

 

It's as good or better a hypothesis any that have been proposed.  It's just weird they can't establish a cause of death, or they haven't tried.  Even if it is something like a final epigenetic switch it must have some outward manifestation.  I'm guessing they just haven't done the study.  I'd imagine that NMR colonies are pretty hectic and maybe they are dying mostly from other NMR bites or something like that. 

 

Here is an intriguing hint that the most hopeful possibility is true.  As it turns out the 30 year quote for max lifespan is indeed because we've only been tracking them for 30 years.  Amazing!

 

Over the 30-year-span they looked at, only around 400 mole-rats actually died of natural causes. “[W]e see animals die with signs of periodontal disease, kidney disease or muscle wasting, but this can occur at any age,” Buffenstein said. They also seem to only very rarely develop other age-related diseases, like cancer. And their behavior largely stays the same as they get older.

 

All of which suggests to Buffenstein and her team that naked mole-rats could theoretically live as long as they’re lucky enough to avoid disease and injury. They also admit that there could be an upper limit where age starts mattering to mole-rats, but if there is, we haven’t seen the number yet.

 

The oldest mole-rat they have now is a 35-year-old male breeder, and Calico scientists plan to keep an eye on it and its long-lived compatriots as long as they humanly can (Buffenstein has kept her own colony, first obtained from Africa, for many years throughout her various jobs in academia and now at Calico). They and other scientists are also diligently doing research to try to suss how exactly the mole-rat pulls off its longevity trick, and whether any of it could ever apply to humans.

Here's an interesting study of vascular aging in NMR, which I fully expected to show some difference between young and old, but they found exactly no difference.  As we already know, this is most attributed to the fact that repair mechanisms don't decline, because NMR take huge hits of damage throughout their lives.  Perhaps we are just innately cynical and it seems to good to be true that any animal could defy aging entirely, but the NMR seemingly does it with ease

 

https://www.physiolo...eart.01287.2006


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#143 xEva

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Posted 18 December 2018 - 07:50 PM

Very unscientific, but as a kid, I always thought each animal simply has a different sized 'life-time battery' in them, that just discharged and when it's gone - so are they.

 

You're not the only one! The same ancient idea is upheld in Traditional Chinese medicine. They call it jing, the finite amount of which is set at conception. Once it runs out, life is over.
 


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#144 QuestforLife

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Posted 18 December 2018 - 09:13 PM

You're not the only one! The same ancient idea is upheld in Traditional Chinese medicine. They call it jing, the finite amount of which is set at conception. Once it runs out, life is over.


Sounds very like telomeres to me. Telomere science has had a bashing because leukocyte telomere measurements are fairly inaccurate, and not that well correlated to age anyway. But I suspect if we could examine telomere lengths in multiple tissues over a lifetime we'd find that they do represent an ultimate limit that kills you if nothing else does first. I suspect that it also correlates quite well will stem cell number. Those are my predictions anyway.
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#145 Castiel

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Posted 20 December 2018 - 06:38 AM

Aging in humans.   There are centenarians that are in some aspects healthier than 70 year olds.   Some humans live to 120+ years dementia free.   This is all despite the aging process being there.

 

Early on with mammals, nature had to solve an issue there were some cells that needed to last for years while being at extreme metabolic rate, the neurons.    So good a solution was found that even transplanting such to an animal with twice the lifespan the neurons would last twice as long.   In humans despite the aging vasculature and glymphatic systems the neurons can last over 120+years, potentially if they could be transplanted to a bowhead whale they could last over 200+years.   Some researchers hypothesize that these are ageless immortal cells, that are limited in lifespan only by their host.    Though parts of their genome appears to be subject to immense change probably for functional reasons, their resilience is stupendous.

 

Yet how does nature do with organisms it wants to have finite lifespan, when it attains immortality at the cellular level, even in nondividing cells, whilst it also posseses immortality in dividing cells within the germline?    Genetic regulation.   The body decays and it brings the whole ship down.

