51 replies to this topic

[jaydfox]

I agree that WILT will be developed pretty late, possibly last, if at all. My two main reasons: technical difficulty, and philosophical opposition (a treatment which in effect gives you a chronic fatal disease, treatable only by further regular treatments.) As for the philosophical opposition, it will certainly not pass current FDA guidelines, so it would have to be developed and initially marketed outside the U.S.A., and I'd be willing to bet that even most European nations wouldn't allow. So we're basically looking to Asia, a point that has come up often. Some have proposed pitching SENS to governments in that region who are currently trying to take the lead in Biotech already, and given the modest price tag, I still think that's a much better route to pursue than to pursue iconoclastic billionaires in the West.

As for myself personally, I have the luxury of being young enough that, if WILT were available today, I wouldn't even need to make the decision to use it. So I can sit here and say that I oppose it, but what about when I'm reaching that age bracket where cancer is a big concern? Actually, I guess as a pragmatist, I would simply weigh the costs of chemo versus WILT, and when cancer comes knocking, make that decision then. After all, by then, cancer will be "treatable", so I could get chemo and WILT at the same time: chemo to kill the current cancer, and WILT to obstruct future cancers. It's a good tradeoff at that point.

But if I'm 50 and in good health (cancer-wise, anyway), then I think WILT would be too risky, as currently postulated.

[ag24]

A few more responses (sorry for brevity - frantic today)

- Premature aging syndromes (humans or mice) caused by faster DNA damage accumulation say nothing at all about whether that accumulation does any damage to us at its normal rate in a normal lifetime. All gerontologists accept this, even when they're writing grant applications and Science/Nature abstracts, though I grant you often have to read them quite carefully to notice this.

- The decrease with age in cancer at late ages shows that there is more heterogeneity in the population in the suscep[tibility to cancer than there is for other major causes of age-related death. It says nothing about whether non-cancer-causing mutations matter in aging.

- The Nature paper doesn't look at mutations (nor epimutations, i.e. stable alteration to methylation) but at pre-mutagenic lesions, specifically 8-oxodeoxyguanine. One of the most pervasive errors in DNA analysis is to presume that rises in the amount of a pre-mutagenic lesion translate to proportional rises in that of bona fide mutations: in fact the relationship is nowhere near that, because the chance of a given 8oxodG becoming a mutation depends on its halflife, i.e. how long on average before it is repaired. So we know that 8oxodG goes up with age, but even if that affects gene expression it is still not a mutation probolem -- it can be fixed by making the brain (etc) not have a rising oxidative stress with age in the first place, eg by clearing up the junk and obviating the mtDNA mutations. There is also nothing in the Nature paper to say that the reason some particular genes are affected is not just that they are more often transcribed and thus exposed.

- I think WILT can do a whole lot better than an order of magnitude, because even if we have 50 tumours forming every year, they will be degenerating at sizes of a few millimetres across.

- Elrond is absolutely right about chemotherapy being nasty. Luckily, with WILT this doesn't really apply, because one part of WILT is to make the engineered stem cells genetically resistant to some types of chemotherapy. yes, it's also carcinogenic, but that too will be OK if the cancers are in telomerase-deleted cells.

- WILT is indeed by some way the hardest of my seven strands. Luckily though, the main reason it's so hard is that there are so many essential bits to it -- so we just need to push them all along.

- There's not so much difference between WILT and the rest of SENS in terms of the philosophical side, because we'll need all these treatments periodically (most on them in ever-improved versions) in order to stay ahead of escape velocity. The only difference with WILT is the frequency, and even in that regard the difference is not huge.

- FDA: pah. Remember we will be in a post-RMR (robust mouse rejuvenation) world at that point.

- Nonetheless, I wish I had a better idea than WILT! Jay is quite right that it's very daunting.

[jaydfox]

There's not so much difference between WILT and the rest of SENS in terms of the philosophical side, because we'll need all these treatments periodically (most on them in ever-improved versions) in order to stay ahead of escape velocity. The only difference with WILT is the frequency, and even in that regard the difference is not huge.

