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Prometheus vs. SENS


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#61 jaydfox

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Posted 15 February 2005 - 02:58 PM

If this question means something like if 50 subunits are needed, how do we assure one mito does not get 75 subunits, while another one gets only 25, then the answer is simple. We don't. For statistical reasons, distributions close to the average are just much more likely than distributions that are far away. This is ultimately due to the same forces that drive the universe towards ever increasing entropy, but I would recommend to google a little bit for introductory thermodynamics, which can be quite revealing about this kind of phenomena.

I hope it is that simple, but prudence tells me that I cannot assume that, I must see it verified in experiment.

There are a great many reasons I can think of why mitochondria will not require relatively similar amounts of various proteins at various times.

First, and simplest, is that I don't know if protein turnover is a continuous, stochastic process, or if it comes and goes. In other words, does a mitochondrion occassionally do "spring cleaning", replacing worn out protein parts? If so, is this activity synchronized among all the mitochondria in a cell, or do some actually have higher demands for replacement proteins from time to time?

Second, rebuilding, repair, division. When a mitochondrion divides, I'm assuming that the two new daughter organelles will require a higher influx of proteins parts for the next few hours.

Third, usage. For all I know, mitochondria that happen to be close to power hungry systems (the nucleus maybe, or ribosomes, or lysosomes, or...) might have a higher workload, and hence a higher protein turnover rate.

Fourth, size. As little as a 7% increase in linear dimensions can add more than 20% to a mitochondrion's volume, and hence it's protein needs, relative to another mitochondrion.

Fifth, density of mitochondria distribution within a cell. If a certain region has a higher density of mitochondria (for function reasons, since statistically the distribution should be fairly uniform, albeit lumpy at the local level), and if the distribution of proteins is fairly uniform, then mitochondria in low density regions will get more proteins.

The list could go on and on. Some of the items on the list may not be concerns. Others definitely will be.

So I can't rely on statistical distribution to fix the problem. We need to know that there is a system that not only ensures proper transport into a mitochondrion upon arriving at one (which de Grey covered), but that we get the proteins to the mitochondria in the first place.

Now, if nature doesn't already have machinery to do this, but relies instead on statistical uniformity to get the job done, then there's no work on our part. BUT, if there IS an existing machinery to cause a non-uniform distribution of proteins, then we must ensure that the 13 new allotropic genes take advantage of that same machinery.

Again, I'm not talking about a practical hurdle, just a scientific difficulty (more work), so don't mistake this for the type of criticism that I've given to WILT. I happen to agree with allotropic expression of mtDNA genes. I'm merely trying to ensure that we have all the basic science out of the way. If not, we may be underestimating the difficulty of allotropic expression versus another method.

If these ideas have already been covered by the SENS participants, I apologize. I am beginning to download the presentations, and I will try to get myself caught up on the science in the coming weeks. So while I have many more criticisms, I will save them until after I've made sure that I'm not rehashing old issues.

But, I had to address this one issue, since the issue was already in discussion.

#62 jaydfox

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Posted 15 February 2005 - 05:16 PM

And now for something completely different..

Sorry, didn't pick up on that. Cute.

#63

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Posted 17 February 2005 - 10:55 PM

In support of the hypothesis that old cells can be reprogrammed to a more youthful state (see previous posts) I am delighted to share this article where it was shown that by some unidentified factor/s in the blood from a youthful mouse old stem cells were induced to behave like young stem cells in an old animal. The technique is called "heterochronic parabiosis".

Absolutely sensational finding because the therapeutic implication is that such a rejuvenative induction may not require gene therapy at all and thus be able to reach clinical trials much faster.

Edited by Bates, 23 July 2005 - 05:43 PM.


#64 John Schloendorn

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Posted 17 February 2005 - 11:07 PM

It would be interesting to see if reactivation of the old satellite cells can increase tumorigenesis. Even if it does, it may help us to reach escape velocity, if we have much better cancer therapies by then.

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Posted 18 February 2005 - 03:24 PM

Yes, I see your point. But I would hazard a guess that the stem cells are still self-renewing at a rate to keep DNA damage (and hence cancer likelihood) down but are not able to proliferate, home and differentiate due to absence of the necessary signaling ligands.

