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Arguing that Heat Shock Response Decline is Programmed


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#1 reason

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Posted 24 July 2015 - 12:24 PM


Researchers here present a fairly compelling case that the characteristic decline in the protective heat shock response with age is an evolved program. Compelling but not airtight: one could still argue that the rapid transition from effective to less effective observed in nematode worms is, along with other changes that occur at the same time, a response to rising levels of cellular damage rather than something that will occur regardless of circumstances. It is not too hard to envisage further studies that might add evidence to either side of the argument, and I will be very interested to see the outcome of similar investigations in mammals, but for now the primary point of interest is to see if the signaling that causes this decline can be usefully interfered with. The expectation is that increased levels of heat shock activity should result in more active maintenance and damage repair in cellular machinery, leading to slower aging and longer healthspan, and thus there is some interest in the research community in finding potential approaches to achieve this end.

Knowing more about how the quality control system works in cells could help researchers one day figure out how to provide humans with a better cellular quality of life and therefore delay degenerative diseases related to aging, such as neurodegenerative diseases. "Wouldn't it be better for society if people could be healthy and productive for a longer period during their lifetime? I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress."

A genetic switch starts the aging process by turning off cell stress responses that protect the cell by keeping important proteins folded and functional. In C. elegans, the decline begins eight hours into adulthood - all the switches get thrown to shut off an animal's cell stress protective mechanisms. Researchers found it is the germline stem cells responsible for making eggs and sperm that control the switch. In animals, including C. elegans and humans, the heat shock response is essential for proper protein folding and cellular health. Aging is associated with a decline in quality control, so researchers looked specifically at the heat shock response in the life of C. elegans. "We saw a dramatic collapse of the protective heat shock response beginning in early adulthood." Once the germline has completed its job and produced eggs and sperm - necessary for the next generation of animals - it sends a signal to cell tissues to turn off protective mechanisms, starting the decline of the adult animal. "All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses."

Using a combination of genetic and biochemical approaches, researchers found the protective heat shock response declines steeply over a four-hour period in early adulthood, precisely at the onset of reproductive maturity. Repression of the heat shock response occurred due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1. This resulted in a repressed chromatin state that interfered with HSF-1 binding and suppresses transcription initiation in response to stress. The animals still appeared normal in behavior, but the scientists could see molecular changes and the decline of protein quality control. In one experiment, the researchers blocked the germline from sending the signal to turn off cellular quality control. They found the somatic tissues remained robust and stress resistant in the adult animals.

Link: http://www.scienceda...50723125244.htm


View the full article at FightAging

#2 corb

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Posted 24 July 2015 - 03:33 PM

Still my question remains - Why did the researcher choose not to go through with a lifespan study even though they had created a hybrid capable of sustaining the youthful level of heat shock response? It would've taken a measly twenty days at most and barely any extra funds.

Until they can't even show the typical 15% of median lifespan increase we've grown accustomed with at this point, this is not only "not airtight" it's blatant charlatanry.

 

Heck if they're making sweeping conclusion which are supposed to overturn decades of research they might as well aim at the golden standard of lifespan extension - the 150% lifespan increase for roundworms treated with superoxide scavengers which was published months back.


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#3 Mind

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Posted 24 July 2015 - 04:26 PM

Agree with Corb, why not a full lifespan study?

 

Good to see a little more detail in at least one species, about how the changes occur after maturity. Humans stop growing and decline in health after maturity as well.



#4 LeeYa

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Posted 24 July 2015 - 04:54 PM

They mention an increase in lifespan: 

 

 In addition, overexpression of jmjd-3.1 in day 2 adults increased median and maximal lifespan by ≈20% and 12%, respectively, suppressed age-related motility and pharangeal pumping defects

 

 

It ist not that simple to switch-off Aging, because it is probably created as a redundant system by evolution.

I guess, there are at least a handfull of such background programs running, probably under epigenetic control.

 

 

 


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#5 corb

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Posted 24 July 2015 - 06:23 PM

They mention an increase in lifespan: 

 

 In addition, overexpression of jmjd-3.1 in day 2 adults increased median and maximal lifespan by ≈20% and 12%, respectively, suppressed age-related motility and pharangeal pumping defects

 

 

It ist not that simple to switch-off Aging, because it is probably created as a redundant system by evolution.

I guess, there are at least a handfull of such background programs running, probably under epigenetic control.

 

 

Scientists have been looking at the genome of C. Elegans for 50 years. Maybe more I can't be bothered to check. They just now found one gene that COULD be down-regulated before aging starts that can have a negative impact.

