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Telomerase does not lead to cancer


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#61 enki273

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Posted 23 December 2006 - 11:03 AM

Yes, I read the paper you posted some time ago on telomerase in the mitochondria.
Indeed, the proposal that telomerase expression is at a finely-tuned equilibrium between quality control and saving resources is sensible. I do not believe it would be a considerable waste of energy to overexpress this particular enzyme a bit, but in general the idea seems good.
Only its application to WILT does not follow to me: If a cell lacks telomerase, its mitochondrial genetic stability will suffer if it has this other role. Ok, but if applied together with AE or another method repairing mtDNA damage, this will have no consequences. Why should, if implemented as a whole, the prevention of telomerase expression have any other effect than preventing most of the cancers?

#62

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Posted 24 December 2006 - 12:56 AM

AE seeks to move the mitochondrial genome to the nucleus but would not alter the fact that telomerase has a mitochondrial localization sequence and that under high cytoplasmic oxidation conditions (according to that paper) would still be targeted to mitochondria for what appears to be a safety self-destruct mechanism. If we remove telomerase then we are also removing this function and then that stands to increase damage to nucleus and increases the risk of cancer or other tyoes of genomic or cellular damage with similarly compromising consequences. And let's not forget that even without telomerase we can still get ALT (alternative lengthening of telomeres) to drive cancer proliferation.

#63 enki273

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Posted 27 December 2006 - 01:28 PM

Concerning oxidative stress and telomerase I do not quite get your point. If AE or a similar method is really successfully implemented, oxidative damage as a whole will be mostly eliminated. If telomerase works as a selective means for destroying mitochondria that have become too faulty, this function will have no importance by then anymore. Of course ALT poses further problems, but that is another issue.

#64 apocalypse

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Posted 30 December 2006 - 01:15 AM

Concerning oxidative stress and telomerase I do not quite get your point. If AE or a similar method is really successfully implemented, oxidative damage as a whole will be mostly eliminated. If telomerase works as a selective means for destroying mitochondria that have become too faulty, this function will have no importance by then anymore. Of course ALT poses further problems, but that is another issue.


The key word is mostly, if this helps the body get rid of cells that for whatever reasons(environmental factors, toxins-some distort mito metabolism leading to higher % free radical production, disease, etc.) are being exposed to a higher oxidative load, it wouldn't be wise to get read of it. The mito may be serving the function of a miner's canary, and we've seen exponential lifespan increases, even in animals with high metabolic rates, achieved by nature without resorting to AE.

#65 lucid

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Posted 24 February 2007 - 12:15 PM

Very interesting thread here, those results about the additional functions of telomerase are very interesting prometheus. That said I wonder what effect adding telomerase would have on benign tumors. My understanding of cancer has always been that there are 2 primary components:

1) Increased and unstable growth rate via self sufficient growth factors (Benign tumors have this too)
2) Telomerase expression for passing the hayflick limit (Causes Malignancy)

*Perhaps there is a third required mutation required for a cancer to survive which is a mechanism allowing cancer to evade apoptosis.

Normally I would have expected that adding telomerase into a benign tumor would trigger more tumor growth by ending senescence; however, given the apoptosis inducing behavior of telomerase and given tumors have genetic damage, then perhaps telomerase would induce apoptosis of benign tumors? I find this unlikely where as cancerous cells have telomerase and manage to avoid apoptosis. Perhaps this is a result of a third mutation in the genome which expresses some anti-apoptosis factor. If so then I would imagine both malignant and benign tumors have this 3rd mutation.

In fact benign tumors do not express telomerase: http://content.karge...e.asp?Doi=19856
I cant manage to find any studies where telomerase was added to benign tumors... anyone seen one?

#66 lucid

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Posted 25 February 2007 - 02:14 AM

Well it appears many types of cancers have both a growth stimulant (c-Myc) and an anti-apoptosis agent (Bcl-XL). In the case of the 2 mentioned agents, they counteract each other. c-Myc has growth stimulant properties as well as pro-apoptosic properties. Bcl-XL has anti-apoptosic properties enough to conteract the pro-apoptosic properties of c-Myc.