#66 jaydfox

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Posted 02 September 2006 - 06:42 AM

I realize this point will likely go unanswered for a while, but I wanted to make it while it was fresh in my mind.

Jay wrote: "If it were incorporated into SENS, then that in itself would make a statement which might help encourage the scientific establishment to work on the problem by itself, thus obviating the need for the eventual IBG to focus on it. Without incorporating it, I fear it may send a message that it's not worth working on at all." I think that's going too far. By that reckoning I should include in SENS everything that will increase lifespan of a lot of people, whether it be vaccine research, nicotine addiction research, etc. SENS has to be somewhat focused in its scope in order to communicate anything.

I think this answer is a bit misleading. We're discussing aging. Obviously, car accidents, smoking, improper diet, lack of exercise, communicable diseases, etc., are for the most part irrelevant. They can be excluded from SENS on general principle, even if addressing them could have a positive effect on lifespan. That average lifespan has doubled (a misleading statement in itself) in the last century or so is irrelevant to aging, since genetically, we haven't changed all that much, and aging as we tend to define it is intrinsic, not extrinsic. Better sanitation and medicine and disease control have dramatically boosted lifespan, but they are not part of a theory of modulating aging itself, even though admittedly they can accelerate aging (i.e., they accelerate normal aging, especially disease, via inflammation, though this connection is only more recently understood).

Where I'm going with this is that repair of nDNA damage is not remotely comparable to diet, exercise, vaccine research, car safety research, better diplomacy to reduce warfare, working to end terrorism, nicotine addiction research, etc. It is definitely in the same league as ablating (pre-)cancerous cells, or obviating mtDNA damage, or degrading lipofuscin.

Whether or not it needs to be a part of a SENS suite (which we can discuss later), I think this argument needs to be refuted, lest others fall for its simplistic (but false) premise. I fully agree that SENS has to be somewhat focused in its scope. nDNA damage is not outside the relevant scope, so this is not a reason to exclude it. Other reasons may exist, but I want to be clear that this particular reason is invalid.

Er, and sorry for bringing this back up, but I'm sure many of us have been reviewing these older threads to see what really has and hasn't been discussed before.

#67 John Schloendorn

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Posted 02 September 2006 - 04:38 PM

nDNA damage is not outside the relevant scope, so this is not a reason to exclude it.

This is precisely the point being debated, so it cannt be used as a premise. It is outside the scope if it does not contribute to non-cancer aging in our lifetime, and may be inside if it does.

Smoking, obesity and some infectious diseases, on the other hand, clearly do contribute to aging and yet are considered outside the scope of SENS.

#68 jaydfox

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Posted 02 September 2006 - 05:39 PM

It was dismissed as being in the same cateogory as extrinsic causes of death. It is an intrinsic modulator of the rate of aging (if for no other reason than that it modulates the incidence rate of cancer), as opposed to an extrinsic modulator such as diet or smoking, so it cannot be so casually tossed aside. Mitochondrial free radicals, mtDNA mutation accumulation, etc., are also intrinsic modulators of aging.

I was making an observation. As I quite clearly state: "Whether or not it needs to be a part of a SENS suite (which we can discuss later)..." As I said, things like smoking can be excluded on general principle, even by people who know nothing of the science. Vaccine research, nicotine addiction research, etc.—the examples used in the quote I provided—can be excluded on general principle, even by people who know nothing of the science. nDNA damage cannot be excluded on general principle: it requires a detailed analysis of the best evidence by the brightest experts in the world. Incidentally, they disagree (meaning the evidence is equivocal).

#69 jaydfox

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Posted 02 September 2006 - 05:51 PM

Smoking, obesity and some infectious diseases, on the other hand, clearly do contribute to aging and yet are considered outside the scope of SENS.

They are extrinsic factors that are not part of a basic theory of aging, though yes, they modulate it and hence are part of a more comprehensive theory of aging. Telling people to stop smoking is not an anti-aging intervention, in the intrinsic sense. Remove all extrinsic causes of death, and aging still occurs. To some degree, this is because you cannot exclude all extrinsic factors: we have to eat, breathe, have thermodynamic interaction with our environment. So we're not a closed system. But to the best that external factors can be controlled, aging still occurs. It is those intrinsic factors that we must concern ourselves with. nDNA damage is most clearly an intrinsic factor in this sense.