 

Some things like cell loss in the breathing reflex control nucleus, mean eventually even if ageless, this lack of regeneration will kill an organism, as the probability of stopping to breathe while asleep goes up with significant cell loss.    This will kill even if the rest of the body is ageless, for true immortality cellular regeneration in tissues such as this would be necessary.    But even without such, should the body be made ageless lifespan, healthspan, and youthfulness should increase substantially.   Does the body lack the ability to regenerate?   During embryonic development, substantial damage can be regenerated by the code, but such is made dormant, perhaps careful reactivation of such could lead to regeneration at least for some types of damage and tissues.

 

 

 

 

Embryos have full human regeneration and regeneration could be key for radical life extension https://www.nextbigf...-extension.html

 



#146 QuestforLife

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Posted 20 December 2018 - 08:47 AM

Aging in humans. There are centenarians that are in some aspects healthier than 70 year olds. Some humans live to 120+ years dementia free. This is all despite the aging process being there.

Early on with mammals, nature had to solve an issue there were some cells that needed to last for years while being at extreme metabolic rate, the neurons. So good a solution was found that even transplanting such to an animal with twice the lifespan the neurons would last twice as long. In humans despite the aging vasculature and glymphatic systems the neurons can last over 120+years, potentially if they could be transplanted to a bowhead whale they could last over 200+years. Some researchers hypothesize that these are ageless immortal cells, that are limited in lifespan only by their host. Though parts of their genome appears to be subject to immense change probably for functional reasons, their resilience is stupendous.

Yet how does nature do with organisms it wants to have finite lifespan, when it attains immortality at the cellular level, even in nondividing cells, whilst it also posseses immortality in dividing cells within the germline? Genetic regulation. The body decays and it brings the whole ship down.

Some things like cell loss in the breathing reflex control nucleus, mean eventually even if ageless, this lack of regeneration will kill an organism, as the probability of stopping to breathe while asleep goes up with significant cell loss. This will kill even if the rest of the body is ageless, for true immortality cellular regeneration in tissues such as this would be necessary. But even without such, should the body be made ageless lifespan, healthspan, and youthfulness should increase substantially. Does the body lack the ability to regenerate? During embryonic development, substantial damage can be regenerated by the code, but such is made dormant, perhaps careful reactivation of such could lead to regeneration at least for some types of damage and tissues.

What I find interesting is that you don't need the whole body to age to make the organism age and die. As you say neurons and (potentially also) heart cells can last a ridiculous amount of time without need of replacement. But the vascular and immune system age very fast and can take the brain and heart down with them.

So one strategy might be to aim for vascular and immune rejuvenation as a first stop, and we'd probably find knock on benefits throughout the 'non aging' parts of the body that previously would have deteriorated.

Edited by QuestforLife, 20 December 2018 - 08:48 AM.

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#147 OP2040

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Posted 20 December 2018 - 12:57 PM

Speaking of neurons, there's an interesting study that links number of cortical neurons to lifespan.  This link is more accurate than other, previous attempts to find some causal factor for the difference between species lifespan.

 

https://www.labroots...ortical-neurons

 

It's also interesting that it's cortical neurons because this isn't the part of the brain that signals hormones or anything.  I'm wondering if it's just an artifact in the sense that this part of the brain is the last part of the body to develop and keeps developing long into adulthood.  So animals worth more cortical neurons would, by definition need a stretched out life history.  But that stretched life history is not necessarily caused by the increased number of neurons. 

 

 

"The data suggest that warm-blooded species accumulate damages at the same rate as they age. But what curtails life are damages to the cerebral cortex, not the rest of the body; the more cortical neurons you have, the longer you will still have enough to keep your body functional,” said Herculano-Houzel.

 

Any ideas on this intriguing evidence?


Edited by OP2040, 20 December 2018 - 01:02 PM.


#148 Castiel

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Posted 21 December 2018 - 04:52 AM

Speaking of neurons, there's an interesting study that links number of cortical neurons to lifespan.  This link is more accurate than other, previous attempts to find some causal factor for the difference between species lifespan.

 

https://www.labroots...ortical-neurons

 

It's also interesting that it's cortical neurons because this isn't the part of the brain that signals hormones or anything.  I'm wondering if it's just an artifact in the sense that this part of the brain is the last part of the body to develop and keeps developing long into adulthood.  So animals worth more cortical neurons would, by definition need a stretched out life history.  But that stretched life history is not necessarily caused by the increased number of neurons. 