Here we can imagine that the apoptosic mitochondrial response to c-Myc evolved to combat tumor growth. Hence only growth factors like c-Myc being present in a cell will result in increased growth rates followed by apoptosis. Hence, we can surmise that the anti-apoptosic expression must occur first in regards to cell mutation. After this point, with regards to the third mutation which will cause malignancy (expression of telomerase), It would appear that it could occur before or after the expression of the anti-apoptosis mutation. Hence, It would appear that it could take as few as 3 genetic lesions to produce a malignant tumor. (only 2 to produce a benign one) That said it is possible that some tumors have growth factors which may not have pro-apoptosic properties.

To continue with some more wild speculation, If tolemerase were to be expressed in all human cells, it would make sense that we should remove all benign tumors in the patient first (This might include moles etc too).

Note the last part of this post is largely speculation. Here is one of the sources for the other part of this post: http://cancerres.aac...t/full/63/1/263
Cheers.

#67 John Schloendorn

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Posted 25 February 2007 - 03:04 AM

After this point, with regards to the third mutation which will cause malignancy (expression of telomerase), It would appear that it could occur before or after the expression of the anti-apoptosis mutation.

Arguably, the main selective pressure for telomerase activation would kick in only once telomeres are critically short. Indeed telomerase activation is a late-stage event. (This doesn't seem to affect your conclusions)

#68 lucid

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Posted 25 February 2007 - 07:37 AM

Interesting, Well I have always understood the selective pressure for the existence of telomerase to be keeping the germ line healthy, we wouldn't want our children to start off life with senescent cells. I don't believe non-germ cells usually have telomerase present unless they are malignant tumors.

It seems that having telomerase always activated in cells would not be favored where as it apparently induces apoptosis. Most cells can function just fine after some genetic damage and it would seem a waste to have telomerase activated in all cells even though it might suppress cancer (by killing cells sustaining heavy genetic damage). There would be lots of needless cell death. For these reasons, I imagine that pressure would induce longer starting telomeres in cells long before it would encourage expression of the telomerase gene in all cells.

#69 John Schloendorn

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Posted 25 February 2007 - 05:02 PM

I was speaking of selective pressure on cells within a cancer (not the evolution of telomerase gene expression in a species), in an attempt to explain the finding that telomerase activation occurs late during the evolution of a cancer (in response to your quoted insecurity).

#70 lucid

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Posted 25 February 2007 - 09:33 PM

Ok, I misunderstood you, but I understand you now :) Thanks for your response.

I just read a couple of studies that really complicate my understanding of this:

#1 Telomerase activity, Cell proliferation, and Cancer
http://www.pubmedcen...rez&artid=34198

The key points here are that they find that telomerase activity is related to cell growth, i:e cells that proliferate more are more likely to have higher levels of telomerase. For example, basal levels of skin as well as some blood cells have high amounts of telomerase.
The impact of this on my understanding of cancer has been that instead of telomerase being activated by some genetic mutation perhaps telomerase production in malignant tumors is a byproduct of the rapid growth a benign tumor has. So it seems there must be some critical mass of growth that will allow a cancer cell to produce enough telomerase to become 'immortal'. This explains the gradual increase in telomerase observed in progressively worse cancer.

#2 Increased Healing rate in transgenic mice
http://www.pubmedcen...ez&artid=125492

Well here the argument is made that Telomerase promotes cell growth, mice with mTERT expressed will have increased chances for epidermal tumors and will also have increased healing rates in mice. When taken in context of Telomerase activity, Cell proliferation, and Cancer, this would suggest that the increased telomerase activity is not the result of increased growth but rather the cause of the growth (or part of it).

Hmm, I'm going to sleep on this hopefully I can figure it out. It is also said that each different cancer may or may not need telomerase. More to think about. Cheers.

#71 crayfish

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Posted 05 March 2007 - 01:40 PM

I've enjoyed reading this thread and it was very interesting to read about the extra function of telomerase, as well as the in vivo activation of p53 and pRb. I may actually have read something about this in the media at some point recently? Rings a bell. Very exciting anyway, congratulations on that research!

To add a little to the points above, in addition to bypassing replicative senescence, becoming self-sufficient in proliferative ability and evading apoptotic mechanisms, cancer also has the immune system to consider.