#70 bgwowk

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Posted 02 September 2006 - 09:25 PM

(jaydfox)
It (nDNA damage) is an intrinsic modulator of the rate of aging (if for no other reason than that it modulates the incidence rate of cancer), as opposed to an extrinsic modulator such as diet or smoking, so it cannot be so casually tossed aside.


Here again you seem to be asserting as a fact the point that is under debate. What is the evidence that DNA damage contributes to pathologies of aging other than cancer? And even with cancer, to what extent is the increased incidence with age caused by DNA damage accumulation vs. immune decline and other factors?

Of course it's trivially true that if someone lives long enough, *eventually* DNA damage will have to be addressed. But is it of such practical signficance that disregarding it for the time being would seriously undercut the life-extending potential of SENS?

#71 jaydfox

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Posted 03 September 2006 - 12:26 AM

Here again you seem to be asserting as a fact the point that is under debate.

Category error. You're making the same false assumption that John made when he answered me.

I'm NOT saying that nDNA must be included in SENS. (Yes, I've said this in the past, and yes I continue to assert that elsewhere, but for the purposes of this last point I was making...)

Yes, I understand that whether nDNA damage matters in an ordinary lifetime is open to debate. Yes, I understand that increasing nDNA repair may not be necessary to effect escape velocity. Yes, I understand that it's possible that only cancer matters. And hence, yes, I understand that nDNA might not need to be a part of the SENS of the future, the version that actually does effect escape velocity. (Whether it's necessary now, to be scientifically complete to the best of current knowledge, is another thing, but again, a point for a separate post...)

I was pointing out that it was a completely intellectually dishonest position to lump nicotine addition research and vaccine research (and by extension, the other factors I described, such as better diplomacy, safer cars...) with nDNA damage. It was a false comparison. I think de Grey made it rather accidentally and without malicious intent; he simply wanted to make a point, and be done with. I pointed it out, and now everyone is ignoring what I'm saying. I tried to make the point nicely, going so far as to edit out terms like intellectually dishonest when I first wrote my points.

But you're the second person today to claim that the fact I'm asserting is in fact on the table, under debate. Please listen to me, not what you think I'm saying, but what I am in fact saying.

#72 jaydfox

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Posted 03 September 2006 - 12:39 AM

By that reckoning I should include in SENS everything that will increase lifespan of a lot of people

Increasing lifespan and slowing/reversing aging are not quite one and the same thing. This was a point Aubrey might have been trying to make. Preventing communicable diseases will "increase lifespan of a lot of people", but it's not an anti-aging therapy, so it's not rightly part of SENS.

Bear in mind, Aubrey's point was made towards "Joe Science" (I can say this with some confidence, because he was making the point to me). It wasn't made with the implicit understanding that I deeply understand biology and the finer points of nDNA damage and its consequences. He was simply pointing out that lots of things can save people's lives, but they aren't rightly a part of SENS. Why? Category. Extrinsic factors aren't what we're concerned with.

nDNA damage might not matter, and perhaps we'll know this with evidence unequivocal enough in the next few years that all the relevant experts will agree with Aubrey. At that point, it can be excluded NOT because of the reason stated here (It's something "that will increase lifespan of a lot of people", but it's not properly in the scope of intrinsic "aging" per se), but because it won't extend lifespan appreciably (which is exactly the opposite of Aubrey said). In other words, perhaps we can exclude nDNA damage for a different reason (i.e., the reason actually under debate), but not for the reason Aubrey stated.

I didn't catch it back then. I was simply pointing it out. It's not something you should feel obliged to refute. Accept it and move on. This post was Joe Science, not for the experts.

Now perhaps I'm reading too much into Aubrey's statement, but Joe Science was the audience, and I'm trying to point out to Joe Science that nDNA damage is NOT in the same category as vaccine research or nicotine addiction research (or diet or exercise). Like I said, it's not something you should feel obliged to refute, unless somehow you do feel that nDNA damage is in the same category as diet and exercise (i.e., not an intrinsic factor, regardless of its affect on the rate of aging or on mortality).