I beg to differ, in one major aspect. All the treatments, as you said, may need to be periodic. But, with WILT, performing the treatment actually reduces your remaining life expectancy, with regards to non-cancer deaths. In other words, if you've got 30 years remaining life expectancy, performing WILT might reduce it to 15 years, unless you get followup treatments. It's sort of like a narcotic drug with fatal withdrawal symptoms, albeit on a timescale of years rather than days. Even assuming that the FDA is obviated, which I don't think will happen overnight (but certainly in less than a decade, perhaps even less than one Presidential term, and just maybe even less than a term of Congress), there will be strong philosophical opposition to WILT.

Think of the situation of if we were to develop all seven "cures" at once. If we can do the other six of seven things, and basically add 30 years to life expectancy, with 95% of people dying of cancer in their 110's. Once everybody's dying of cancer, they'll fall in line. But that 30 year gap when people stop dying, and chemo is able to keep people going for the first couple decades of severely cancer-ridden life, WILT won't be acceptable to any but the already cancer-stricken. It won't be an "aging" treatment, it will be a cancer treatment for the already cancer-afflicted. Like I said, it will probably be a situation where, upon contracting your first malignant tumor, and assuming you're in a high-risk group (i.e. excepting the relatively rare 30-year-old cancer patient), you would be given both chemotherapy and a WILT treatment.

As for "preventive" WILT treatments, I seriously don't see those being accepted for at least the first couple decades, until we reach the point where cancer is the 90% cause of mortality among the extremely elderly.

[jaydfox]

Don't get me wrong. As Dr. de Grey said, WILT isn't the most desired option to cure cancer, just the most technically feasible. And until we come up with a better technical solution that is also more desirable, it's all we've got. But as long as we're not currently actively researching WILT, we've got time to search for better options. Which is the direction Prometheus is suggesting. A more desirable option, though not technically sufficient for de Grey... yet. Let's keep brainstorming, people. (Here again is a situation where I wish I had a molecular biology degree, or at least more training, so I could be a little more constructive than just pointing out the obvious.)

[jaydfox]

Dr. de Grey and Prometheus,

I have some questions regarding both WILT and DNA's role in cancer formation rates.

First of all, I don't know the correct terminology, so I'll define my terminology, and if more precise terminology exists, please let me know.

Cancer formation rate: not to be confused with the cancer progression rate. This is the "statistical" rate at which new cancerous tumors might come into existence. This is the rate which doubles every 7-10 years, up until that late life plateau.

1) Is the cancer formation rate dependent primarily on current genome fidelity, or is it primarily dependent on non-DNA damage/junk?

1a) In other words, if we could go into an 80-year-old, and replace the DNA in every cell of his body with an identical "pristine" DNA sequence, would that make a significant impact on that person's cancer formation rate?

1b) On the flip-side, if we could patch up every type of damage in the body (intra- and extra-cellular junk, misfolded proteins, damaged structural components like mitochondria and ribosomes, etc., etc.), with the one exception of DNA damage, would that make a significant impact on that person's cancer formation rate?

2) Would the technologies required for WILT be just as capable of delivering such a "pristine" genetic sequence to every cell in the body, and more especially every stem cell resevoir?

2b) Would the technologies required for WILT be able to tweak/reset the gene expression profiles of senescent cells back to their youthful state, concurrent with delivering the "pristine" genetic sequence.

I hope you can see where I'm going with this. If WGRT is not significantly more difficult than WILT, then why not skip directly to WGRT and avoid the philosophical dilemma of creating a treatment that actually makes you terminally ill.

I am wondering, since WILT has to be periodic anyway, if we couldn't just regularly clean up the DNA itself. If we have "pristine" DNA, and we've cleaned up the other six of seven things, then shouldn't our cancer formation rate be similar to that of someone in his 20's or younger? And with advanced cancer treatments, e.g. next-gen chemotherapy, wouldn't that be enough to obviate cancer? With this scheme, WGRT would still need to be periodic, but performing the therapy would not reduce your remaining life expectancy, at least, not as I see it.

