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The birth of neoSENS


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#61

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Posted 04 March 2005 - 10:47 PM

An illustration of what I meant by an evolutionary ceiling and the variance in mutation rates between somatic and germ-line cells.

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#62

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Posted 05 March 2005 - 12:22 AM

As I said, evolution thinks nothing of having whole genes that are germline-specific DNA repair genes.  The whole of gametogenesis is an entire system that can evolve its own DNA repair or lack of it, or selection away of damage, etc, completely independently of the rest of the body.  There is no way that the constraint you're proposing is one that evolution would have a problem escaping.  I have no idea why this isn't obvious, even to non-biologists.


Au contraire. It should be evident to a biologist that there is no selective pressure for evolution to escape such a constraint since the highly conserved core mechanisms of DNA repair, have evolved to fight DNA damage very successfully within the requisite lifespan and environment of the organism. In single celled organisms, the knife's edge balance between DNA repair and rate of evolution is quite apparent. This balance may be more difficult to conceptualize in more complex organisms, but it is nevertheless still there, albeit cloaked in more intricate mechanisms. In any event, you have identified one of the pillars of the EGA theory.

We can group the genomic stability influencing activities which take place within each generation timeframe:

1. DNA repair mechanisms associated with somatic cells
2. DNA repair mechanisms associated with germ-line cells

or another grouping could be

1. DNA repair mechanisms associated with mitosis
2. DNA repair mechanisms associated with meiosis

or based on DNA repair type

1. Recombination (HR, NHEJ, meiotic)
2. Mismatch repair
3. Base excision repair
4. Nucleotide excision repair
5. Photoreactivation

or based on damage type, etc.

Each of these activities makes up a component of the total DNA repair potential of an organism. The EGA theory will propose that for reasons including, but not limited to, the molecular phylogeny of DNA repair enzymes, their distribution amongst organisms and the correlation between lifespan and mutation rates that the sum of individual genomic stability mechanisms is more likely to be coupled than not.

#63 ag24

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Posted 05 March 2005 - 12:46 AM

Prometheus: First of all, I thought your argument was based on the existence of an evolutionary floor (lower bound), not a ceiling, for germline mutations. Please elaborate if this is not what you're saying.

Second, the rest of your latest post seems to say nothing at all. If there is evolutionary pressure for the germline mutation rate to be at least X and there is also evolutionary pressure for the somatic mutation rate to be at most Y, what do you claim is stopping evolution from satisfying both constraints for essentially any values of X and Y, and especially for values such that Y > X ?

#64

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Posted 05 March 2005 - 02:30 PM

Prometheus: First of all, I thought your argument was based on the existence of an evolutionary floor (lower bound), not a ceiling, for germline mutations. Please elaborate if this is not what you're saying.


By ceiling I mean the upper limit that the mutation rate of germ-line cells will reach before it destabilizes the genome pathologically resulting in progeroid syndromes and cancer. Lower mutation rates would tend to be selected against due to slow adaptation response. Somatic cells extend beyond the limit of germ-line cells due to poorer DNA repair mechanisms. Due to repair mechanism conservation, however, somatic cells are influenced by the germ-line pressure to keep genome adaptable.

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#65

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Posted 05 March 2005 - 03:14 PM

Second, the rest of your latest post seems to say nothing at all.


What I presented were examples of various ways of categorizing DNA repair activities, (eg by cell type, damage type, repair type etc.) to illustrate that each contributes a component of the total DNA repair activity of the cell. I then explained that the various repair activities are more likely to be interlinked than not.

#66

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Posted 05 March 2005 - 04:21 PM

What was shown in that study was that some genes are more sensitive to oxidative damage (to their promoters) than others both in vitro and in vivo: specifically, to oxidation of guanine bases forming 8-oxodG and to unspecified changes altering expression patterns. Since no mutation accumulation was shown, this says nothing about nuDNA damage being a primary component of aging. There is no evidence here that the steady-state level of these lesions is not simply a readout of the oxidation state of the DNA's environment -- the nucleoplasm and the more distant environment (cytoplasm, CSF, circulation). If that's all it is, these levels and the consequent gene expression patterns will automatically revert to youthful levels when the systemic and hence cellular redox state is restored to youthful levels by fixing the things that are causing the oxidation, e.g. mutant mitochondria, arterial junk.

(my emphasis in italics)


The nuclear DNA damage in vivo is the mutation accumulation. The nuclear DNA is damaged - period. The evidence was provided by the oxidative damage that was observed in terms of 8-oxoguanine levels at specific promoter sites and the downregulation of genes associated with those promoter sites. As the authors say, "oxidative DNA damage can reduce gene expression" , and "increased initial damage and reduced base-excision repair may contribute to oxidative DNA damage in age-downregulated genes" . The authors then conclude by saying, "these findings suggest that accelerated DNA damage may contribute to reduced gene expression in the human brain after the age of 40".

It looks like a very unambiguous case for an age related increase in nuclear DNA damage adversely influencing cell function and promoting the aging phenotype. Enhanced DNA repair would prevent this damage and its phenotypic effects. The authors actually did this in the study by overexpressed OGG1, a DNA repair enzyme in a model of DNA damaged neurons and it was able to completely restore damaged DNA.

One more point, damaged DNA can only be repaired by DNA repair enzymes. Restoring the cellular redox state to youthful levels, as you say, will not automatically repair molecular lesions that have been induced by aged levels - you need DNA repair enzymes to do that - preferably at increased levels particularly if the redox levels are so high they are overwhelming the endogenous rate of DNA repair, or worst still, if the DNA repair genes have themselves been damaged. And whilst I completely agree that improving mitochondrial stability is of paramount importance, mitochondrial DNA repair enhancement can be done today without waiting for allotopic expression.

#67 ag24

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Posted 05 March 2005 - 05:00 PM

> I then explained that the various repair activities are more likely to be interlinked than not.

