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Telomerase does not lead to cancer


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#1

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Posted 23 May 2006 - 01:51 PM


Utilising cells from the older patient with which to engineer tissues to replace dysfunctional ones poses a special problem: the replicative lifespan of cells from such patients is severly limited and thus cannot be used to synthesize replacement tissues. One way around this is to utilize cells donated from a younger person but then we encounter the problem of histocompatibility. There is another way involving the use of telomerase to increase the replicative potential of cells derived from very old patients. A recent study reported that by inserting a genetic construct that encoded the telomerase gene, cells from 85 year old patients that would normally only be able to undergo 15 population doublings before entering senescence were able to slingshot to 100 population doublings! In comparison similar cells from 17 year old patients untreated with telomerase could only achieve 41 population doublings before entering senescence. Most exciting of all, was that in this study the cells which were made to express telomerase for increased replicative lifespan the incidence of carcinogenicity did not increase over the control cells. In fact, is some cases the incidence of carcinogenicity decreased as compared to the controls.

#2 Lazarus Long

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Posted 23 May 2006 - 02:44 PM

This is great and what I suspect can also be done for mitos in principle. I wonder if such a *genetic construct* can be found for mitos. We have discussed before my suspicion that such a code sequence must exist for the mitos to be reset during ovogenesis.

#3 rahein

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Posted 23 May 2006 - 05:33 PM

I am glad to here positive news about telomerase. All the news in the last few years has been about silencing it in tumors. Telomerase is why I first thought that humans could become immortal and started my quest that lead to here and transhumanism.

#4 nimcha

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Posted 08 June 2006 - 04:29 PM

Couple of comments on this paper...

First, does anyone know what the PCR signal at about 6.5 bp in fig 1 is in the control group? Offhand I wouldn't expect there to be any signal at all, since a cell with inactive telomerase would not be affected by the addition of the substrates for telomerase repeat addition, which is my understanding of how the telomere repeat amplification protocol works. (See here for more info on the assay.)

It is curious that the incidence of tumorigenesis in the hTERT SMC actually appeared to be lower than in the control group. I think one instructive follow-up to this would be to expose these telomerase-active SMC to a variety of external stresses, including known mutagens, and then check the cancer formation rates. Since, as the authors note, telomerase activation is not in and of itself sufficient to cause cancer, but is (often) rather one of many steps, I wonder if the low rates of aneuploidy etc could be attributed to a lack of other cancer-causing environmental stresses?

#5 John Schloendorn

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Posted 12 June 2006 - 08:26 PM

expose these telomerase-active SMC to a variety of external stresses, including known mutagens

Great idea. Since telomerase activation is a late-stage event, perhaps its tumor-promoting role would become evident only when the early stages are provided by mutagen treatment... On the other hand, if that were done and still proven safe, it might be even more glorious news for potential telomerase-activation therapies.

#6 ag24

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Posted 12 June 2006 - 09:47 PM

If someone can offer an explanation other than tumour suppression for why all human cell types express only the absolute minimum quantity of telomerase that is compatible with their lifelong function, I'll start to take the life-extension potential of these reports more seriously. Until then...

#7

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Posted 13 June 2006 - 12:39 AM

An explanation is likely to be found in the other, recently discovered function of telomerase - genomic quality control via increasing ROS sensitivity in mitochondria.

#8 ag24

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Posted 13 June 2006 - 09:58 AM

Um... even if telomerase has other functions, how does that explain why human cells express so little of it? Please elaborate.

#9

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Posted 13 June 2006 - 10:26 AM

Um... even if telomerase has other functions, how does that explain why human cells express so little of it? Please elaborate.


Because an excess of telomerase may lower the apoptotic threshold and in non-rapidly dividing cells that could be catastrophic.

#10 ag24

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Posted 13 June 2006 - 02:52 PM

Um... Sorry if I'm being dim, but if so, wouldn't that just mean that artifically stimulating telomerase was a bad idea for two reasons rather than just one?

#11

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Posted 13 June 2006 - 04:02 PM

It would be a bad idea only in the sense that non-dividing cells become more vunerable to ROS damage when telomerase finds its way to mitochondria. In effect, telomerase could be used to cull ROS-infected cells that would otherwise continue to survive whilst stabilizing the genomes of healthy ones.

#12 ag24

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Posted 13 June 2006 - 04:23 PM

Um... but in that case, why don't human cells naturally express more telomerase than would be necessary for telomere maintenance, for just this purpose?

#13

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Posted 14 June 2006 - 12:08 AM

Increasing the rate of quality control would be an unnecessary expenditure of resources and be evolutionary disadvantageous -- sort of like replacing a reasonably functional car with a brand new model as soon as it needed some work.

Evolution seems to be averse to long lifespans and very stable genomes.

#14 ag24

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Posted 14 June 2006 - 09:04 PM

Um... but hang on, telomerase expression is something that could certainly mutate to slightly higher levels. It's true that evolution only invents *new* repair/maintenance machinery when there is selective pressure to slow aging, i.e. when a respectable proportion of the species is dying of aging, which won't have been the case in our ancestry since we achieved the sort of rate of aging we have today. But when *slightly breaking existing* machinery would extend lifespan, there's no selective pressure to get rid of mutations that break the machinery (which must always be occurring). In other words, your argument seems to rely on "programmed aging" - right?

#15 Mind

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Posted 14 June 2006 - 09:29 PM

Ok, now I may be dim, or just ignorant in the field, but has anyone definitively pegged telomere shortening to a "program" or "damage" theory? Or is it unsettled?