#73 jaydfox

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Posted 03 September 2006 - 01:06 AM

Okay, I will try to calm down. I guess we're all a bit jumpy still, even me.

#74 bgwowk

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Posted 03 September 2006 - 04:08 AM

Indeed. That's the second time in as many days I've reflexively replied to a post I read without context and interpreted as provocative. Sorry about that.

There is actually a certain philosophical blurring between intrinsic and extrinsic age-associated problems. To the extent that DNA damage can be caused by variable extrinsic causes (mutagen exposure, ionizing radiation, excessive cell turnover caused by factors such as chronic immune stimulation), DNA damage could be regarded as an extrinsic injury. So I don't think Aubrey's comparison, as you've described it in the last two posts, is entirely wrong.

#75 jaydfox

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Posted 03 September 2006 - 05:47 AM

There is actually a certain philosophical blurring between intrinsic and extrinsic age-associated problems. To the extent that DNA damage can be caused by variable extrinsic causes (mutagen exposure, ionizing radiation, excessive cell turnover caused by factors such as chronic immune stimulation), DNA damage could be regarded as an extrinsic injury.

Yes, this is true, and as I pointed out above, somewhere, it's difficult to eliminate extrinsic factors entirely, since we're not a closed system. In fact, some forms of extrinsic causes could even be considered intrinsic, to the extent that they're unavoidable. For example, let's say for the sake of argument that neutrinos caused a small but detectable rate of nDNA damage (or mtDNA damage, or non-degradeable protein leading to lipofuscin, or whatever). Well, you can't shield the neutrinos, and the neutrino flux is roughly constant at all times, so you may as well consider the resultant nDNA damage intrinsic, because it's as if the damage were happening spontaneously.

#76

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Posted 03 September 2006 - 12:16 PM

(jaydfox)
It (nDNA damage) is an intrinsic modulator of the rate of aging (if for no other reason than that it modulates the incidence rate of cancer), as opposed to an extrinsic modulator such as diet or smoking, so it cannot be so casually tossed aside.


Here again you seem to be asserting as a fact the point that is under debate. What is the evidence that DNA damage contributes to pathologies of aging other than cancer?


The consensus amongst the biogerontology community is that nDNA damage is a major contributor to aging. It is only within the SENS framework that its role is relegated only to cancer - one can conduct a pubmed search using the terms "DNA, damage, aging" and there is abundance of reports and reviews that are in support of this notion. Therefore the only ones who seem to be debating it are SENS supporters. The motivation for a resistance to acknowledge nDNA damage as a contributor to aging is puzzling. Brian, considering you appear to be with the SENS camp on this matter, could you provide evidence to show why nDNA damage is NOT a contributor to aging?

And even with cancer, to what extent is the increased incidence with age caused by DNA damage accumulation vs. immune decline and other factors?

A very important point, demonstrably ignored by the SENS camp. Cancer is not only a consequence of dna damage but also a failure of immune surveillance. We may ask what effect on lifespan would complete cancer resistance provide. This question was answered - at least in the murine model - with the discovery of the cancer resistant mouse. Absolutely none. Therefore, whilst cancer resistance prevents death from cancer it does not prevent death by aging.

Of course it's trivially true that if someone lives long enough, *eventually* DNA damage will have to be addressed.

You make it sound like DNA damage is of very little importance to the fucntioning of the cell. Yet, once again, a pubmed search indicates that nDNA damage contributes to many pathologies.

But is it of such practical signficance that disregarding it for the time being would seriously undercut the life-extending potential of SENS?

Brian, what is the actual life-extending potential of SENS anyway? Can you seriously see WILT or AE ever becoming real interventions? Furthermore, in what way would SENS have its potential "seriously undercut" by incorporating the very real and established axis of nDNA damage?

#77 bgwowk

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Posted 04 September 2006 - 07:57 AM

The consensus amongst the biogerontology community is that nDNA damage is a major contributor to aging.

Is it? My question about the role of nDNA mutations in aging is sincere. I don't seriously follow gerontology, although I know people who do. Coincidentally, I was at a social gathering today with two members of the GRG, both published in gerontology, both who follow the field, and one in particular who has done so closely for 30 years. They both said they didn't believe it was yet established that mutations are a major factor in aging, and one of them was especially skeptical.