 

 

Any ideas on this intriguing evidence?

 

This is a link to the direct research paper.

https://onlinelibrar....1002/cne.24564

 

Will comment based on the news, will read the research paper and update later:

 

Though one could assume that aging taking a toll could be fought with spare capacity, I'm not sure that's the reason for this correlation.

 

I can say whatever the reason, do not think it is due to additional spare capacity in the brain, at least not in the cortex, unless some other brain area correlates with cortical neuron numbers(news didn't seem to specify perhaps research will) do think could be something else.   There are individuals with half a brain since childhood, and I've not heard of seriously limited lifespan but admit haven't looked, will check.   There are also individuals with very high education, who can reach very advanced ages while experiencing massive neurodegeneration and remain practically asymptomatic(which is good to know, because if we were to ensure proper support tissue maintenance, indicates that with enough education substantial tissue damage can be withstood whilst practically asymptomatic and waiting for cell replacement therapies.  Brain Tissue damage accumulation should be highly minimized if the vasculature and glymphatic system as well as support organs are made ageless.).

 

To me it seems like this research could support the programmed idea, as nature seems to have been able to tune lifespan apparently to what could be the needs of the organism's brain across a wide swath of species, with orders of magnitude difference in lifespan and vast variations in metabolic rate, and seems mostly content with this.

 

In humans it is said even the most rapidly dividing cells, even after a century of lifespan have negligible number of mutations.   Around 400~ vs a newborn with 50~, truly insignificant in a genome of billions of bases, and this may in part be also due to downregulation of maintenance and repair mechanisms.


Edited by Castiel, 21 December 2018 - 04:56 AM.


#149 Castiel

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Posted 21 December 2018 - 06:14 AM

Can't edit previous post to update this caught my attention from the research article linked above

 

Crucially, the finding that no correlation between
maximal longevity and metabolic rate remains after accounting for
variation in numbers of cortical neurons argues strongly against
the common notion that damages accumulate at rates that scale
across species depending on metabolism (West et al., 1997).-Herculano Houzel (2018)

 

Read paper first it seems no other brain area is as highly correlated in terms of cell number correlation

 

She seems to suggest spare capacity in number of cells could be the deciding factor

 

While this new possibility has yet to be investigated, it
leads to one clear prediction: those species with the largest number
of cells in the relevant organ(s) will live longer before succumbing
to physiological breakdown and disintegration and,
consequently, death.-Herculano Houzel (2018)

But there should be data not just in animals but as I said in humans to validate or dispute this.  As there are children with half a brain, which if this is the critical organ whose spare capacity is being exhausted, should suffer significant decrease in lifespan.

 

PS

 

People could say but what about the mitochondria, we already know nuclear dna damage is negligible even after a century and even despite the aging program, even in some of the most rapidly dividing cells even after a century of living.  Well neurons are high metabolic rate cells even in large animals and animals with greater number of neurons, yet it seems these can reach up to at the least 200+years of lifespan in mammals.   Given how energy dependent, hungry neurons are, that they start dying within minutes of oxygen deprivation, obviously the mitochondria which produces energy would have to be maintained functional somehow long term or there'd be mass neural death due to insufficient energy production in most cells given time.


Edited by Castiel, 21 December 2018 - 06:31 AM.

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#150 Harkijn

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Posted 21 December 2018 - 07:59 AM

 

 

I partially agree with Stefan, that "There is no intelligence inside a cell or the wider organism," in the sense that a 'dumb program' governs a cell's behavior and the organism as a whole -- and it does so according to the clues in its environment. I hope we could find a way to trick an older cell 'to think' that it's in a much younger environment than it id and that it's gotta keep up -- this should turn on the repairs and restore youthful phenotype, no?

Is there a dumb programme? These are extremely complicated issues.  A , for me, completely new scientific way of looking at this is pointed to by Josh Mitteldorf:

https://mail.google....QQxrJnlwZXBlZRG






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