No you didn't -- you **asserted** that, without giving any explanation whatsoever to back up your assertion. My question is, again: If there is evolutionary pressure for the germline mutation rate to be at least X and there is also evolutionary pressure for the somatic mutation rate to be at most Y, what do you claim is stopping evolution from satisfying both constraints for essentially any values of X and Y, and especially for values such that Y > X ?

> The nuclear DNA damage in vivo is the mutation accumulation.

No it isn't -- the only damage that was assayed was 8OHdG, which as you well know is a repairable precursor of mutations, not a mutation itself. Since it's repairable, the observed value is a steady-state equilibrium between occurrence and repair, so if the occurrence is slowed by restoring the redox state then the steady-state level will fall without any need to increase the repair rate. The fact that increaing OGG1 reduces the steady-state level of 8OHdG tells us exactly nothing about what increasing OGG1 does to the rate of accumulation of actual mutations, and the very fact that the steady-state level of 8OHdG is allowed to be so high that it's the lesion of choice to measure (easiest to assay) is in and of itself strong circumstantial evidence that it is virtually never allowed to mature into a true mutation in vivo anyway. More evidence for this is the mitochondrial OGG1 study you mentioned earlier (losing OGG1 doesn't accelerate mtDNA mutation accumulation), which disproves your suggestion that mtDNA repair enhancement can be done today because it shows that we don't know what to do to slow mtDNA mutation accumulation (specifically, that OGG1 overexpression won't do that), as does the transition/transversion ratio which I mentioned weeks ago (namely: to the extent that 8OHdG does cause mutations it causes transversions, whereas the base pair substitutions actually seen in mtDNA in vivo are mostly transitions). For those who don't know -- adenine and guanine are purines, thymine and cytosine are pyrimidines, transitions are changes from a purine to the other purine or a pyrimidine to the other pyrimidine, transversions are changes from a purine to a pyrimidine or vice versa.

Michael and I have been through all this with you at great length already. Why are you repeating yourself? Telling us that 8OHdG and mutations are interchangeable when they quite plainly aren't is just wasting everyone's time.

#68

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Posted 06 March 2005 - 03:49 AM

> The nuclear DNA damage in vivo  is  the mutation accumulation.

No it isn't -- the only damage that was assayed was 8OHdG, which as you well know is a repairable precursor of mutations, not a mutation itself.  Since it's repairable, the observed value is a steady-state equilibrium between occurrence and repair, so if the occurrence is slowed by restoring the redox state then the steady-state level will fall without any need to increase the repair rate.  The fact that increaing OGG1 reduces the steady-state level of 8OHdG tells us exactly nothing about what increasing OGG1 does to the rate of accumulation of actual mutations, and the very fact that the steady-state level of 8OHdG is allowed to be so high that it's the lesion of choice to measure (easiest to assay) is in and of itself strong circumstantial evidence that it is virtually never allowed to mature into a true mutation in vivo anyway.  More evidence for this is the mitochondrial OGG1 study you mentioned earlier (losing OGG1 doesn't accelerate mtDNA mutation accumulation), which disproves your suggestion that mtDNA repair enhancement can be done today because it shows that we don't know what to do to slow mtDNA mutation accumulation (specifically, that OGG1 overexpression won't do that), as does the transition/transversion ratio which I mentioned weeks ago (namely: to the extent that 8OHdG does cause mutations it causes transversions, whereas the base pair substitutions actually seen in mtDNA in vivo are mostly transitions).  For those who don't know -- adenine and guanine are purines, thymine and cytosine are pyrimidines, transitions are changes from a purine to the other purine or a pyrimidine to the other pyrimidine, transversions are changes from a purine to a pyrimidine or vice versa.

Michael and I have been through all this with you at great length already.  Why are you repeating yourself?  Telling us that 8OHdG and mutations are interchangeable when they quite plainly aren't is just wasting everyone's time.


1. You're asserting that 8-OXO-dG is not a "true mutation". This is a semantic defense because it depends on what you mean by mutation. It is not a base change per se but inferring that it has no other consequence is a mistake. If translated it does result in a base change, an effect that may not impact the nuclear DNA of post-mitotic cells but does impact mitochondrial DNA nearly 1/3 of the time. If transcribed it may affect gene expression by interfering with RNA polymerase binding. At the end of the day, it does constitute DNA damage and directly influences transcription and translation. It's sometime transient nature, does not mean it does not impact cell function when present, particularly as it is found to increase in older organisms suggesting accumulation. The longer it persists for - or goes unrepaired - the greater the damage.

2. Describing 8-OXO-dG as a transient molecular modality that is not a reliable indicator of mutagenesis can be misleading in light of its nearly ubiquitous application in mutagenesis studies. I agree, however, that it would be better to have more direct evidence of mutation. In the meanwhile, we must be more clever about our use of such information. If you are losing patience with me then you must have a dim view of the scientific community that relies on such quantification.

3. Transitions and transversions still result in base changes. You are making it sound to the uninitiated like transitions are less harmful. Both have the potential to alter a codon and consequently an amino acid and therefore protein structure which is what is of concern.

4. An interesting use you are putting the study I referred Michael to (OGG1 deficient mice with no adverse phenotypic effects). Firstly the organism is a mouse with a considerably shorter lifespan and less time for the OGG1 deficiency to manifest fully in. Secondly, as the authors mentioned, there could be a backup DNA repair process (ie mismatch repair) that could be taking the place of OGG1 - but this does not imply that increased OGG1 would not reduce the mutagenicity rates. Thirdly even if OGG1 is not a rate limiting factor - and even though that study implies it, it does only in the limited lifespan of mice - it is very sensible to presume another rate-limiting DNA repair factor exists. It is much, much easier to identify a rate-limiting DNA repair factor using knock out or RNAi studies rather than allotopic expression. With a suitable rate-limiting DNA repair factor identified, it is easier to induce an increase of DNA repair levels in both the nucleus and mitochondria than to perform allotopic expression.

5. As an alternative to allotopic expression of the mitochondrial genome, it would be easier to investigate adding nucleotide repair capacity to mitochondria. This type of DNA repair function does not appear to exist in mitochondria and would likely decrease the levels of mtDNA mutagenesis. Have you ever considered this?