[eternaltraveler]

Thoughts on WILT:

The number one problem (aside from developing it to begin with) with WILT is that you are absolutely required follow up doses of stem cells every 10 years or you die. This means some relatively minor social turmoil that results in a decade sometime (in the coming millennia) without stem cell therapies would kill every immortal in the world.

Well as far as I'm concerned one more problem just means one more solution.

The simplest would be to store samples of your original stem cells in case of such an emergency.

Slightly less simple would be to remove all the DNA from these stem cells that doesn't directly relate to their function but leave the telomerase gene in them so they can go about their work indefinitely. Removing all other DNA leaves a lot less of an avenue for cancerous mutations.

In the same category as the above, and what I view as a no brainer. Tag these new cells you're implanting in your bodies with something that makes them very easy to kill off if the need arises. Make them very susceptible to a substance that is normally non-toxic which you would never run into by accident. Put 50 copies of this death gene in the cells so it would never get mutated away. Make a specific death gene for each type of cell you're inoculating.

Seems like a solution to me. Leave the telomerase gene in the inoculated cells, just make them incredibly easy to kill if they start doing anything you don't want them to be doing, then simply add more. This way you wouldn't need treatments forever to keep your stem cells up. Only on those occasions when they're misbehaving.

Even the FDA might pass that.

[ag24]

Jay notes: " Once everybody's dying of cancer, they'll fall in line. But that 30 year gap when people stop dying, and chemo is able to keep people going for the first couple decades of severely cancer-ridden life, WILT won't be acceptable to any but the already cancer-stricken." I think this may be pretty close to the truth --- BUT, precisely how close, i.e. where people strike the balance between prevention and cure, depends critically on the details of how and when the therapy comes onlike, i.e. on things like how safe it turns out to be for robust people and how effective it is for people with already-advanced cancer. These currently-unknowable trade-offs will define people's choices.

Jay asks: is DNA or non-DNA damage more important for cancer. No question, it's the DNA damage.

Jay asks: could we do WGRT as easily as WILT? Nowhere near, no. WILT involves making changes to only a few genes, and changes to specific genes is all we have the technology for as yet. But the most critical point of WILT is being overlooked: that having all your stem cells die off after a decade or so is part of the advantage of WILT, not part of the disadvantage, because it means no cell has longer than a decade to accumulate mutations while it's in the body. It may very well turn out, for example, that the ALT (telomerase-independent) pathway for telomere maintenance is simply not amenable to targeted deletion the way telomerase is. If so, our main defence against it will be simply that it is evidently rather hard to activate (else we would see it more than telomerase) so it must take a lot of mutations, which take a lot of time to accumulate in a single cell, and stem cells won't have that long if they keel over after a decade.

Prometheus says: improving DNA maintenance and repair is surely easier than allotopic expression. Quite true. Such experiments are worth doing -- their onlyshortcoming is that they don't tell us anything if lifespan is unchanged -- the process could still be vital, just not be the only vital one. What would be considerably more worth doing is a diminution of DNA maintenance and repair but by a modest, controllable degree, rather than by eliminating a whole gene. If even a rather modest inhibition of some process shortens lifespan, then one really CAN say that the process matters -- whereas, if it doesn't, one can say pretty unequivocally that the process does not matter. So the interesting experiments in this area are not with homozygous knockouts but heterozygotes, tissue-specific knockouts, drug-inducible ones, etc. Of course one has to establish that the process really is inhibited, not (eg) compensated by extra expression of the other copy in a heterozygote.