C. Elegans has 90 megabase pairs. Humans have 3,200 megabase pairs.

Meaningless endeavor. Handful, only if handful is a code word for hundreds of thousands.

If there's a well hidden "aging" gene like that in the human genome it will only take us 1,778 years to find it if we're working with the same speed. Good luck finding all of them before the Solar System implodes.

 

And still the "proof" is shallow as can be. C. Elegans suffers from significant proteom damage as it ages - there's more then enough on that in the cited materials, one could say that's it's main type of aging damage. So these scientists supposedly keep it's protein quality program running and ... it gains a massive ONE DAY of extra life - we could safely work on the assumption the program was imperfect from the get go.

I'm not even going to go into the fact that 12% is so low it might as well be considered statistical noise for species so short lived. Something I'm sure the researchers were quite aware of because they didn't even bother mentioning it for the press release.


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#6 Avatar of Horus

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Posted 24 July 2015 - 06:46 PM

...
And still the "proof" is shallow as can be. C. Elegans suffers from significant proteom damage as it ages - there's more then enough on that in the cited materials, one could say that's it's main type of aging damage. So these scientists supposedly keep it's protein quality program running and ... it gains a massive ONE DAY of extra life - we could safely work on the assumption the program was imperfect from the get go.
I'm not even going to go into the fact that 12% is so low it might as well be considered statistical noise for species so short lived. Something I'm sure the researchers were quite aware of because they didn't even bother mentioning it for the press release.


there were some other experimentations too in connection with the H3K27me3 and lifespan, for instance:

from the topic:
Creating a unified theory of aging
http://www.longecity...ndpost&p=727921
 

... 
If these above really are somewhat relevant to aging, the manipulation of the members of these protein complexes and pathways may or should result in life extension.
I checked whether it has been examined, and yes, some of it was. And resulted in about 30-76 % life span elongation in the worm C. elegans and fruit fly Drosophila species*.

The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner
Maures et al. 2011
http://www.ncbi.nlm....pubmed/21834846

Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway
Jin et al. 2011
http://www.ncbi.nlm....pubmed/21803287
...
Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance
Siebold et al. 2009
http://www.ncbi.nlm....pubmed/20018689
...
also a relevant review:

Histone methylation makes its mark on longevity
Han and Brunet 2012
http://www.ncbi.nlm....pubmed/22177962
Abstract
How long organisms live is not entirely written in their genes. Recent findings reveal that epigenetic factors that regulate histone methylation, a type of chromatin modification, can affect lifespan. The reversible nature of chromatin modifications suggests that therapeutic targeting of chromatin regulators could be used to extend lifespan and healthspan. This review describes the epigenetic regulation of lifespan in diverse model organisms, focusing on the role and mode of action of chromatin regulators that affect two epigenetic marks, trimethylated lysine 4 of histone H3 (H3K4me3) and trimethylated lysine 27 of histone H3 (H3K27me3), in longevity.

 
I don't know about any specific data on this in higher species ...


*: in some supplementary experiments they've achieved 88 %.

more details on this, in-depth too, are available there, including various tissues, organs and species, like the mouse and human.

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#7 corb

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Posted 24 July 2015 - 09:24 PM

there were some other experimentations too in connection with the H3K27me3 and lifespan, for instance:

from the topic:
Creating a unified theory of aging
http://www.longecity...indpost&p=72792

 

No one is arguing that maintenance gets down-regulated as we age.

The argument I'm presenting is in a completely different direction.
 

To say it in the most compact and easy to understand way.
If cutting of the damage at the beginning of aging doesn't stop the cascade the redundancy as LeeYa put it ... might be endless - if you decide to look at aging as a program or a cascade (although cutting of the first step and getting no results pretty much proves it's not a cascade. But I digress)

OR

You could look at it as random events - like we look at it now.

Really want I want to ask you is - at what number of completely redundant aging "programs" do you stop calling it a program and just decide to call it damage accumulation?

 

Aging being looked at as a program only makes sense if there's a detectable interaction between the processes. If all the genes do their own thing then ... I'm sure you can see the futility in wasting time in such research? How many genes will we have to regulate with medication? A hundred? A thousand? A million?

 

It's meaningless for us. Maybe when parents are ordering kids with synthesized DNA in 300 years it will be important, but for us, right now? No.

 

Oh and a little clarification - I'm not saying I agree that aging is a program. I'm just saying if you do wish to look at it as a program the near future treatment you should be striving for is still directly targeting the damage because it's the saner thing to do.

 

And a clarification for the internet because people take everything literally : I know how many genes we have.