6. You have not commented on the conclusions of the authors that I highlighted. They seem repudiate your claim that nuclear DNA damage is only responsible for cancer. An entirely different picture emerges from their studies. This is what we all want to hear your views on! What, in your view, is causing the increased 8-OXO-dG levels and changes in gene expression?

#69

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Posted 06 March 2005 - 04:16 AM

> I then explained that the various repair activities are more likely to be interlinked than not.

No you didn't -- you **asserted** that, without giving any explanation whatsoever to back up your assertion. My question is, again: If there is evolutionary pressure for the germline mutation rate to be at least X and there is also evolutionary pressure for the somatic mutation rate to be at most Y, what do you claim is stopping evolution from satisfying both constraints for essentially any values of X and Y, and especially for values such that Y > X ?


My claim is that X and Y are coupled and thus proportionally related, hence the limit in independent variance in values for X and Y. I believe that the basis of that coupling lies in conserved mechanisms of repair and the imperative to save energy. The explanation of this matter is something Jay and I are presently working on and which we are looking to see culminate in the form of a published scientific paper. We of course would be delighted to have your feedback as the manuscript matures.

#70 ag24

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Posted 06 March 2005 - 12:36 PM

> My claim is that X and Y are coupled and thus proportionally related

In other words that there is some minimum possible ratio, 10 say, between somatic and germ-line mutation rates -- that somatic mutation rates "have" to be at least (say) ten times germ-line mutation rates? Well, if you can figure out a persuasive reason why evolution can't raise germ-line mutation rates without raising somatic rates just by trying a little less hard to keep germ-line rates low, you'll have a decidedly original idea to publish. I'm not holding my breath, but good luck.

#71

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Posted 06 March 2005 - 12:52 PM

Cheers. We are scouring the literature for supporting vs contradictory evidence.

Would you mind responding to the above points, particularly 5 and 6, when you get a chance.

#72 ag24

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Posted 06 March 2005 - 01:14 PM

> 1. You're asserting that 8-OXO-dG is not a "true mutation". This is a
> semantic defense because it depends on what you mean by mutation.

I mean what it says in the dictionary...

> It is not a base change per se but inferring that it has no other
> consequence is a mistake.

Correct -- and I was making no such inference. I was saying that 8OHdG has no **irreversible** consequence.

> If translated it does result in a base change

I imagine you mean "replicated", not "translated". This is rather an important difference for the nuclear DNA of postmitotic cells, which is never replicated.

> an effect that may not impact the nuclear DNA of post-mitotic cells but
> does impact mitochondrial DNA nearly 1/3 of the time.

Correct again, which tells us that either 8OHdG must be repaired really well in mtDNA before replication (else most of the point mutations seen in mtDNA would be transversions) or that the level of point mutations even in mito-OGG1-deficient mice is too low to matter.

> If transcribed it may affect gene expression by interfering with RNA
> polymerase binding. At the end of the day, it does constitute DNA
> damage and directly influences transcription and translation. It's
> sometime transient nature, does not mean it does not impact cell
> function when present, particularly as it is found to increase in older
> organisms suggesting accumulation. The longer it persists for - or goes
> unrepaired - the greater the damage.

All correct. In principle, the changes in gene expression caused by such changes could accelerate the accumulation of truly irreversible, primary damage such as mutations and junk - though no one, certainly not the studies you have discussed, has shown any evidence even hinting at this, let alone a proof of it. But I evidently need to remind you that the SENS approach sidesteps such details by repairing primary damage rather than just slowing down its accumulation. If the primary damage is being repaired, slightly changing the rate at which it was laid down in the first place is irrelevant. And I hope you're not going to try to tell me that these changes of gene expression are the main cause of the accumulation of primary damage, such that the change of rate would not be slight, because you would need to provide some evidence for that.

> 2. Describing 8-OXO-dG as a transient molecular modality that is not a
> reliable indicator of mutagenesis can be misleading in light of its
> nearly ubiquitous application in mutagenesis studies. I agree, however,
> that it would be better to have more direct evidence of mutation. In
> the meanwhile, we must be more clever about our use of such information.

Yes, but "clever" means knowing which inferences are safe and which are not. It doesn't mean making unsafe inferences just because no safe ones are available, which is what you've been doing.

> If you are losing patience with me then you must have a
> dim view of the scientific community that relies on such quantification.

Of course. It's my job as a scientist to have a dim view of work that needs improving.

> 3. Transitions and transversions still result in base changes.

They **are** base changes.

> You are making it sound to the uninitiated like transitions are less
> harmful.

Nonsense -- go and reread what I wrote. I said that the major lesion in mtDNA, namely 8OHdG, causes transversions, yet transversions are rarer in mtDNA than transitions, hence the system for stopping 8OHdG from turning into a mutation must be considerably better than the corresponding systems for other types of damage. Now, there is more to this in the mtDNA -- there is evidence that mtDNA deletions may be caused by things like 8OHdG -- which may well be why 8OHdG accumulation is slower in long-lived species than in short-lived ones in the mitochondrion but not in the nucleus (where the mechanism whereby mtDNA deletions are believed to form cannot happen).

> 4. An interesting use you are putting the study I referred Michael to
> (OGG1 deficient mice with no adverse phenotypic effects). Firstly the
> organism is a mouse with a considerably shorter lifespan and less time
> for the OGG1 deficiency to manifest fully in. Secondly, as the authors
> mentioned, there could be a backup DNA repair process (ie mismatch
> repair) that could be taking the place of OGG1 - but this does not
> imply that increased OGG1 would not reduce the mutagenicity rates.
> Thirdly even if OGG1 is not a rate limiting factor - and even though
> that study implies it, it does only in the limited lifespan of mice -
> it is very sensible to presume another rate-limiting DNA repair factor
> exists. It is much, much easier to identify a rate-limiting DNA repair
> factor using knock out or RNAi studies rather than allotopic
> expression. With a suitable rate-limiting DNA repair factor identified,
> it is easier to induce an increase of DNA repair levels in both the
> nucleus and mitochondria than to perform allotopic express

All correct. I have repeatedly said that I'm all in favour of more research to identify more about what's rate-limiting for aging (just so long as that's not done at the expense of SENS), and that includes more research to identify enzymes that may be rate-limiting for DNA repair. My prediction is that there are no such enzymes, because the fidelity of repair depends not only on the amount of enzyme but on its accuracy and I predict that all DNA repair enzymes are already present in considerable excess. But obviously I may be wrong, so it's great that excellent scientists like Bohr are working on this. And because they are, the idea needs no promotion from some strange beardy bloke.