Prometheus says: "Essentially you're saying 8-oxodG does not equal mutations. But would you say that it is proportional to mutations? Of course it is." No, this was precisely my point. Why do people use fibroblasts to study cell senescence? - crazy, as fibroblasts hardly divide at all in vivo! Answer: because they gtow really nicely in culture. Why do people study aging in hepatocytes? - crazy, as the liver functions well into old age! Answer: because hepatocytes are really easy to work with bioichemically. Why do people persist in slavishly using 8OHdG (note to others: this is functionally synonymous with 8oxodG, they interconvert in a spontaneous and reversible molecular rearangement) for DNA damage assays? Answer: because it's by far the most abundant oxidative lesion. Which is precisely why we should NOT consider it meaningful ... because it happens a lot, we have good defences to cope with it. So in fact, if you up the 8OHdG creation rate a lot, so that you double the steady-state level of 8OHdG, all thatdoes is make the repair enzymes work harder and the number of consequent mutations need hardly rise at all. Classic demonstration of this in mtDNA is that again 8OHdG is by far the most common lesion, but the class of mutations that it leads to (transversions) are a lot less common than transitions.

Prometheus says: " The Nature paper concludes that accruing DNA damage alters transcription." Careful. They show that huge DNA damage in vitro alters transcription, and they show that vastly milder DNA damage localises to a similar set of genes as are transcription-impaired in vivo. The latter is not a cause-and-effect, because (a) there is a very plausible non-causal explanation (genes being transcribed more will plausibly exhibit both effects) and (b) the change in transcription is much much more than the DNA damage.

Elrond suggests putting a lot of inducible suicide genes in stem cells. Nice idea, not new -- problem is that one of the many ways cancer cells have to resist chemo is that they become really good at chucking out any unusual chemical that gets into them before it can do anything. So the chemical that turns on the suicide will not get to its target. There is a transporter gene called "multi-drug resistance" that is a key player in this.

[John Schloendorn]

I think we all agree that the central theme of future anti-aging and anti-cancer therapy will be large scale cellular replacement. Gadgets like WILT, enhanced DNA repair or high-dose chemotherapy are all seeking to defeat cancer once we've got that.
I chose chemotherapy as an anti-cancer gadget because it is already there, its side effects are known, and only comparatively small developments are required to use it in conjunction with large scale cellular replacement. I will detail this in the form of answers to objections / questions to that proposal.

(Elrond)
many kinds of chemotherapy are potent carcinogens (even the more gentle modern kinds certainly aren't good for you). People often develop new cancers as a result of their chemo.

1. As Aubrey acknowledges, the same holds for telomerase deletion. It would not result in life threatening cancers in a WILT scheme, but in more telomere-depleted, growth arrested mini-cancers which also need not be right away good for your health.
2. You are forgetting that we are also doing large scale cellular replacement. The replacement cells could be engineered to be chemoresistant, and would thus suffer very little from the effects of the chemotherapy. Of course, once the replacement cells are "old" enough to become cancerous themselves, a different chemotherapy - chemoresistance scheme would be needed, and then the next one, until every cell in the body has been replaced and one can switch back to the first. As you pointed out, this will probably not be the issue, due to appropriate suicide gene and chemosusceptibility engineering of the replacement cells.

(Elrond)
There are plenty of cancers that are not due to rapidly dividing cells. My grandfather currently has cancer that his physicans plan to do absolutely nothing about. Why? Well he's 85 right now and they estimate it will be more than 20 years before this cancer becomes a danger

Much as your grandfather, we also do not need to bother very slow growing tumors. We can remove 98% of such a cancer by traditional surgery or radiation therapy, give it 20 years to regrow and then simply do it again, until someone thinks of something better. No real threat to escape velocity here. (If it starts to divide rapidly, then we will get it with the therapy we're just discussing.)

(Jay)
You see, chemo doesn't cure cancer and simultaneously innoculate you against further cancer.

I hope it has become clear now that I was not arguing for chemo alone, but for chemo with complete cellular replacement, and that is a big with!

(Jay)
A long-term cure for cancer would thus involve securing nuclear DNA

More precisely: It would involve replacing the nuclear DNA, i.e. reversing the damage already done to it.

(Jay)
Would the technologies required for WILT be just as capable of delivering such a "pristine" genetic sequence to every cell in the body, and more especially every stem cell resevoir?