Edited by corb, 24 July 2015 - 10:21 PM.

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#8 Avatar of Horus

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Posted 24 July 2015 - 10:56 PM

 

there were some other experimentations too in connection with the H3K27me3 and lifespan, for instance:

from the topic:
Creating a unified theory of aging
http://www.longecity...indpost&p=72792

 
No one is arguing that maintenance gets down-regulated as we age.
The argument I'm presenting is in a completely different direction.
 
To say it in the most compact and easy to understand way.
If cutting of the damage at the beginning of aging doesn't stop the cascade the redundancy as LeeYa put it ... might be endless - if you decide to look at aging as a program or a cascade (although cutting of the first step and getting no results pretty much proves it's not a cascade. But I digress)
OR
You could look at it as random events - like we look at it now.

Really want I want to ask you is - at what number of completely redundant aging "programs" do you stop calling it a program and just decide to call it damage accumulation?
 
Aging being looked at as a program only makes sense if there's a detectable interaction between the processes. If all the genes do their own thing then ... I'm sure you can see the futility in wasting time in such research? How many genes will we have to regulate with medication? A hundred? A thousand? A million?
 
It's meaningless for us. Maybe when parents are ordering kids with synthesized DNA in 300 years it will be important, but for us, right now? No.
 
Oh and a little clarification - I'm not saying I agree that aging is a program. I'm just saying if you do wish to look at it as a program the near future treatment you should be striving for is still directly targeting the damage because it's the saner thing to do.
 
And a clarification for the internet because people take everything literally : I know how many genes we have.

 


The sub-title of the article quoted in the first post is:
"Scientists pinpoint start of aging, discover it is not a slow series of random events"

But I don't know whether aging is caused by a program or the random damage accumulation.
Because of this state of things I support and conduct both types of research.
At present all we have are hypotheses.

For example in the same topic (in a later post) I presented studies that produced results which suggest that the lipofuscin accumulation is a controlled process.

The fact is that we don't even know what the concrete damages are, and what is their role and function, etc.;
if someone calls some things as "aging damage", that doesn't make it that.

Even it is possible that some of those are actually protective mechanisms and extend lifespan,
for example, the following study illustrates well this problem, about the "aging damage" known as "protein aggregates":

Widespread Proteome Remodeling and Aggregation in Aging C. elegans
Walther et al. 2015
http://www.ncbi.nlm....pubmed/25957690

Abstract
Aging has been associated with a progressive decline of proteostasis, but how this process affects proteome composition remains largely unexplored. Here, we profiled more than 5,000 proteins along the lifespan of the nematode C. elegans. We find that one-third of proteins change in abundance at least 2-fold during aging, resulting in a severe proteome imbalance. These changes are reduced in the long-lived daf-2 mutant but are enhanced in the short-lived daf-16 mutant. While ribosomal proteins decline and lose normal stoichiometry, proteasome complexes increase. Proteome imbalance is accompanied by widespread protein aggregation, with abundant proteins that exceed solubility contributing most to aggregate load. Notably, the properties by which proteins are selected for aggregation differ in the daf-2 mutant, and an increased formation of aggregates associated with small heat-shock proteins is observed. We suggest that sequestering proteins into chaperone-enriched aggregates is a protective strategy to slow proteostasis decline during nematode aging.

 
Besides: Why would someone need to wait for the accumulation of the damage, if these processes are the consequences of a progam and are controlled and as such, might be slowed or halted or reversed internally?

Imho until it is known, i.e. confirmed by hard evidence, what are the main causes there's no such thing as saner approach.


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#9 LeeYa

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Posted 25 July 2015 - 01:00 PM

 

Really want I want to ask you is - at what number of completely redundant aging "programs" do you stop calling it a program and just decide to call it damage accumulation?

 

I wouldn't really search for genes. I would look at the epigenetic program. Imagine the change from a caterpillar that becomes a butterfly. Some kind of "damage accumulation"?  Maybe we should call this"change" instead of "damage"?The aging phenotype is mainly controlled by a small fraction of particular epigenetic (=reversible!) changes. This epigenetic regulation of gene expression ALLOWS and ENFORCES damage accumulation by turning of the repair mechanisms.

 

If your boat has a leakage, water causes damage. Do you try to bail out the water out of the boat? Or would you at least try to plug the leakage first?

 

 

 

 


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#10 niner

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Posted 26 July 2015 - 12:38 AM

The sub-title of the article quoted in the first post is:

"Scientists pinpoint start of aging, discover it is not a slow series of random events"

But I don't know whether aging is caused by a program or the random damage accumulation.
Because of this state of things I support and conduct both types of research.
At present all we have are hypotheses.