> 5. As an alternative to allotopic expression of the mitochondrial
> genome, it would be easier to investigate adding nucleotide repair
> capacity to mitochondria. This type of DNA repair function does not
> appear to exist in mitochondria and would likely decrease the levels of
> mtDNA mutagenesis. Have you ever considered this?

Yes, of course, but as you well know this would not be an alternative to allotopic expression but a complement to it, since it would not obviate pre-existing damage. But also, though you may think it likely, I think it is unlikely that adding such capacity would perceptibly reduce mtDNA mutation rates, because other repair systems are probably already fixing everything in mtDNA that NER fixes in the nucleus. But obviously this is just a prediction, and adding NER to the mitochondrion is a very straightforward thing to try in vitro and probably not very hard in live mice, and I look forward to the result.

> 6. You have not commented on the conclusions of the authors that I
> highlighted. They seem repudiate your claim that nuclear DNA damage is
> only responsible for cancer. An entirely different picture emerges from
> their studies. This is what we all want to hear your views on! What, in
> your view, is causing the increased 8-OXO-dG levels and changes in gene
> expression?

As I said (twice now -- I do wish you would go back and check before saying I haven't commented on something...), the increased 8OHdG is in my view being caused by the increasing oxidation of the nuclear, cellular and extracellular milieu, which is in turn being caused by things like the appearance of mitochondrially mutant cells and the accumulation of arterial junk. The changes in gene expression may be partly due to 8OHdG on their promoters, partly due to other oxidative lesions, and partly in a compensatory response to the oxidation state. Please don't ask me this again...

#73

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Posted 06 March 2005 - 02:19 PM

The changes in gene expression may be partly due to 8OHdG on their promoters, partly due to other oxidative lesions, and partly in a compensatory response to the oxidation state.



Now, wait a minute - have I read you correctly - you just mentioned changes in gene expression, not only mitochondrial but nuclear transcriptional changes, if I am not mistaken, not exclusively associated with cancer and that could be putatively reduced by an increase in OGG1 or other repair enzyme/factor concentration.

But this does not mean much in light of the fact that you think that a) there is no DNA repair limiting activity and b) even if there was Bohr et al working on it is sufficient.

I would argue that even if other highly competent scientists are working on elucidating DNA repair mechanisms does not mean that they would be as driven as you to see such discoveries transformed into interventions.

#74 ag24

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Posted 06 March 2005 - 03:18 PM

Yes you have read me correctly. You may well be right about the motivation to transform discoveries into interventions, and that is why I pay attention to ongoing discoveries. In the absence of said discoveries, however, I focus on other interventions -- ones that can already be (a) designed and (b) predicted to have a fair chance of being beneficial, either on their own or jointly with other SENS components.

#75 John Schloendorn

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Posted 07 March 2005 - 12:33 AM

"strange beardy bloke" (google that)

Heh, congrats, you left Jesus far behind you on that one [thumb]

I'll buy you dinner

Don't fall for it! Remember all meals are free on SENS2! Btw, is beer so?

#76 ag24

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Posted 07 March 2005 - 11:33 AM

All drinks, including alcohol, are free at SENS poster sessions, which start at 9pm and (at IABG10 anyway) tended to last until 1am. (Poster presenters are asked to be by their poster from 9pm to 10pm on one of the three nights.)

#77 jaydfox

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Posted 07 March 2005 - 03:06 PM

The changes in gene expression may be partly due to 8OHdG on their promoters, partly due to other oxidative lesions, and partly in a compensatory response to the oxidation state.

Now, wait a minute - have I read you correctly - you just mentioned changes in gene expression, not only mitochondrial but nuclear transcriptional changes, if I am not mistaken, not exclusively associated with cancer...


It appears that de Grey has admitted that nDNA damage is responsible for more than cancer. However, before we all celebrate, let's examine his statements further. I'm going to try to summarize for all here who have been enjoying this back-and-forth discussion.

While de Grey may have admitted that nuDNA damage is responsible for more than cancer, he did so in a purposefully ambiguous way, allowing him "plausible deniability."

He agreed that the 8OHdG levels (and other lesions) may be affecting changes in gene expression (i.e. the changes associated with aging), and hence may be responsible for more than cancer. But, he has not backed down from his assertion that the 8OHdG levels indicate a higher level of yet-to-be-repaired (as opposed to unrepaired and indeed irreparable) damage. In other words, older cells have a greater "backlog" of damage to repair than younger cells, due possibly to lower DNA repair factor levels, or possibly to a higher rate of this type of damage. Or in other words, the damage can be repaired, but the cells are just taking longer to get to it.

de Grey still asserts that if these old cells are rejuvenated (e.g. by removing the oxidative load on old cells caused by non-nuDNA sources, e.g. mutant mitochondrial ROS production), the level of yet-to-be-repaired damage will drop, exposing the true level of irreparable damage to be much lower. He asserts that this lower level will be negligibly higher than in truly young cells, and hence he will reassert that nuDNA damage is not important in aging.

Am I correct Dr. de Grey?

This is an important point for both sides to settle. Neither side has presented a strong case that they are correct, or that the other side is incorrect. It's been a lot of conjecture so far as I can tell, and conjecture is a poor reason to state that nuDNA damage is unimportant (or important, I suppose I should say in fairness, though declaring something as fundamental to all cellular processes as DNA unimportant requires far more evidence than declaring it important, in my opinion, as its importance is established precisely by the controlling nature of nuDNA.)