Brian, considering you appear to be with the SENS camp on this matter, could you provide evidence to show why nDNA damage is NOT a contributor to aging?

I don't follow gerontology closely enough to identify with any camp on this issue. All I can say from the little rubbernecking I've done is note that the issue seems controversial, not consensual. I admit I find Aubrey's evolutionary argument intriguing. Specifically, he notes that the effects of carcinogenic mutations to a single cell are so devastating to the whole organism that cancer provides powerful pressure for species to evolve efficient DNA repair. There's also the fact that Cynthia Kenyon was able to extend the lifespan of nematodes six-fold by a simple genetic modification that (to my knowledge) did not involve upregulation of DNA repair.

You make it sound like DNA damage is of very little importance to the fucntioning of the cell.

The question is not whether DNA damage is of importance to a cell. The question is how significant DNA damage is as a casual factor in the general decline of the health of a whole organism with age.

Yet, once again, a pubmed search indicates that nDNA damage contributes to many pathologies.

But is the general decline of health known as biological aging one of them?

Brian, what is the actual life-extending potential of SENS anyway? Can you seriously see WILT or AE ever becoming real interventions?

I don't like WILT at all. But that's a tactical disagreement, not a strategic one. I think the strategy of breaking down aging into a limited number of treatable cellular pathologies is valuable, and could extend lifespan greatly.

Furthermore, in what way would SENS have its potential "seriously undercut" by incorporating the very real and established axis of nDNA damage?

That isn't what I said. My question was the reverse. Specifically, is DNA damage such a large factor in aging that the life extending potential of SENS would be seriously undercut by not dealing with DNA damage as part of "round one" of SENS ?

Edited by bgwowk, 04 September 2006 - 08:10 AM.


#78 jaydfox

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Posted 04 September 2006 - 08:22 AM

I admit I find Aubrey's evolutionary argument intriguing. Specifically, he notes that the effects of carcinogenic mutations to a single cell are so devastating to the whole organism that cancer provides powerful pressure for species to evolve efficient DNA repair.

Sideline commentary: I too was once fascinated with this rather elegant argument. If one cancerous cell can be deadly, then the DNA repair capacity selected for by evolution to prevent even one cancerous cell, should be more than capable of preventing DNA damage from mattering in any other meaningful context.

I mean, let's say that it takes 0.01% of all cells in an organ to be dysfunctional (due to DNA damage) before that organ fails. This is grossly underestimating how much dysfunction an organ could actually handle, so it should be safe for argument's sake. Well, if there are tens of billions of cells in a typical organ, and DNA repair is sufficient to prevent even one cancerous cell for most of a lifetime, then surely the DNA repair capacity is sufficient to prevent a million defective cells in that typical organ. I mean, maybe DNA repair can't prevent 10 dysfunctional cells, or even a thousand, but surely it can prevent a million, right?

This was the logic that went through my mind, and it had me pretty much convinced, until Harold kept repeating his questions, over and over, like a litany, and everyone got pissed at him for failing to realize that Aubrey had answered his questions...

So I started thinking about it more. For cancer to occur, it's not just a matter of a cell acquiring an unrepaired mutation. It takes anywhere from 4 to 8. And not just any 4 to 8. There are genes that detect when a cell goes haywire, which order the cell to self-destruct. It takes 4 to 8 very specific mutations, in a fairly specific order, for a malignant cancer to occur. On the other hand, for a cell to become dysfunctional, it only takes a handful of fairly random mutations to occur. Any particular cell relies on thousands of essential genes for survival and function. Knock out both copies of any one of those genes, and if the cell doesn't die from losing a critical function (or triggering apoptosis), it will at the least end up dysfunctional (to some degree). For some genes, losing a single copy might lead to a dysfunction, if 50% functionality isn't sufficient for peak performance. (The counter-argument here would be that for some complexes/systems, built up of perhaps dozens of proteins (coded by dozens of genes), that the loss of a particular protein wouldn't render that complex completely useless. Not sure how many complexes this is true for.)

Now it no longer seems like the DNA repair that keeps cancer at bay will also be able to prevent dysfunctional cells with as much tenacity. On the one hand, I don't mean to suggest that most cells will accumulate such critical mutations, but on the other hand, it seems almost absurd that next to none will fall victim to this problem.