For example in the same topic (in a later post) I presented studies that produced results which suggest that the lipofuscin accumulation is a controlled process.

The fact is that we don't even know what the concrete damages are, and what is their role and function, etc.;
if someone calls some things as "aging damage", that doesn't make it that.

Even it is possible that some of those are actually protective mechanisms and extend lifespan,
for example, the following study illustrates well this problem, about the "aging damage" known as "protein aggregates":

 

I think that the title "Scientists pinpoint start of aging, discover it is not a slow series of random events" was quite an overstatement.  Not only did they not find the start of "aging", they also did not show that random events were not important.  They're reading way too much into one small, albeit interesting result.

 

I agree with you that we can't say that aging is due to a program or to random damage.  I don't think that we will ever be able to say that it's one or the other, because both processes appear to be at work.  I was quite interested in the lipofuscin as controlled process paper, but it looks to me like it's not controlled.  The paper showed that a particular KO resulted in more oxidative stress, and this lead to more lipofuscin.  If the same gene becomes disregulated with age, that's neither a program nor a controlled process, it's just the result of something going wrong. 

 

We may not know every possible form of aging damage, and we may not know every consequence of them, but I don't think it's fair to suggest that we don't know what any of them are.  We know that lysosomes get filled with indigestible molecules (e.g. 7-ketocholesterol), and we know that long-lived proteins get glycated and oxidized; we know that transthyretin gradually forms amyloids that become life-threatening in supercentenarians, and that some cells senesce and refuse to die, resulting in the inflammatory SASP.    We know that these are some of the major differences between young and old tissues.  Is there any evidence that these things have a useful, positive role, or that they are created in a planned or purposeful way?
 


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#11 xEva

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Posted 26 July 2015 - 04:05 AM

Still my question remains - Why did the researcher choose not to go through with a lifespan study even though they had created a hybrid capable of sustaining the youthful level of heat shock response? It would've taken a measly twenty days at most and barely any extra funds.
Until they can't even show the typical 15% of median lifespan increase we've grown accustomed with at this point, this is not only "not airtight" it's blatant charlatanry.
 
Heck if they're making sweeping conclusion which are supposed to overturn decades of research they might as well aim at the golden standard of lifespan extension - the 150% lifespan increase for roundworms treated with superoxide scavengers which was published months back.


"blatant charlatanry"?! "making sweeping conclusion which are supposed to overturn decades of research"? What research? In the last year discussion on aging as failure of repair mechanisms it was established that there is no evidence of accumulation of damage in children and young adults -- hard as you and niner looked you could not come up with anything, other than one obscure Czech forensic study available only as abstract, which hardly qualifies as "decades of research".

This paper confirms what can be plainly seen, namely, that young people appear young, 'cause whatever metabolic damage they sustain is efficiently repaired.


Edited by xEva, 26 July 2015 - 04:23 AM.

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#12 xEva

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Posted 26 July 2015 - 04:12 AM

The aging phenotype is mainly controlled by a small fraction of particular epigenetic (=reversible!) changes. This epigenetic regulation of gene expression ALLOWS and ENFORCES damage accumulation by turning of the repair mechanisms.


well said!

I wonder now about the animals with negligible senescence, like some turtles. What, they don't have this switch in place?

But how marvelously simple and elegant this Nature's solution is, simply downregulate the repairs and voila, death is guaranteed.

#13 corb

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Posted 26 July 2015 - 07:03 AM

The aging phenotype is mainly controlled by a small fraction of particular epigenetic (=reversible!) changes. This epigenetic regulation of gene expression ALLOWS and ENFORCES damage accumulation by turning of the repair mechanisms.

 

Go to the thread Avatar of Horus posted, and tell me if his list looks like a small fraction of changes.
And he's listed a speckle of all the research covering genetic down regulation during aging. There's many more genes that change their expression with age.

As for them being reversible that says nothing about how they can be reversed, and still the most efficient way of doing it remains stem cell transplantation or parabiosis which is the same just with the progenitor cells found in blood.

 

Another thing - there's not an endless amount of "signals" your genetics can use to decide when it starts its programs - an organ reaching a certain size and operating in a certain way is one of them and we call that reaching maturity, but that's not a process we can halt or reverse once reached, and no one would want to do it even if we could. The only other viable signals we know of as of now is damage accumulation - and accumulation of damage is certainly a signal when it comes to genetic expression and the other and much dubious one is telomere shortening.