This makes for a fascinating discussion. Clearly nuDNA damage is responsible for a lot of the problems of aging, but if de Grey is correct, then nuDNA damage is not a cause, but a symptom of aging, a symptom that will clear up by solving the root cause, which he asserts is not nuDNA damage.

Personally, I feel that neither mtDNA nor nuDNA damage on its own is the root cause, but that there is some degree of interplay between the two, so that solving one entirely will not allow an indefinite lifespan, as the other will still be an MLSP-limiting factor. In other words, even if we accomplish allotopic expression of mtDNA, nuDNA damage will still lead to progeroid syndromes in humans that should otherwise be living hundreds and hundreds of years. Conversely, solving the nuDNA damage completely will cure cancer and reduce many of the symptoms of aging (including the rate of accumulation of mutant mtDNA, due to mtDNA repair factors that are expressed from the nucleus), but mutant mtDNA will continue to collect to the point that they become fatal because of the extracellular oxidative load.

If de Grey's version of the mitochondrial free radical theory of aging is correct, then solving the mtDNA problem will probably extend lifespan more than perfecting mtDNA repair, but at the end of the day, nuDNA damage will still matter. If you should be living to 500, but you die at 170 of progeroid syndrome due to DNA damage accumulation, then clearly nuDNA damage matters.

If you cure cancer, etc., by perfecting nuDNA repair, but your mitochondria continue to accumulate mutations until they kill you at 150, then clearly mtDNA damage matters.

To say that mtDNA damage has a more direct (i.e. proportional) impact on aging doesn't mean that nuDNA damage must be irrelevant. For that matter, the non-correlation of nuDNA damage and aging in interspecies studies is simply a sign that cancer and senescence defenses are more sophisticated in longer-lived species. Conversely, the correlation between mtDNA damage and aging in interspecies studies is a sign of the lack of increased sophistication in defenses against mutant mitochondria (the most sophisticated evidence pointed out was that birds have better protection against leakage and membrane oxidation, a feat that should be reproducible in humans with the same degree of benefit, without allotopic expression of mtDNA. Although, if I recall, humans are already well outside the correlation curve...).

#78 DJS

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Posted 07 March 2005 - 04:00 PM

jay

If de Grey's version of the mitochondrial free radical theory of aging is correct, then solving the mtDNA problem will probably extend lifespan more than perfecting mtDNA repair, but at the end of the day, nuDNA damage will still matter. If you should be living to 500, but you die at 170 of progeroid syndrome due to DNA damage accumulation, then clearly nuDNA damage matters.


Yes, clearly it would matter Jay, but not until the first generation of ENS humans (or a hypothetical primate population) reached the ripe old age of 170 (or its equivalent)! Isn't this exactly what Aubrey means when he talks about reaching "escape velocity"? SENS, as it is currently formulated, isn't claiming to be the ultimate solution. It's only claiming to be the first step in a much more intensive and protracted bioengineering program that will allow us to attain true negligable senescence. If we can boost our life expectancies up to 170, we've just bought ourselves a lot of time to worry about the nuDNA damage that you believe will become a problem.

The main area of contention, it would seem to me, is whether nuDNA damage "matters" during the course of a "normal" life time. If you believe it does (as I believe you do), then there is cause for concern. However, if you believe - as Aubrey does - that it is a secondary concern, then there would be no reason to incorporate it into SENS proper, since it could be dealt with at a later time, perhaps SENS II circa 2040.

#79 DJS

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Posted 07 March 2005 - 04:11 PM

As an observer of this thread, I have found myself swayed back and forth by a number of powerful arguments made by both sides.

With that said, I find that, in order for the neoSENS camp's position to be tenable, a persuasive argument must be made that somatic and germline mutation rates are coupled. I currently see no reason why they must be. Thus, I find myself siding with Aubrey.

#80 jaydfox

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Posted 07 March 2005 - 04:14 PM

The main area of contention, it would seem to me, is whether nuDNA damage "matters" during the course of a "normal" life time. If you believe it does (as I believe you do), then there is cause for concern. However, if you believe - as Aubrey does - that it is a secondary concern, then there would be no reason to incorporate it into SENS proper, since it could be dealt with at a later time, say SENS II circa 2040.

Which brings us back to WILT, and whether it's necessary (especially given that there are alternatives which can build on the WILT scaffolding).

If de Grey is right about mitochondria, then curing 6 of the 7 aspects of SENS, save nuDNA damage, will probably be enough to double (and maybe triple, though I won't hold my breath) remaining life expectancy, buying us critical time. The WILT scaffolding, minus any sort of DNA repair strategy, will provide rejuvenation therapies and, short of cancer, allow us to survive that doubled lifespan (since programmed aging still seems to be there, e.g. menopause, which seems to be a programmed response to the increasingly oxidative nature of estrogen with age).

Cancer rates will drop significantly with respect to chronological age, although they'll probably rise per capita given our increasing average chronological age and the doubling rate of cancer incidence. DNA repair and WILT proper will be competing (and perhaps complementing) strategies to build upon the WILT scaffolding, and only 10-25 years from now will we be able to tell if resorting to the draconian backup plan (WILT proper) will be necessary. It is now too early to give up on either approach; too early to give up on DNA repair, as we don't have nearly enough research supporting the claim that it can't be significantly improved; too early to give up on WILT proper, as cancer is too unpredictable to assume we'll be able to reign it in with even our best efforts.

#81 jaydfox

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Posted 07 March 2005 - 04:20 PM

As an observer of this thread, I have found myself swayed back and forth by a number of powerful arguments made by both sides.

With that said, I find that, in order for the neoSENS camp's position to be tenable, a persuasive argument must be made that somatic and germline mutation rates are coupled. I currently see no reason why they must be. Thus, I find myself siding with Aubrey.