Yes, but merely because WILT, like everything we're talking about, requires complete cellular replacement with genetically modified cells. If these new cells were derived freshly from the germ line WRGT would be accomplished. Such cells are what you call "pristine", or else babies would come out with DNA errors and species would go extinct as quickly as telomerase deleted mouse strains

(Jay)
If WGRT is not significantly more difficult than WILT, then why not skip directly to WGRT

On the contrary, WGRT is even easier than WILT! We are already able to derive stem cells from the germ line, so all new developments required by WGRT is complete cellular replacement. (Immune tolerization to eventual foreign MHCs would be achieved by cellular replacement of the immune system by precursors derived in the same way. This could be possible in one initial step.)
WILT, on the other hand, requires complete cellular replacement plus deletion of telomere lengthening capacity plus compensation of any side effects this might have (e.g. hypothesized ALT functions in DNA repair)

WGRT in this form is precisely what I was suggesting to achieve with the chemotherapy / cell replacement proposal.

(Aubrey)
Elrond suggests putting a lot of inducible suicide genes in stem cells. Nice idea, not new -- problem is that one of the many ways cancer cells have to resist chemo is that they become really good at chucking out any unusual chemical that gets into them before it can do anything. So the chemical that turns on the suicide will not get to its target. There is a transporter gene called "multi-drug resistance" that is a key player in this.

An inducer could be chosen that is completely harmless to other cells. Take lactose as an example. We should be able to overwhelm / outsmart even the multi drug resistance carrier with an extremely high dose of a harmless, normal molecule. I don't think this has been investigated enough in the context of inducible suicide genes to warrant a conclusion. Otherwise one may try to develop radiation inducible systems, which can hardly be "chucked out".

In conclusion, I suggest to push towards full body cellular replacement, tissue engineering and transplantation strategies and at full force. This has to include strategies for the (gradual) ablation of existing "old" cells, including cancers. If we accomplish this only once, repetitions of the therapy will become easier, because of inducible suicide genes. The most difficult cell ablation step will be the one targeting all the first generation wild type cells that presently make up our bodies. Did I miss any unrebutted argument against using chemotherapy, nearly as we know it, to achieve this?
By definition, repeated complete cellular replacement would allow us to forget about any quarrel with intracellular causes of deviation from infantile health. Does that sound like a strategy we desperately need, and thus warrant a second thought?

Edited by John Schloendorn, 28 January 2005 - 12:03 PM.

[ag24]

Prometheus: "Fibroblasts are located in connective tissue, represent a diverse population of cells and are responsible for wound repair (differentiation into myofibroblasts) amongst other things. I cannot understand the basis for your criticism on the use of fibroblasts as a cell model since you know that any cell taken out of its complex regulatory environment will cease to behave as it does in vivo. It is studied as in all things on the basis of "all other things being equal". Can you suggest a better in vitro solution than the use of the fibroblast?"

No, but that's not my point -- my point is that a fair chunk of the effort that biogerontology expended in trying to understand aging in the 1960s, 70s and even 80s was based on the idea that what fibroblasts do after 50 divisions is in some way indicative of what some cell types do in vivo. There was no biological basis for that assumption.

Prometheus: "The liver functions well as an organ generally well into old age as an organ because of its tremendous redundancy. A substantial amount of the liver can be removed and the patient still be provided with adequate function. Cellularly, it is a different matter. Hepatocytes will readily die under toxic conditions without any grossly adverse symptom in liver function."

Right (well, actually it's because of the liver's tremendous regenerative potential rather than its redundancy -- the liver grows back pretty fast after partial hepatectomy). But the point is that biochemical or other differences between hepatocytes of old and young people are, for just this reason, very unlikely to mean anything about aging in the liver: rather they almost certainly mainly indicate aging elsewhere in the body and consequent elevation of the work rate the liver is having to sustain in order to detoxify the body.