The easiest way to interfere with the aging phenotype remains damage repair, which has always been the aim of SENS.

 

Finally I evaluate therapies by their efficacy in treating aging pathologies.
Has controlling "aging" genes ever cured or halted any disease in a lab animal? No.
Has directly repairing the damage be it with stem cells or a a compound targeting molecular damage ever cured or halted any disease in a lab animal? Yes.

 

Did the water get in the boat from the hole or did the water cause decomposition to eat through the wood to make a hole so more water can get in?
It's a good analogy because it shows you consider the water as something that can only safely wash around the boat when in reality most holes in boats are caused by water exposure. I find this irony amusing.


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#14 LeeYa

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Posted 26 July 2015 - 12:06 PM

 Is there any evidence that these things have a useful, positive role, or that they are created in a planned or purposeful way?
 

 

 

From an evolutionary perspective, the answer is quite simple:

 

 

Without aging, it is difficult for nature to put together a stable ecosystem. Populations are rising exponentially or collapsing to zero. With aging, it becomes possible to balance birth and death rates, and population growth and subset crashes are tamed sufficiently that ecosystems may persist. This is the evolutionary meaning of aging: Aging is a group-selected adaption for the purpose of damping the wild swings in death rate to which natural populations are prone. Aging helps to make possible stable ecosystems.

http://joshmitteldor...theory-of-aging

 

Avatar of horus,

Thanks for the great posts about the epigenetic basis of aging from the topic "creating a unified theory of aging".

What kind of deadly damage will remain if we have sufficient tools for epigenetic editing available, using cells with a young phenotype as a blueprint? I'm sure that we'll refer to the remaining damage (if it exists) as "post-aging diseases". And then, there is far more time to deal with it.

 

xEva,

thanks for joining the discussion!

Yes, this switch should be absent in all species with negligible senescence.

 

By the way: Do you know how to keep the heat shock protein-related repair system running?

 

 

Increased frequency of sauna bathing is associated with a reduced risk of SCD, CHD, CVD, and all-cause mortality.

http://www.ncbi.nlm....pubmed/25705824

 

(I doubt that this can fully restore the off-switch, but I think this habit is usefull untill better strategies are at hand.)


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#15 xEva

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Posted 26 July 2015 - 05:37 PM

I think that the title "Scientists pinpoint start of aging, discover it is not a slow series of random events" was quite an overstatement.  Not only did they not find the start of "aging", they also did not show that random events were not important.  They're reading way too much into one small, albeit interesting result.

 
 

Go to the thread Avatar of Horus posted, and tell me if his list looks like a small fraction of changes.
And he's listed a speckle of all the research covering genetic down regulation during aging. There's many more genes that change their expression with age.
As for them being reversible that says nothing about how they can be reversed, and still the most efficient way of doing it remains stem cell transplantation or parabiosis which is the same just with the progenitor cells found in blood.
 
Another thing - there's not an endless amount of "signals" your genetics can use to decide when it starts its programs - an organ reaching a certain size and operating in a certain way is one of them and we call that reaching maturity, but that's not a process we can halt or reverse once reached, and no one would want to do it even if we could. The only other viable signals we know of as of now is damage accumulation - and accumulation of damage is certainly a signal when it comes to genetic expression and the other and much dubious one is telomere shortening.
The easiest way to interfere with the aging phenotype remains damage repair, which has always been the aim of SENS.
 
Finally I evaluate therapies by their efficacy in treating aging pathologies.
Has controlling "aging" genes ever cured or halted any disease in a lab animal? No.
Has directly repairing the damage be it with stem cells or a a compound targeting molecular damage ever cured or halted any disease in a lab animal? Yes.


That's right, we should pooh-pooh this study by all means possible and maybe even make those charlatans-authors retract it by threatening to burn them at the stake in a public square.

But seriously I think this is a seminal paper. We are witnessing history. At last, the first real steps in discerning causes of aging -- and so ingeniously simple!

@corb: using your own arguments, I'm not aware of any studies that showed life extension through some SENS-like repair therapies. To the contrary, the latest AD study that "repaired" the patients' brains by removing amyloid deposits seemed to have hastened their demise.
 
 

Yes, this switch should be absent in all species with negligible senescence.
 
By the way: Do you know how to keep the heat shock protein-related repair system running?




Increased frequency of sauna bathing is associated with a reduced risk of SCD, CHD, CVD, and all-cause mortality.

http://www.ncbi.nlm....pubmed/25705824
 
(I doubt that this can fully restore the off-switch, but I think this habit is usefull untill better strategies are at hand.)