Don, why do you find that the somatic and germline mutations rates must be coupled in order for neoSENS to be tenable? There are certainly a lot of evolutionary theories why longer lifespans and better DNA repair are not selected for; Prometheus's is not the first. Michael Rose's work with Drosophila showed that in an evolutionarily blink of an eye, lifespans can be doubled. This clearly shows that evolution has selected against longer lifespans (for whatever reasons—the reason doesn't matter, just the outcome). If a few evolutionary tweaks are all it takes to double lifespan, then even this could buy us the critical time we need.

There are good reasons to doubt that we'd be able to double lifespan with a few tweaks and minor adjustments, but nonetheless there's no doubt that evolution has not created the longest-lived humans that can be made with small adjustments, and given the conservation of those adjustment mechanisms from yeast to worms to flies to mice, it stands to reason that those adjustments are basic in nature an conserved across the entire animal kingdom.

Which is the same argument I made in defending the Fly Prize six or seven months ago.

There are many, many reasons to believe that neoSENS is tenable, and it is predicated neither upon Michael Rose's work nor upon Prometheus's theory. However, either of those would be sufficient weight to make the platform tenable; neither is required. Sufficient, but not necessary.

#82 DJS

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Posted 07 March 2005 - 04:24 PM

Which brings us back to WILT, and whether it's necessary (especially given that there are alternatives which can build on the WILT scaffolding).

If de Grey is right about mitochondria, then curing 6 of the 7 aspects of SENS, save nuDNA damage, will probably be enough to double (and maybe triple, though I won't hold my breath) remaining life expectancy, buying us critical time. The WILT scaffolding, minus any sort of DNA repair strategy, will provide rejuvenation therapies and, short of cancer, allow us to survive that doubled lifespan (since programmed aging still seems to be there, e.g. menopause, which seems to be a programmed response to the increasingly oxidative nature of estrogen with age).

Cancer rates will drop significantly with respect to chronological age, although they'll probably rise per capita given our increasing average chronological age and the doubling rate of cancer incidence. DNA repair and WILT proper will be competing (and perhaps complementing) strategies to build upon the WILT scaffolding, and only 10-25 years from now will we be able to tell if resorting to the draconian backup plan (WILT proper) will be necessary. It is now too early to give up on either approach; too early to give up on DNA repair, as we don't have nearly enough research supporting the claim that it can't be significantly improved; too early to give up on WILT proper, as cancer is too unpredictable to assume we'll be able to reign it in with even our best efforts.


This is all true Jay (edit: looking at Aubrey's subsequent post, perhaps not), but why do you insist on having DNA repair incorporated into SENS when such interventions are speculative at best? Shouldn't SENS remain a "concrete" proposal until break throughs in DNA repair make their inclusion into SENS a reasonable/realistic consideration?

Edited by DonSpanton, 08 March 2005 - 12:14 AM.


#83 jaydfox

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Posted 07 March 2005 - 04:35 PM

Concrete?

It's no more speculative than allotopic expression of mtDNA. Recet work (2003) has shown that such expression is both toxic in the cytosol and ineffective at import, and what few proteins make it into the mitochondria don't seem to affect the bioenegertic state. Sounds about as effective as anti-oxidant and DNA repair research so far. Entirely speculative.

Of course, the theory seems sound. Move mtDNA to the safe harbour of the nucleus. Except that nuDNA don't correlate well with aging, meaning that in longer-lived species, mtDNA would be more exposed to damage than in shorter-lived species. Which means that allotopic expression of mtDNA in mice might be sufficient to prevent a huge amount of damage, tripling life expectancy, but in humans the amount of damage mitigated would be relatively quite smaller, and hence lead to much less benefit. That is, if it can be done at all.

Back to DNA repair, anti-oxidant levels don't seem to help, but the problem seems to be with targetting. Free radicals have implications for feedback cycles, so over aggressive scavenging across the board could be deleterious, and it doesn't focus enough oxidant quenching power at the hotspots where it's needed anyway. Targetted anti-oxidants seems to have a lot of promise, but it's just as speculative as allotopic expression. Of course, promising work has been done, showing that anti-oxidants can be targetted to some extend to the inner membrane of the mitochondria, and the benefits are significant.

DNA repair enzymes have some sort of negative consequence, or the nucleus would be teeming with them. Evolution provides the key here, as there are several scenarios where enhanced repair would be selected against, and several scenarios where reduced repair levels would be selected for. In the end, it's just speculative.

But it's not speculative that WILT would program death into us unless we had frequent, scheduled reseedings.

Saying DNA repair is speculative is not enough to say it's not SENSworthy.

#84 jaydfox

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Posted 07 March 2005 - 04:43 PM

Shouldn't SENS remain a "concrete" proposal until break throughs in DNA repair make their inclusion into SENS a reasonable/realistic consideration?

Which is what the Fly Prize aims to help us understand. And no such breakthrough has been demonstrated with WILT proper or allotopic expression, by the way, yet they are included.

On the other hand, p53-enhanced mice have been shown to live nearly cancer-free (breakthrough!), and the WILT scaffolding should address the sort of lifespan-limiting problems associated with overexpression of tumor suppression (such as exhaustion of stem cell reserves, not to be confused with programmed time limits on said reserves).

No cancer + rejuvenation = have your cake + eat it too

What's missing is enhanced DNA repair, which will greatly increase the time span between rejuvenation therapies (as opposed to required reseedings) and reduce the requisite sensitivity of tumor suppressors, as the decline in stem cell function is probably non-linear with respect to DNA damage rates, or we'd be dying a lot sooner than we do now (since we accumulate more damage than mice, etc.).

#85 jaydfox

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Posted 07 March 2005 - 04:59 PM

And no such breakthrough has been demonstrated with WILT proper or allotopic expression, by the way, yet they are included.

Allotopic expression: it has been shown that a few species (very distant from us, evolutionarily speaking) express one or two of the 13 genes allotopically. This might be viewed as a "breakthrough". Furthermore, one gene (to my knowledge) has been successfully moved to the nucleus, though I don't remember the species, and I don't remember what effect if any it had on the mean and maximal lifespan of that species.