The argument has lost its instant appeal, its "decisiveness", if you will. It is no longer an argument won on deduction alone. Now we need experiments to validate the various theories. I for one am curious to read de Grey's paper that he mentioned a few weeks ago. I've checked PubMed and don't see anything recent enough to be the one he mentioned, so I'm left with little hard information to go by: just the educated opinions of world experts past and present.

I've always understood it to be a consensus that nDNA damage mattered in aging, so I find it interesting that you said "the issue seems controversial, not consensual". A consensus doesn't mean everybody agrees, so of course the fact that there is some disagreement doesn't mean that there isn't still a "general consensus". (On a sidenote, some online dictionaries state the term "general consensus" is redundant, since by definition a consensus doesn't necessarily mean that everyone agrees, so it's already "general".)

Obviously I don't rub elbows with the relevant experts, so I'm just conveying what I know from my position as a typical "Joe Science".

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Posted 04 September 2006 - 11:29 AM

The consensus amongst the biogerontology community is that nDNA damage is a major contributor to aging.

Is it? My question about the role of nDNA mutations in aging is sincere. I don't seriously follow gerontology, although I know people who do. Coincidentally, I was at a social gathering today with two members of the GRG, both published in gerontology, both who follow the field, and one in particular who has done so closely for 30 years. They both said they didn't believe it was yet established that mutations are a major factor in aging, and one of them was especially skeptical.

By consensus I mean what a survey of related publications suggest. I have yet to come across a publication that concludes that nDNA damage is not a contributor to aging other than those of SENS.

Brian, considering you appear to be with the SENS camp on this matter, could you provide evidence to show why nDNA damage is NOT a contributor to aging?

I don't follow gerontology closely enough to identify with any camp on this issue. All I can say from the little rubbernecking I've done is note that the issue seems controversial, not consensual. I admit I find Aubrey's evolutionary argument intriguing. Specifically, he notes that the effects of carcinogenic mutations to a single cell are so devastating to the whole organism that cancer provides powerful pressure for species to evolve efficient DNA repair. There's also the fact that Cynthia Kenyon was able to extend the lifespan of nematodes six-fold by a simple genetic modification that (to my knowledge) did not involve upregulation of DNA repair.

Cancer appears to be at least as much a failure of immune surveillance as it is a consequence of unrepaired DNA damage. Support for this notion comes strongly from the discovery of the cancer resistant mouse and indirectly from the failure of DNA repair mechanisms such as in Werner's Syndrome, which result in the acceleration of a broad range of aging characteristics yet in the manifestation of limited types of cancer. In contrast to most types of cancer which arise from epithelial tissues, Werner's patients' cancers arise mainly in mesenchymal tissues. This is an interesting and important distinction which could be explained by a lack of accessibility to immune responses in these tissues due to anti-inflammatory cytokines (such as TGF-beta which is constitutively expressed by mesenchymal stem cells). It is likely that immune responses work together with DNA repair to hold off carcinogenesis. These observations are ignored by SENS and by the evolutionary argument which suggests that DNA repair is more than good enough. Furthermore, SENS ignores the evolutionary pressure for DNA repair to be not overly good since this may slow down the very process of evolution itself. Therefore, not only does DNA repair not have to be "good enough" from a cancer perspective due to immunological barriers but it is not desired to be "good enough" in order for the genome to be adaptable.

You make it sound like DNA damage is of very little importance to the fucntioning of the cell.

The question is not whether DNA damage is of importance to a cell. The question is how significant DNA damage is as a casual factor in the general decline of the health of a whole organism with age.

DNA damage, even if transient, results in the inability of that portion of the genome to transcribed or to be bound by transcription factors or may alter chromatin configuration. If the damage occurs in a critical gene or regulatory region the ramifications could be adverse not only to that cell but to surrounding cells either by paracrine or ligand-ligand interactions or the bystander effect.

Yet, once again, a pubmed search indicates that nDNA damage contributes to many pathologies.

But is the general decline of health known as biological aging one of them?

Does accumulated cell dysfunction contribute to tissue and organ dysfunction?