Well, this study focused on just one stress response out of many, but I believe that they all are affected by this switch. And it's curious that any type of stress, within reason, upregulates the repairs, be it excessive heat, cold, radiation, lack of oxygen or even lack of nutrients, like in fasting. This implies the presence of conflicting processes, some downregulating the repairs and some stimulating them.

In this regard it's fascinating to watch how post-fasting effects change with age. With passing decades they become progressively ephemeral, i.e. on one hand the repairs obviously go on during the fast, on the other hand they just as obviously get erased at a faster rate upon refeeding -- why? There must be something else, besides the 'switch', that ensures that this aging program is enforced. Parabiosis research implies that something fundamental changes in the cellular environment, and even the telomere attrition could be yet another way to ensure that repairs will eventually stop, even if something impeded the full run of this program.


btw @corb: the parabiosis research implies that repairs a la SENS will remain useless -- unless cellular environment is changed to a youthful state/ But then I have a hunch that no additional therapies will be needed.
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#16 niner

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Posted 26 July 2015 - 06:35 PM

LeeYa and xEva, you guys need to read this paper.


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#17 LeeYa

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Posted 26 July 2015 - 09:21 PM

LeeYa and xEva, you guys need to read this paper.

 

Kirkwoods theory has a "little" problem -  the predictions of this theory don't fit with reality:

 

On the programmed/non-programmed aging controversy

http://link.springer...00629791207005X

 

 

Aging as a particular case of phenoptosis, the programmed death of an organism (A response to Kirkwood and Melov “On the programmed/non-programmed nature of ageing within the life history”)

http://www.ncbi.nlm....les/PMC3249457/

 


Edited by LeeYa, 26 July 2015 - 09:24 PM.

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#18 xEva

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Posted 27 July 2015 - 01:25 AM

LeeYa and xEva, you guys need to read this paper.


Why do you recommend it? It's a speculation about speculations. I stopped reading it at this point:


"Firstly, it is now generally accepted that natural selection acts primarily at the level of the individual, rather than at the level of the species or group."


Is that the extent of hard data it has to offer? Being "generally accepted" is not enough to make something true.

See, unlike you guys, I don't have an agenda. I don't have a pet theory that I have nurtured for years and now don't want to part with. I am flexible and try to go by facts. Last year I made what to me seemed an obvious, though somewhat overlooked, observation that efficient repair mechanisms must be what keeps young people young -- and was very surprised by the hostile response I got. Now this paper not only confirms my simple observation, but also offers an explanation as to why the repairs start failing at a certain age. It makes perfect sense to me.

Regarding various aging theories, I admit that have not studied them in depth but only skimmed them, mainly because I don't like to spend time on reading speculations based on insufficient data. And so regarding group selection theory, the quote that LeeYa posted above made good sense to me. It also agrees with the key observation about the animals with negligible senescence. Correct me if I'm wrong but aren't they mostly the species that roam the whole planet (well, the ocean actually) rather than being confined to a specific habitat with invariably limited resources? I'm thinking of albatrosses, sea turtles, lobsters, whales. If I'm not mistaken about the details, the examples of these species fit the group selection theory very well. They don't need to age, 'cause they are not confined to a specific habitat but are free to move on to another space at any time.

Edited by xEva, 27 July 2015 - 02:01 AM.

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#19 niner

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Posted 27 July 2015 - 01:25 AM

 

LeeYa and xEva, you guys need to read this paper.

 
Kirkwoods theory has a "little" problem -  the predictions of this theory don't fit with reality:
 
On the programmed/non-programmed aging controversy
http://link.springer...00629791207005X
 
Aging as a particular case of phenoptosis, the programmed death of an organism (A response to Kirkwood and Melov “On the programmed/non-programmed nature of ageing within the life history”)
http://www.ncbi.nlm....les/PMC3249457/

 

 

Skulachev finds a handful of odd exceptions, mostly plant-based.  We're really a lot more interested in mammalian, specifically human aging.  Skulachev doesn't address most of Kirkwood and Melov's critique of the sort of evolutionarily selected aging that the (non-biologist) simulationists favor.    On the other hand, the simulationist results don't agree with fundamental and widespread observations in mammalian aging.  There is no need to evolve programed death when death from predation or infection is as common as it is in nature. If the theory was right, then animals with a low risk of predation would be expected to have relatively short lives, similar to the rate of aging seen in similarly-sized high-predation species. In fact, just the opposite occurs. This is not a special case, it's closer to a universal observation.