Prometheus: "You persist in discounting the relationship between 8-oxodG lesions and mutation incidence, mainly on the basis where you say the cell is almost always able to always repair such damage. Consequently according to you, and in contradiction to many scientists who are using 8-oxodG lesions as a mutation assay, 8-oxodG lesions are not a suitable protocol. I understand this to be your view. If it is more than your opinion is there any data you could point me to?"

I think most scientists entirely agree with me that 8OHdG is a poor marker of mutations, because there is abundant data -- the transition/transversion ratio that I mentioned last time is just one that I happen to know. Certainly Will Bohr readily accepted this when I asked him about it a few years ago, and if he does then you can be pretty sure most DNA damage experts do. But scientists do the experiments that they can do, not necessarily those that they'd like to do.

Prometheus: "Do you think that even a small rise in mutations is harmless to the cell? Do you believe the cell's capacity to repair DNA damage is not a limiting factor - and if so, why?"

A small rise is harmful to the extent that it may cause cancer, and it has a small probability of being harmful to the cell in non-cancer ways but therefore a zero chance of being harmful in non-cancer ways to the tissue of which the cell is a part. The cell's capacity to repair DNA damage is a limiting factor on lifespan because of cancer but not for any other reason, because the fidelity of DNA repair and maintenance required to keep cancer at bay in the whole body until middle age is sufficient to keep all tissues working for many times that long.

Prometheus: "1. Once more, is it not better to target cancer in a non-stem cell associated way? There are tumor specific genes and/or transcriptional profiles other than telomerase. Why not target these?"

Telomerase has the advantage that all our cells can do without it for a decade, so we don't have to target the cancer cells specifically. targeting cancer cells specifically is the Achilles heel of all existing therapies because cancer cells are so good at being not very different from non-cancer cells when they need to, hence therapeutic index problems.

Prometheus: "2. In respect to the accumulation of mutations, you mentioned in a previous post that it is not until middle age that mutations begin to cause cancer. In this post, by referring to the advantage of a 10 year cycle of stem cell replacement you infer that mutation accumulation during such a comparatively shorter period could still increase cancer incidence. So pertinent to one of the advantages of WILT, what is it going to be - 10 years or 40 (middle age) where the accumulation of mutations becomes critical?"

Good question. Ten years is imposed by the stem cells themselves, not by the cancer risk, so the option of lengthening the stem cell telomeres somewhat more than to normal lenths so that they could last 15-20 years after introduction is certainly not excluded. Going as high as 40 years would run too high a risk of the cells having time to find something ingenious.

Prometheus: "2.1 You must agree that decreasing the incidence of nuclear mutations will have an effect on cancer incidence. So why not a solution for decreasing the incidence of nuclear mutations?"

I'm certainly not opposed to such things in principle, but they are in my view going to be very hard to do without side-effects. Classic examples are the p53-overexpresing mice of the Donehower and Serrano labs, which have next to no cancer but do not have an extended life expectancy (the Donehower ones actually live less long than normal); this is odd since most mice die of cancer and most people think the extra p53 is making the stem cells more hair-trigger suicidal.

Prometheus: "3. Finally, are you prepared to go on the record as saying that nuclear mutations/and or DNA damage do not contribute to aging? You don't need to answer this because it is obviously no. It is a well known fact that nuclear DNA damage will induce senescence (1). So why underestimate its importance to aging?"

Sure I am: nuclear mutations and/or DNA damage do not contribute to aging in a currently normal lifetime in mammals except to the extent that they promote cancer, and possibly arthritis. Of course nuclear DNA damage causes senescence, but we have hardly any senescent cells in any tissue yet found except chondrocytes in the articular cartilage (Martin and Buckwalter, various papers).

John S: "An inducer could be chosen that is completely harmless to other cells. Take lactose as an example. We should be able to overwhelm / outsmart even the multi drug resistance carrier with an extremely high dose of a harmless, normal molecule. I don't think this has been investigated enough in the context of inducible suicide genes to warrant a conclusion. Otherwise one may try to develop radiation inducible systems, which can hardly be "chucked out"."

Good points -- certainly well worth exploring.