Going back a little further, I would certainly argue against the suggestion that cancer is a programmed function on several grounds:

From an evolutionary view, as mentioned cancer onset tends to be at ages that would not have been relevant to selection for much of anthropoid history. As a more general point regarding ageing as a whole in evolution, the Weismannian idea that aged individuals must be removed in a programmed manner so that the young might flourish is fundamentally flawed for a number of reasons. Firstly, predation pressure removes more individuals than ageing in natural populations in any case and so such a mechanism would be virtually redundant. Secondly, without the progressive decline of function associated with ageing old group members would be equally fit to younger members and so there would be no group-level selectional drive to replace them with younger individuals. Planarians do fine.

Mechanistically, why would so many mechanisms evolve to limit cancer if it was a desirable function? An immense amount of energy is divested in proteins and systems that exist for little reason other than to prevent cancer - the immune systems that recognise and destroy cancer, the checkpoints to sense DNA damage and trigger apoptosis, the complex mechanisms regulating apoptosis itself - all seem designed with the primary function of protecting against cancer.

I think that enough lines of evidence exist to believe that cancer is a major threat to multicellular species rather than an evolved feature. The way I see it is that cancer is one of the reasons why complex metazoa have any mechanisms limiting longevity - oxidative molecular damage is unavoidable and a challenge that life has been combating since the start. DNA damage disturbs function in such a way that a minority of cells will become dysfunctional. In unicellular communities this is fine, a dysfunctional cell will be less fit and will simply die without affecting others (I see a parallel here in the production of independent spermatazoa and the mechanisms in place to ensure that only very strong, healthy sperm will fertilise an egg, in my opinion this single-celled competitive gamete stage is essential for the perpetuation of complex multicellular organisms, where the germline would otherwise deteriorate as the soma does).

In strongly interdependent communities such as complex metazoa, dysfunction can lead to phenomena such as cancer. Mechanisms have evolved to limit cancer by inducing apoptosis in damaged cells and limiting the absolute replicative ability of cells through telomeres, which have the side effect of capping longevity. The hormonal systems regulating development also seem instrumental in controlling longevity, though I'm less sure whether this is a side effect or an 'intentional' feature. Ageing in the complex metazoa is now a compound issue of the accrual of genomic/proteomic damage through oxidative stress (and transcription / translation errors, to a lesser extent) and the regulatory systems evolved to combat this.

If telomerase has a strongly pro-apoptotic function in response to oxidative stress, wouldn't overexpressing it systemically be quite a bad idea? On the other hand, basal epidermal stem cells have high hTERT levels and despite being locating in a site of high ROS impact don't all spontaneously apoptose...

Seems that it doesn't do wonders for mice though http://www.nature.co...s/1208413a.html

Edited by crayfish, 05 March 2007 - 02:45 PM.


#72 lucid

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Posted 05 March 2007 - 04:14 PM

If telomerase has a strongly pro-apoptotic function in response to oxidative stress, wouldn't overexpressing it systemically be quite a bad idea? On the other hand, basal epidermal stem cells have high hTERT levels and despite being locating in a site of high ROS impact don't all spontaneously apoptose...

Well, Telomerase seems to only aid in the induction of apoptosis after significant genomic damage has occurred. Hence, alone, telomerase has a function as a tumor suppressant. I believe the studies are in my earlier posts. 'Bad Idea' is an oversimplification. Being very sensitive to genetic damage will result in too much apoptosis, hence the organism will be less efficient as organisms with less self destructive behavior. Having too little sensitivity to genetic damage will result lots of tumors, and in the case of germ cells: a weaker germ line. So the evolutionary trick is to have a proper balance: the right combination of damage regulation via apoptosis and efficiency.

In regards to the basal epidermal cells. I believe areas of particularly high ROS would be the ones most needing genetic damage regulation. Such activity would be wasted in areas with little potential for damage. I would suspect basal epidermal cells would apoptosize more frequently than tissues without hTERT active. And as I just said, I think this would be a good thing for the organism.

Seems that it doesn't do wonders for mice though

Well this study says that although tumors are more likely in mice during their early years, it does increase average lifespan by 10%. This is speculated not to be the result of telomere lengthening, but rather because of other functions of telomerase. Perhaps there was tumor suppression in later years?

Interesting. Will post more later.

#73 pyre

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Posted 03 April 2007 - 09:11 PM

In 1996 Michael Fossel, former editor of Aubrey's Rejuvination Research Journal, published a book called 'Reversing Human Aging,' which elaborated on the recent discoveries of Geron Corp. relating to the now commonplace immortalization of human fibroblasts.