#20 niner

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Posted 27 July 2015 - 01:40 AM

 

LeeYa and xEva, you guys need to read this paper.


Why do you recommend it? It's a speculation about speculations. I stopped reading it at this point:


"Firstly, it is now generally accepted that natural selection acts primarily at the level of the individual, rather than at the level of the species or group."


Is that the extent of hard data it has to offer? Being "generally accepted" is not enough to make something true.

 


If you haven't read the paper, then don't pick a dodgy-sounding fragment of text and present that as an argument. Either address the points brought up in the paper, or not.
 

See, unlike you guys, I don't have an agenda. I don't have a pet theory that I have nurtured for years and now don't want to part with. I am flexible and try to go by facts.


You don't even know what my stance on aging theories is. It doesn't match your rather insulting description.


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#21 xEva

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Posted 27 July 2015 - 04:46 AM

LeeYa and xEva, you guys need to read this paper.


Why do you recommend it? It's a speculation about speculations. I stopped reading it at this point:


"Firstly, it is now generally accepted that natural selection acts primarily at the level of the individual, rather than at the level of the species or group."


Is that the extent of hard data it has to offer? Being "generally accepted" is not enough to make something true.


If you haven't read the paper, then don't pick a dodgy-sounding fragment of text and present that as an argument. Either address the points brought up in the paper, or not.
 

See, unlike you guys, I don't have an agenda. I don't have a pet theory that I have nurtured for years and now don't want to part with. I am flexible and try to go by facts.


You don't even know what my stance on aging theories is. It doesn't match your rather insulting description.


I thought you repeatedly made your stance very clear: it's accumulation of damage (mostly invisible to the naked eye), right from the moment of conception -- no?

And I don't see what's "insulting" in my description. You are uncharacteristically touchy when it comes to SENS and aging.

Edited by xEva, 27 July 2015 - 05:26 AM.

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#22 Edit_XYZ

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Posted 27 July 2015 - 05:43 AM

 

 

LeeYa and xEva, you guys need to read this paper.

 
Kirkwoods theory has a "little" problem -  the predictions of this theory don't fit with reality:
 
On the programmed/non-programmed aging controversy
http://link.springer...00629791207005X
 
Aging as a particular case of phenoptosis, the programmed death of an organism (A response to Kirkwood and Melov “On the programmed/non-programmed nature of ageing within the life history”)
http://www.ncbi.nlm....les/PMC3249457/

 

 

Skulachev finds a handful of odd exceptions, mostly plant-based.  We're really a lot more interested in mammalian, specifically human aging.  Skulachev doesn't address most of Kirkwood and Melov's critique of the sort of evolutionarily selected aging that the (non-biologist) simulationists favor.    On the other hand, the simulationist results don't agree with fundamental and widespread observations in mammalian aging.  There is no need to evolve programed death when death from predation or infection is as common as it is in nature. If the theory was right, then animals with a low risk of predation would be expected to have relatively short lives, similar to the rate of aging seen in similarly-sized high-predation species. In fact, just the opposite occurs. This is not a special case, it's closer to a universal observation.

 

 

Programmed aging has a serious flaw - it needs the existence of "group selection" - that the individual evolved to favor the ecosystem or individuals carrying other genes. Which was proven to be false - see, for example:

http://edge.org/conv...group-selection

 

In darwinian evolution, the genes always evolve to replicate themselves and not some general "species". Altruism is present in nature only with regards to very close copies of one's genes - to the tight family circle.

Indeed, with sexual reproduction, the genes payed a very high price in order to gain the ability to quickly adapt to changing environments - only 1/2 of the genes of a parent were transmitted to an offspring. Why? Because this arrangement far outcompeted the genes which did not pay this price.

 

We have 2 parents and their children - all carrying different, random combinations of the same genes. A new environment appears - the genes of the children could be better adapted to it, but then again, the genes of the parents could be the ones better adapted. There's no rule whatsoever that says the children are better adapted.

This means that there is no evolutionary pressure whatsoever to create a program to kill the parents and favor the offspring - there's no advantage to the blood-line but there are many disadvantages.

 

Of course, as you said, predation and infection are common in nature.

This means that, after the age most individuals of a species die due to external causes, there's no evolutionary pressure to change anything in the anatomy of the individuals (they have no or too few offspring to matter).

Thus, I suspect that aging is primarily driven by deleterious signals that begin to appear after one reaches sexual maturity and one is likely to die in the wild. They were not selected for, there is no "death program" - the settings of the organism just become random, and this progressively damages the organism - as it would damage any complex system.
 


Edited by Edit_XYZ, 27 July 2015 - 06:08 AM.