John S: "In conclusion, I suggest to push towards full body cellular replacement, tissue engineering and transplantation strategies and at full force. This has to include strategies for the (gradual) ablation of existing "old" cells, including cancers. If we accomplish this only once, repetitions of the therapy will become easier, because of inducible suicide genes. The most difficult cell ablation step will be the one targeting all the first generation wild type cells that presently make up our bodies. Did I miss any unrebutted argument against using chemotherapy, nearly as we know it, to achieve this? By definition, repeated complete cellular replacement would allow us to forget about any quarrel with intracellular causes of deviation from infantile health. Does that sound like a strategy we desperately need, and thus warrant a second thought?"

Sounds good to me. All I would really say is that in this context WILT is a sort of insurance policy to make sure that we aren't relying on perfect 100% elimination of all the cells with the suiucide genes.

[jaydfox]

Prometheus: "The liver functions well as an organ generally well into old age as an organ because of its tremendous redundancy. A substantial amount of the liver can be removed and the patient still be provided with adequate function. Cellularly, it is a different matter. Hepatocytes will readily die under toxic conditions without any grossly adverse symptom in liver function."

Right (well, actually it's because of the liver's tremendous regenerative potential rather than its redundancy -- the liver grows back pretty fast after partial hepatectomy). But the point is that biochemical or other differences between hepatocytes of old and young people are, for just this reason, very unlikely to mean anything about aging in the liver: rather they almost certainly mainly indicate aging elsewhere in the body and consequent elevation of the work rate the liver is having to sustain in order to detoxify the body.

But as I recall, the gene expression changes in kidneys (I know, they're not the same as the liver) with age are similar among different specific tissue types, indicating that the changes were applied to the organ as a whole, and not just to tissues based on function.

Given the variety of functions of specific tissues, wouldn't this indicate that the gene expression changes are inherent to the cells themselves, and not to changes in their disparate environments? In other words, don't these changes indicate intrinsic senescence, not a response to extrinsic degradation/senescence? Although we need a followup study in the liver, surely the kidneys would face the same blood toxification (due to body-wide degradation) that the liver does.

Surely there are a variety of tissues within the liver, each facing different levels of exposure to the inherent increase in blood "toxicity" with age. Is there any evidence yet, one way or the other, that could link hepatic senescence (differences between old and young livers) to the "elevation of the work rate the liver is having to sustain in order to detoxify the body"?

[ag24]

Prometheus:

"So you're saying that even if some cells are affected by unrepaired DNA damage in "non-cancer ways" by which I would interpret as becoming senescent or having altered physiological characteristics, the overall impact on the tissue that they belong to is minimal. This does not explain the myriad other effects that are observed in the aging organism, particularly with gradual organ dysfunction."

No, of course it doesn't -- but why should it? -- the other SENS components explain those effects.

"There are substantial advances in the use of tissue and tumor specific promoter gene expression systems (targeting specific transcriptional patterns) and tissue and tumor specific delivery systems (capsid modified and replication specific adenoviruses). A theoretical construct could deliver a caspase signal when it encounters an abnormal transcription profile. What makes you think that such approaches will not become increasingly successful?"

Oh, I think they will -- but only incrementally. Here's a parallel: the liver and kidney both have a system of filtering material (into, respectively, the biliary system and the urine) that involves chucking stuff out rather indiscriminately and then hauling specific valuable stuff back in again. This is a brilliant way to be thrifty with useful stuff that gets contaminated but not have to have specific machinery to recognise and discard every type of contaminant. It's as different from the incremental approach as WILT is from the sort of things you list.

"P53 is notorious for being the price the cell pays in lifespan in return for decreasing cancer incidence so it is not a particularly good example. How about overexpressing factors in other DNA repair pathways that have no known similar side-effects?"

I'm absolutely in favour of trying -- but I'm as entitled as you to my scientific intuition re whther there will be side-effects.

"Hypothetically speaking, supposing a cell were to have nil mutations or DNA damage in the nuclear and mitochondrial genome, and it were to be telomerase positive but had all other regulatory controls intact, what would you say would be its chances of tumorigenesis, senescence or apoptosis?"