Brian, what is the actual life-extending potential of SENS anyway? Can you seriously see WILT or AE ever becoming real interventions?

I don't like WILT at all. But that's a tactical disagreement, not a strategic one. I think the strategy of breaking down aging into a limited number of treatable cellular pathologies is valuable, and could extend lifespan greatly.

I strongly agree with breaking down aging into a limited number of treatments but does that mean we should not be vigilant to new discoveries and seek to refine the model of interventions accordingly? You mentioned once in respect to neoSENS that SENS should not be diluted into obscurity, or something like that. This is not about dilution but about refinement which is what science is about (in contrast to PR where a strong consistent brand is paramount).

Furthermore, in what way would SENS have its potential "seriously undercut" by incorporating the very real and established axis of nDNA damage?

That isn't what I said. My question was the reverse. Specifically, is DNA damage such a large factor in aging that the life extending potential of SENS would be seriously undercut by not dealing with DNA damage as part of "round one" of SENS ?

Frankly, I am convinced that there is nothing in SENS "round one" that can deliver a treatment of any sort within our present technological abilities. Enhancement of nDNA repair is in the same boat - if it cannot be implemented systemically, across the vast majority of cells then it is as useless as SENS. This is why the short term future must focus on stem cell interventions.

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Posted 04 September 2006 - 11:44 AM

This was the logic that went through my mind, and it had me pretty much convinced, until Harold kept repeating his questions, over and over, like a litany, and everyone got pissed at him for failing to realize that Aubrey had answered his questions...

That's unfair. Aubrey did not answer my questions, Jay. Not in the way I was hoping they would be answered, which is why I persisted. I know many here seem to think he did answer them, but I invite those individuals to look over the trascripts once more.

The argument has lost its instant appeal, its "decisiveness", if you will. It is no longer an argument won on deduction alone. Now we need experiments to validate the various theories. I for one am curious to read de Grey's paper that he mentioned a few weeks ago. I've checked PubMed and don't see anything recent enough to be the one he mentioned, so I'm left with little hard information to go by: just the educated opinions of world experts past and present.

A simple experiment to test whether the hypothesis that nDNA repair is "good enough": It is known that the cancer resistance of the Cui mouse is transferable to wild type mice by leukocyte transplantation. Perform the transplantation in the mouse model of Werner's Syndrome (or any other DNA repair homozygous negative strain) which is cancer prone. If these DNA repair insufficient mice also show cancer resistance, we can say that cancer resistance (in mice at least) is more associated with immunity rather than DNA repair and thus provide support for the notion that DNA repair is not being driven by the threat of cancer, but by some other factor.

#81 caston

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Posted 04 September 2006 - 02:56 PM

What about RNA repair?

#82 jaydfox

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Posted 04 September 2006 - 07:58 PM

This was the logic that went through my mind, and it had me pretty much convinced, until Harold kept repeating his questions, over and over, like a litany, and everyone got pissed at him for failing to realize that Aubrey had answered his questions...

That's unfair. Aubrey did not answer my questions, Jay. Not in the way I was hoping they would be answered, which is why I persisted. I know many here seem to think he did answer them, but I invite those individuals to look over the trascripts once more.

Which is precisely the point I intended to make, though I can be a little less than direct and clear with my answers sometimes. Aubrey presented his answers in a way that, without deep understanding of the subject, would pass as solid answers. So when you persisted, you looked like an ass. To those without a deep understanding of the subject, anyway...

Upon closer examination, Aubrey's answers were not as airtight as everyone seems to believe they were. That's not to say he was wrong; it's just that the answer he gave was, in and of itself, insufficient. And while you may have looked like an ass to those without a deep understanding of the subject (and hence, that everyone seems to have a negative opinion of your style for this reason among others), you actually were on to something.

A simple experiment to test whether the hypothesis that nDNA repair is "good enough": It is known that the cancer resistance of the Cui mouse is transferable to wild type mice by leukocyte transplantation. Perform the transplantation in the mouse model of Werner's Syndrome (or any other DNA repair homozygous negative strain) which is cancer prone. If these DNA repair insufficient mice also show cancer resistance, we can say that cancer resistance (in mice at least) is more associated with immunity rather than DNA repair and thus provide support for the notion that DNA repair is not being driven by the threat of cancer, but by some other factor.