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#23 LeeYa

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Posted 27 July 2015 - 11:26 AM

Well, let's go back to the topic.

 

If you massively damage c.elegans by  blocking the germline from sending signals, what would be the prediction according to the viewpoint of aging as caused only by damage accumulation? If this signal from the germline is in favor of maintainance of the individuum, this intervention should SHORTEN the worms life.

 

Moreover, if you move to humans, what would be the prediction of damage theories for the lifespan of eunuchs? The "repair of damage"-approach would predict a shorter lifespan due to massive disruption of endocrine systems.

"Experiments" done in history tell us a diffrent outcome.

 

Ever wondered why restauration of youthfull hormonal levels by hormone replacement therapy has no positive effect on maximum lifespan?

 


Edited by LeeYa, 27 July 2015 - 11:27 AM.

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#24 niner

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Posted 27 July 2015 - 03:30 PM

 

 

See, unlike you guys, I don't have an agenda. I don't have a pet theory that I have nurtured for years and now don't want to part with. I am flexible and try to go by facts.


You don't even know what my stance on aging theories is. It doesn't match your rather insulting description.

I thought you repeatedly made your stance very clear: it's accumulation of damage (mostly invisible to the naked eye), right from the moment of conception -- no?

And I don't see what's "insulting" in my description. You are uncharacteristically touchy when it comes to SENS and aging.

No.  I don't believe that aging is caused by a "single thing".  It's a combination of things.  One kind of thing is damage that accumulates in a regular, almost clock-like manner, like glycation of long-lived proteins caused by the constant level of sugar that most of us maintain in our blood, or the gradual accumulation of indigestible compounds, like 7-ketocholesterol, in our lysosomes because we lack an enzyme to degrade that particular molecule.   Another kind of thing is changes in epigenetic controls on expression.  That may or may not be an example of a "running on" of developmental programs, that essentially don't have a mechanism to completely stop because there was never any evolutionary pressure to do so.  There are changes in stem cell niches and in levels of paracrine signaling molecules that contribute in important ways to the aging phenotype.  Those things might be caused by some form of damage or might be due to the previously mentioned (epi)genetic causes.

 

Here is where we might disagree:  I don't think any of the "programming-like" causes provide any evidence whatsoever that damage is not important.  I also do not believe that there is any evolutionarily-selected program that kills us "on purpose".  Such a thing is extremely discordant with what we observe throughout the animal kingdom.

 

Regarding insults, you say that I have an "agenda", a "pet theory" that I've "nurtured for years" and "don't want to part with".   You're essentially telling me that I'm a lousy scientist.  Since I spent many years in scientific training and made it my career, I find that insulting.


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#25 HighDesertWizard

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Posted 27 July 2015 - 08:21 PM

It looks like there are at least a couple dozen studies about Heat Shock and NF-kB Inhibition. They point in the same causal direction. Here are a few...

 

Heat Shock Inhibits NF-kB Activation in a Dose- and Time-Dependent Manner

 

The abstract title speaks for itself.

 

Stress–inducible responses and heat shock proteins: New pharmacologic targets for cytoprotection

 

YoLUxcq.png

 

The immune modulating properties of the heat shock proteins after brain injury

 

ddoxYZMl.png

 

Figure 1 text below

 

<< SNIP >

Cytosolic Hsp70, presumably through its chaperone activities, has been shown to interact with and inhibit various components of the pro-inflammatory transcription factor nuclear factor kappa B (NF-kB). IKK, IkB, and NF-kB subunits have all been documented to interact with Hsp70. iNOS, inducible nitric oxide synthase.

 

 

Meanwhile, the details around the biologically intimate relationship of NF-kB and Telomerase continue to get filled in. It’s now a statistical improbability that the relationship and its association with morbidity, mortality, and longevity can be falsified. Most details, of course, remain undiscovered, even if the larger puzzle pieces are coming into view...

 

Given the science implicated in the links in this post, that Heat Shock is a non-trivial independent variable associated with Longevity is only a surprise if you’re not paying attention or are not psychologically ready to acknowledge it...

 

Tick Tock...


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#26 Mind

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Posted 27 July 2015 - 10:30 PM

 


I thought you repeatedly made your stance very clear: it's accumulation of damage (mostly invisible to the naked eye), right from the moment of conception -- no?


 

 

Maybe you are thinking of me. I did ask that question. Does metabolic junk accumulate from the time we are born. Michael did try to answer the question, but couldn't find a lot of data because scientists rarely test the tissue of young people for age-related waste/compounds.


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