Tumorigenesis nil, at least if we also exclude whole-chromosome aneuploidy. Senescence nearly nil (so long as very short telomeres counts as DNA damage). Apoptosis not nil because factors other than DNA damage can cause it.

"Arthritis is an autoimmune disorder. If you include all autoimmune disorders there are numerous pathologies and implications of damage to the haemopoietic system with all sorts of further pathologies possible."

Um, rheumatoid arthritis is autoimmine but osteoarthritis is mainly just a degeneration of the cartilage. However, you do remind me that yes, immune senescence is largely an accumulation of cells in a senescent state that is as yet not persuasively linked to DNA damage but may well be. Luckily the haematopoietic nature of almost every part of the immune system means that WILT will give us the means to fix immunosenescence more or less in one go (the main exception being the thymus, re which there is already great prpogress in rejuvenation).

"I beg to differ on your view of the presence of senescent cells in aging tissue."

Er, but then you give a bunch of examples concerning cell loss (stem cell loss, specifically). What's the connection? - ex-cells and senescent cells are rather different things, aren't they?

"Your assumptions on the causes of aging have led you to formulate your SENS solutions. However, it appears that these assumptions are not congruent with what is emerging in the research community. Namely, you underestimate the contribution of nuclear genomic damage to aging and its role in organ dysfunction."

You and I clearly have different interpretations of "what is emerging in the research community", not to mention the literature! But I an bemused that you feel you can generalise about the research community as you do above, given that I've responded specifically to every point you've made with reference to published data.

"If this were a scientific debate meant to test the mettle of various theories then one could simply shrug at your inflexibility and discount it as scientific myopia. What I find disturbing, however, about your views is that in your developing role as a scientific spokesman and leader for those who desire a fast solution to the aging problem, your are not simply placing your reputation in peril but the lives of those who would stand to benefit from such scientific advances."

Bollocks, if I may say so. I refer you, to take merely the most convenient example, to my statement in this very thread that "In an ideal world there would be several IBG's competing for the MMP". I don't hold it against you that you dispute my reading of the available experimental evidence -- that's a central part of what being a scientist is, to hone one's sense of what's behind the data, and the existence of a spectrum of interpretations of the same data is an essential substrate for rapid progress. But if you think that the correct approach for someone in the leadership role that I currently occupy is to roll over and agree with someone who has not, in my sincere and painstakingly-explained estimation, provided any argument that their view is more supported by the data than mine, then to put it brutally bluntly you are part of the problem, not the solution. I have not blown off anything you've put forward -- I've responded point-by-point with reference to established data, just as I always do to everyone. If I were reluctant to listen to your arguments ("myopic"), why would I bother replying to your arguments at all? -- I'm doing so precisely in order to tease out whether there is anything valid in them that I've so far overlooked.

"Molecular technology and knowledge of aging systems has evolved since the 6+ years you formulated the first SENS. Is it time that SENS evolved too?"

SENS (defined as the range of projects that I think are urgent, which I presume is what you mean hy it) is evolving all the time. WILT is under three years old. I am constantly exposed to new reasons to refine both the SENS problems and their solutions. The second SENS conference (this coming September) has only one
invited speaker who spoke in 2003. There is no shortage of evolution in SENS.

I suggest you go and read some of Vijg's work on the role of nuclear mutations in mammalian aging before commenting further. Vijg is an outstanding scientist whose main research goal for the past decade has been to answer this question and who is recognised throughout biogerontology as having generated the most valuable data in the area. He still agrees with you, mind -- but he has better arguments.

[John Schloendorn]

Prometheus, Aubrey,
Hmm, both of you seem to agree that somatic cell nuclear mutation accumulation is bad - be it because of aging, or cancer, or some yet unknown future form of phenotypical demise, or all three of them. I agree, and I am happy to read from the SENS2 programme that it is very much evolving into the direction I have just advocated so passionately, to get to the root of this problem.