However, it has not been shown to my knowledge whether that had any affect whatsoever on mtDNA damage rates, nor was it shown whether the problem was solved in a means that reduced the efficacy of those proteins in the mitochondria and whether that reduced efficacy might not lead to other problems. It shows only that moving one or two of those genes might be possible. That over 600 mitochondria-related genes rapidly moved to the nucleus, and yet 13 have escaped what should be an overwhelming evolutionary pressure to move to the nucleus for almost a billion years, shows that there are indeed very difficult technical challenges to overcome: toxicity, hydrophobicity, import, clogging of import mechanisms, rate-limiting factors of co-translational ribosomes, etc. At the end of the day, it's going to take more than the fact that it has been done once or twice or ten times in nature to count as a breakthrough.

Don't get me wrong. Allotopic expression is my cure of choice, unless and until it can be demonstrated that mitochondrially targetted DNA repair/maintenance can be improved greatly. However, it probably won't take much. A reduction in leakage similar to that found in the furthest outliers among birds (e.g. canaries, pigeons), reduced oxidizability of mitochondrial membranes, synthesis of a MIMS-residing SOD, and increased mtDNA repair and maintenance are all incremental gains (well, probably not the MIMS-residing SOD, it should be more than just incremental), but taken as a whole could reduce mtDNA damage rates by a large factor, even an order of magnitude, buying us nearly as much time as allotopic expression.

Which is why I consider such a fine plan the backup plan to allotopic expression. Hence my "weak refinement". And this doesn't even address the issue of trying to thwart the mechanism(s) of clonal expansion of mutant mtDNA, or the ablation of bioenergetically deficient cells, either of which would be much more than a mere incremental fix.

#86 ag24

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Posted 07 March 2005 - 05:59 PM

> It appears that de Grey has admitted that nDNA damage is responsible for
> more than cancer.

> Am I correct Dr. de Grey?

No, completely wrong -- and please desist from all that accusatory language.

Changes in gene expression are the way that mutations cause cancer. Thus, the argument that cancer drives down mutation rates (by forcing the evolution of otherwise unnecessarily good DNA repair and maintenance) applies equally to anything else that changes gene expression, such as methylation changes, or indeed oxidative lesions like 8OHdG. There are thus two separate things here: first, would 8OHdG levels fall if oxidative stress were reduced even if no direct action were taken to improve DNA repair/maintenance, and second, do 8OHdG lesions alter gene expression to an extent that matters? I've so far only addressed the former of these. On the latter, since the cancer-based argument applies just as well for any gene-expression-changing lesion as for mutations, I conclude that the changes seen in 8OHdG that are independent of the cell cycle are just as harmless as cell-cycle-independent mutations are.

> Clearly nuDNA damage is responsible for a lot of the problems of aging,
> but if de Grey is correct, then nuDNA damage is not a cause, but a
> symptom of aging, a symptom that will clear up by solving the root
> cause, which he asserts is not nuDNA damage.

Wrong again (as statements starting with "clearly" have a habit of being). It is not clear at all that nuclear DNA damager is responsible for any of the problems of aging other than cancer. Showing that it causes changes of gene expression does not show that it causes problems.

> If de Grey is right about mitochondria, then curing 6 of the 7
> aspects of SENS, save nuDNA damage, will probably be enough to double
> (and maybe triple, though I won't hold my breath) remaining life
> expectancy

No it won't, in my view: it'll add a couple of decades if we're lucky and we'll mostly die of cancer. As I've said, repeatedly. It's not helpful to readers to carry on stating things as fact when the discussion has clearly demonstrated that they are merely your unsubstantiated opinions.

#87 jaydfox

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Posted 07 March 2005 - 06:21 PM

If nuDNA damage is not responsible for anything significant other than cancer, and if cancer rates rise significantly faster than DNA damage rates, and if indeed those cancer rates have a doubling period approximating most of the other age-related causes of death, and if all these age-related causes of death have their roots in non-nuDNA damage causes (primarily oxidaditive damage and accumulation of intra- and extra-cellular junk and crosslinks, as well as defective/inadequte cells and cells with aberrant hormonal output or function; i.e. the other 6 of 7 aspects of SENS), then shouldn't we see an appreciable drop in both the rate and doubling rate of cancer incidence?

Any other conclusion seems to admit that there's much more to nuDNA damage than you've admitted so far. Why would curing 6 of the 7 aspects of SENS, save nuDNA damage, not cause a radical reduction in the rate of aging (as defined by the doubling rate of age-related disease incidence), or not cause an dramatic increase in MLSP? If DNA damage rate is such a lifespan limiting factor (effectively making the other 6 of 7 aspects of SENS incremental in their benefit), then why is any proposal to reduce that rate considered incremental and hence inferior?

#88 jaydfox

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Posted 07 March 2005 - 06:42 PM

if all these age-related causes of death have their roots in non-nuDNA damage causes (...), then shouldn't we see an appreciable drop in both the rate and doubling rate of cancer incidence?

Allow me to rephrase. If the mutations seen in older age are not accumulated mutations, but merely the steady-state presense of more yet-to-be-repaired mutations, and if that steady-state level of mutations will revert to a youthful level by rejuvenating the body and reducing the oxidative load (via 6/7 SENS), then won't the accumulated damage level in those rejuvenated cells approximately match the level youthful cells? If not, Prometheus doesn't owe you dinner, if I understood the bet correctly.

If so, however, then why would the cancer incidence rate remain high (and continue to double every 7-10 years), if there is not appreciable difference between the rejuvenated tissue and truly youthful tissue? Something must be fundamentally different between the two for there to be a difference in the cancer rates, just as there is something fundamentally different between the cells of a 20-year-old and a 50-year-old.