Interesting. Though a negative result (the mice still get cancer) could be attributable to other causes, if one isn't careful, so a positive result will tell us far more than a negative result.

#83 eternaltraveler

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Posted 04 September 2006 - 08:02 PM

Upon closer examination, Aubrey's answers were not as airtight as everyone seems to believe they were. That's not to say he was wrong; it's just that the answer he gave was, in and of itself, insufficient. And while you may have looked like an ass to those without a deep understanding of the subject (and hence, that everyone seems to have a negative opinion of your style for this reason among others), you actually were on to something.


others with a deep understanding thought the opposite.

#84 eternaltraveler

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Posted 04 September 2006 - 08:41 PM

Not to be misunderstood. I think it is a matter of data interpretation, not to say that prometheus was looking like an ass as you say. As Brian pointed out there is no clear consensus about the matter amoung the biogerontology community, and even if there was it isn't a popularity contest. Each individual scientist is free to draw their own conculsions. If they didn't they wouldn't be scientists at all

#85 John Schloendorn

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Posted 04 September 2006 - 09:33 PM

Aubrey's answers were not as airtight as everyone seems to believe they were

I can't see anyone here who thinks Aubrey's answers were airtight. I take them as speculations, just like Prometheus' challenges.

(There is nothing seriously wrong with the naked fact that Prometheus was challenging Aubrey. I have made clear enough what was wrong.)

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Posted 05 September 2006 - 02:26 AM

others with a deep understanding thought the opposite.

This is worth exploring, if not for the sake of upholding ethical principles in the context of sholarly debate, at least for the sake of scientific clarification.

What specific questions that I asked, do you, and any others who perceived that my persistence to be unfounded, believe were answered conclusively?

#87 eternaltraveler

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Posted 05 September 2006 - 02:29 AM

Not conclusive prometheus. I think some of the issues under debate do not yet have conclusive answers. I'd really prefer not to get into it at the time being, so consider the above statement retracted.

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Posted 05 September 2006 - 02:37 AM

What about RNA repair?


Excellent question, Caston. RNA molecules represent a whole layer of critical genetic regulation as well as being the intermediate for the expression of genes. An issue that I, who has championed DNA repair, has ignored. It constitutes a target of nucleic acid (NA - as a means of collectively describing DNA and RNA) damage that extends in scope beyond mDNA and mtDNA and has NOT been represented in studies that seek to interpret the impact of NA damage in aging.

A worthwhile introductory review on the subject of RNA repair:

http://www3.umdnj.ed...llacosaMoss.pdf

#89 jaydfox

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Posted 05 September 2006 - 03:39 AM

others with a deep understanding thought the opposite.

Yet I was the first to bring up the the numerical analysis which puts Aubrey's logic in a completely different light. :)

What about RNA repair?

Excellent question, Caston. RNA molecules represent a whole layer of critical genetic regulation as well as being the intermediate for the expression of genes.

You'll have to forgive my ignorance on this matter, but isn't RNA a transient molecule, with a rather short (compared to a lifetime) half-life? Why would RNA damage levels increase with age? Wouldn't that be a sign that something else is degraded, not the RNA itself? Wouldn't that something else be the target of intervention? (This is assuming that RNA integrity degrades with age, which I've never heard, so I can't really comment outside of hypotheticals.) And wouldn't that something else likely be either damaged DNA, or increased ROS, or damaged proteins/enzymes, which themselves are damaged due to damaged DNA or increased ROS, etc.? I.e., wouldn't the problem be either something non-transient (DNA) or something environmental (ROS or enzymes) that has changed due to something non-transient (DNA, mtDNA, etc.).

Just a question. Outside of RNA as a template for the DNA it represents, for use in protein synthesis, I'm ignorant of the many uses of RNA.

#90 jaydfox

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Posted 05 September 2006 - 03:44 AM

Yet I was the first to bring up the the numerical analysis which puts Aubrey's logic in a completely different light. :)

I'm not trying to puff myself up here, though in looking back, that does sound rather arrogant. I'm not quite sure how to say it without sounding arrogant, though. Sometimes, a deep understanding of a subject can prevent someone from doing a simple analysis.




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