In this book, Fossel proposed an ageless system in which telomerase would be upregulated constitutively. To my knowledge, this option was first explored at Harvard by Ron DePinho, who created the first mTR +/+ mouse, and published the first study on the association of telomerase expression and cancer incidence. (A later review by him: http://www.jci.org/c...full/113/2/160)

However, as DePinho points out, the only two scenarios of altered telomerase have been hyperfunction and inactivation.

Fossel, in his later book, “Cells, Aging, and Human Disease,” went on to cite the great quantity of malignant tumors which possessed overactive telomerase, further dismissing his own hypothesis as an all-too-hopeful proposition.

Could Fossel’s 1996 Book have been right
While certainly not the do-all end-all of aging research, there may still be some promise in the overexpression of telomerase, as Prometheus was suggesting in his numerous posts. I think that we need to highlight the different aspects on both sides that we’ve seen, and, in endeavoring to understand the content of this thread, I will try to do just that.

Not Enough Telomerase
As proposed in de Grey’s WILT and current Geron Corp. anti-cancer therapies involving Telomerase, the elimination of lengthening telomeres would seem to be the perfect method to counteract the observations that the vast majority of malignant tumors have a telomere lengthening mechanism. However, realistically, we run into the trouble of cells senescing more quickly in the absence of Telomerase, and these senescent cells are, in turn able to induce tumorgenesis.
While knocking out Telomerase may be able to play an important role as an anti-malignant-cancer therapy, it would likely in a human system have a variety of undesirable consequences, including premature stem cell senescence and T-cell dysfunction.

Too Much Telomerase
As we’ve talked about, it’s no coincidence that the vast majority of malignant cancers express Telomerase abundantly. In order for cancers to mutate and metastasize, they must surpass their division limits, and in order to do so, activate telomerase. In the constitutive presence of telomerase, one of the activation barriers for a cell becoming cancerous has already been achieved. And, although a number of factors must be achieved for a malignant cancer to be formed (p53 mutation, growth factor, anti-apoptotic factor, DNA mismatch repair mutation/irregularity, surpassing the Hayflick limit), the fact that all these mutations must happen in a single cell (and thus, that cell’s descendents) makes the subtraction of one checkpoint two to three orders of magnitude more probable to develop a tumor. This is generally considered a ‘bad thing.’

If readers would like to enumerate additional pros and cons of these two extremes that have been studied feel free to do so. For purposes of brevity I won’t do any more here.

I do have something to add to this discussion, though, so that my analysis may not have been entirely in vain. But first, I must add a third category of Telomerase activation.

Wild Type Telomerase Expression[
We live, grow old, and die. Not always, but to many, considered a bad thing, especially the last two.

All right, now onto what’s missing, have you guys noticed it yet? We have a system of two extremes, all telomerase and no telomerase, in which the only well understood median is the wild type system. Therefore, there are regions between the wild type and each of the two extremes that are not understood, and could have radically different phenotypes.

Therefore, I propose that someone (perhaps me in a few years, but I expect it will have been done by that point) develop this:

The Dose-Dependent Knock-in
Given everything we’ve learned in this thread and associated papers about telomerase, doesn’t it seem like it would be a great thing if we could ramp up it expression in our stem cells if we needed to? We wouldn’t want to constitutively give cancers a checkpoint for developing into metastases, but we wouldn’t want to pass up the opportunity for immortalized, healthy somatic cells that telomerase promised the world in 1996. If we placed telomerase (preferably mutated to get rid of its mtDNA mutating segment through a ‘hack’ as was mentioned earlier) into a murine or primate model system under the control of a specific promoter, while simultaneously knocking out the incumbent telomerase, we could tune the perfect expression of telomerase to, in fact, immortalize our cellular DNA, while simultaneously avoiding the necessary spike in cancers and the other goodies implicated in constitutive telomerase systems.

It seems like an interesting and unexplored possibility (if it has already been done my sincere apologies to the researcher who’s data I have been unable to find).


Concluding
As you guys can see, this is my first post, so let me take a second to introduce myself: My name is James, I’m an undergraduate at the University of Chicago who for 5 years now has known that I was going to go into aging research.
And now: I’m rather excited to become a part of this community, and hope to learn a lot from the compilation of knowledge presented here.

-James.




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