I suppose this goes back to a question of whether cancer rates are indicative of an exponential cascade of DNA damage (feedback), or of the collapse of redundant anti-cancer mechanisms (reliability theory), or a mix of both. What is the fundamental source of the doubling rate, and why wouldn't fixing 6/7 SENS modulate that doubling rate and/or dramatically lower the current rate (hence buying us several more "doublings")?

#89 DJS

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Posted 07 March 2005 - 08:05 PM

Jay

Don, why do you find that the somatic and germline mutations rates must be coupled in order for neoSENS to be tenable?

There are certainly a lot of evolutionary theories why longer lifespans and better DNA repair are not selected for; Prometheus's is not the first. Michael Rose's work with Drosophila showed that in an evolutionarily blink of an eye, lifespans can be doubled. This clearly shows that evolution has selected against longer lifespans (for whatever reasons—the reason doesn't matter, just the outcome). If a few evolutionary tweaks are all it takes to double lifespan, then even this could buy us the critical time we need.


As you later alude to, dramatically affecting the rate of senescence with only a "few tweaks" to our extremely complex mammalian physiology is highly unlikely. This is not to say that I am against proposals dealing with nuDNA repair (if you want to point me toward a few good studies I'd be happy to take a look), it is just that, at my level of comprehension, I have a hard time imagining how such repair mechanisms could be programmed for (at our current - or even near future - level of technological sophistication).

Also, I am in no way arguing that DNA repair has not, to a certain extent, been selected for. What I am questioning is whether a certain minimal level of damage/mutability has been programmed into our somatic line because there exists a basal rate of mutation within our germ line (necessary for evolvability). In order for this argument to be made, the two (somatic and germ line) must be connected.

There is a qualitative difference between being able to program in better nuDNA repair for the purposes of improving metabolic efficiency, and being *required* to address the issue of nuDNA repair because there are systemic, *programmed* defects that will make SENS, as Aubrey proposes, insufficient to attain escape velocity.

From the first perspective, one can view nuDNA repair as an option. From the second perspective, one must view nuDNA repair as a necessity. Big difference.

Edit is in smaller font

Edited by DonSpanton, 07 March 2005 - 08:33 PM.


#90 jaydfox

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Posted 07 March 2005 - 08:49 PM

Don, why do you find that the somatic and germline mutations rates must be coupled in order for neoSENS to be tenable?

There is a qualitative difference between being able to program in better nuDNA repair for the purposes of improving metabolic efficiency, and being *required* to address the issue of nuDNA repair because there are systemic, *programmed* defects that will make SENS, as Aubrey proposes, insufficient to attain escape velocity.

From the first perspective, one can view nuDNA repair as an option. From the second perspective, one must view nuDNA repair as a necessity. Big difference.

So you didn't mean tenable, you meant required? Prometheus's theory must be correct for a better DNA repair strategy to be a necessity? But what, at a minimum, would make it tenable? What would make DNA repair seem likely to work in the absense of WILT proper, in the presense of the other 6/7 aspects of SENS?

Second, I bolded the part about escape velocity. All we're asking is to be able to give people a few extra decades, until technology can presumably do better. In other words, give 70-year-olds an extra 15-30 years above the 15 years they statistically have left, or at least give 50-year-olds those 15-30 years above the 30 years they have left. Preferably, we'd even like to give them twice that much, just to ensure that enough of them survive to see that next step in technology.

Even better would be to give everyone an extra 40 years, but we can't have everything. Is DNA repair "required" for SENS to effect escape velocity? No. Some small percentage will make it, with just 6/7 SENS, or a larger percentage with 7/7 SENS. But I contend that a much larger percentage will make it with 6/7 SENS plus DNA repair, for two simple reasons:

1) Greater increase in lifespan, even if only incremental. Worst case, 6/7 WILT w/ DNA repair versus 6/7 WILT, an extra 15 years instead of 10 for the 70-year-olds (100 versus 95 mean), and an extra 35 years instead of 25 for 50-year-olds (115 versus 105 mean), etc.; or, if we're absurdly optimistic (about either approach, given de Grey's feelings about cancer in the absense of WILT proper), an extra 60 years instead of 30 for 70-year-olds (145 versus 115 mean), and an extra 100 years instead of 50 for 50-year-olds (180 versus 130 mean).

Versus 7/7 SENS, it will be harder to quantify, as postmitotic tissues are more exposed to life-threatening problems including cancer with WILT proper, but rapidly dividing tissues are more exposed without WILT proper.

Presumably, with both strategies, we've covered our bases, protecting brain and heart and other tissues negligibly impacted by WILT proper, and we've allowed some relaxation of the 10-year reseeding period through increased telomere length in blood, skin, and gut stem cell pools, due to lower cancer incidence rates. With WILT, a 99.9% effective cure is worse than a 99% effective cure if the former requires reseeding every 10 years, and the latter every 15 years, because of availability and safety of the reseeding. For that matter, a 95% effective WILT would be more desirable than a 99% effective WILT if the reseeding time could be further extended out to 20 years. DNA repair modulates the effectiveness of a WILT cure with a given telomere length, thus allowing an extension the reseeding time, and increasing the overall effectiveness of WILT in the societal context, in the dual-solution approach.

At some point, a level of effectiveness is reached with WILT (cancer rates rise to the point that further extending telomeres for practical reasons is no longer "practical") which isn't significantly better than what can be achieved by improved DNA integrity, and without programming death (though, to be honest, if the reseeding time can be extending beyond two decades, and especially if beyond three, I wouldn't be quite as opposed to the idea).

2) More availability to the public due to less frequent/less stringently required reseedings. If we prevent 99.9% of cancer (for the sake of argument) with WILT, and only prevent 80% of cancer (though it should be much higher) with DNA repair/WILT scaffolding, but the latter is available to 100 million people in the first decade and 1 billion people in the second decade, and the former is available to 50 million in the first decade and 250 million in the second, then clearly the latter is more effective at effecting actuarial escape velocity (even if not more effective at effecting one's personal escape). The rich can still pay for and get WILT (with WILT proper as part and parcel), but to the masses we must present the option which will be the most widely available and the most stable in response to any future societal chaos.




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