#16

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Posted 15 June 2006 - 10:10 AM

The phenomenon of telomere shortening certainly appears to have a consistent, step-wise routine. In those cells that do not express telomerase each cell division results in a fairly uniform amount of loss from the chromosome caps. Due to the consistent length of telomeres this loss constrains a telomerase-negative cell to a specific number of divisions known as the 'Hayflick limit' after its discoverer. Like the systematic process of cell differentiation that occurs during development, telomerase status and the quantal nature of telomere loss display qualities more consistent with a program rather than random damage.

The point of contention is what happens once a certain age is reached since the changes observed in the cell are interpreted as stochastic rather than continuing to follow a program (more on this another time).

In reponse to Aubrey's implication which is that if telomerase were as beneficial as I am suggesting it could be, then why hasn't evolution increased its expression, I direct his attention to the reports by Santos et al (2006) where it was found that telomerase a) contains a mitochondrial targeting sequence (under the control of a ROS-sensitive kinase activating switch) and b) once telomerase enters the mitochondrion its role appears to be to facilitate apoptosis. This new role is very far removed from telomere maintance but is in keeping with maintaining genomic stability -- an elegant way to ensure that telomerase positive cells who by nature of their indefinite lifespan require a higher level of mitochondrial quality control to be more sensitive to ROS. Any increase in telomerase activity would likely increase ROS sensitivity and induce apoptosis prematurely therefore selection would not favour an increase in telomerase activity.

What was also particularly relevant from a WILT perspective in the Santos study was that when telomerase was confined to the nucleus a substantial anti-apoptotic effect resulted. This implies that if telomerase is removed from stem cells entirely, as is proposed in WILT, then the rate of cancer would actually increase rather than decrease (ROS sensitivity is decreased with a concomitant increase in risk for genomic instability).

And that brings us to a replacement for WILT and solution for DNA damage. :)

#17 caston

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Posted 18 June 2006 - 03:01 PM

Perhaps the Hayflick limit is there to minimise inbreeding?

#18 John Schloendorn

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Posted 18 June 2006 - 08:48 PM

"program" or "damage" theory?

Program -- yes, but not "in order" to achieve aging. The days of program theories of aging seem to be numbered, because many species that age in captivity can expect to die from non-age-related causes before they get the chance to age in the wild, and this would have prevented any selective pressure to evlove aging. So if interpreted as a program, telomere shortening must be a program for something else, perhaps with late-age degeneration as a side-effect. I know only one good suggestion of what else it might be a program for, and that is the interdiction of tumor progression to a life-threatening stage. But that doesn't mean alternative explanations could not exist. So far, there has been no rigorous test of the tumor progression idea (e.g. a long-term study of telomerase overexpression in a clinically relevant large animal). Nimcha's suggestion (providing early stages of transformation by in-vitro mutagenesis) might also provide a clue, especially if the result was positive.

Caston,
it is good to think about alternative ideas what it might be a program for, but please explain -- how so?

#19 caston

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Posted 19 June 2006 - 06:00 AM

John:

I think that ageing may be more about survival of the species than about the individual.
Inbreeding increases the chance of genetic flaws being compounded and probably also holds back adaptation to changing environments. Ageing may be a mechanism to decay an organism so that it no longer can breed. After that death follows because the organism hasn't evolved to avoid it.

I don't know enough to back this up with any really solid science but I would like those here such as yourself to consider or at least debunk this as a possibility.

Also take a look at:
http://www.agingtheory.com/

#20 opales

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Posted 19 June 2006 - 07:44 AM

John:

I think that ageing may be more about survival of the species than about the individual.
Inbreeding increases the chance of genetic flaws being compounded and probably also holds back adaptation to changing environments. Ageing may be a mechanism to decay an organism so that it no longer can breed. After that death follows because the organism hasn't evolved to avoid it.

I don't know enough to back this up with any really solid science but I would like those here such as yourself to consider or at least debunk this as a possibility.

Also take a look at:
http://www.agingtheory.com/


Caston, the current consensus in gerontology is that aging is not selected for in evolution, which is exactly what your suggestion of inhibiting inbreeding would call for. Here is an ultra-short primer on development of evolutionary aging theories by Aubrey de Grey:

http://groups.google...a90a18302b8e3fb

Further comment by Steven B. Harris in the same thread:

http://groups.google...86ea16cc974efcd

Here is paper by Aubrey that is not about aging theories as such but still has a rather informative passage about the (the evolutionary pressure to aging)

http://www.sens.org/weatherPP.pdf

Edited by opales, 19 June 2006 - 08:00 AM.


#21 opales

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Posted 19 June 2006 - 09:37 AM

Caston, the current consensus in gerontology is that aging is not selected for in evolution, which is exactly what your suggestion of inhibiting inbreeding would call for.


Hmmm, Aubrey characterizes disposable soma theory as in sloppy maintenance is selected for, in some sense contradicting my above stament. I might have to review the disposable soma argument again.

Anywhoo, here is another paper [1] by Kirkwood (originator of the disposable soma theory) reviewing the evolutionary theories aging

http://www.ub.unimaa...20/kirkwood.pdf

[1] Kirkwood TB. "Evolution of ageing."
Mech Ageing Dev. 2002 Apr;123(7):737-45. Review.
PMID: 11869731 [PubMed - indexed for MEDLINE]

#22 ag24

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Posted 19 June 2006 - 11:11 AM

I wasn't quite so good at expressing myself in 1998 :-)

There isn't really a contradiction above -- it's just a question of what one means by "selection". The sort of selection I meant in my 1998 post is what should probably be called "directional absence of selection" or something like that. Looking at it mechanistically: if a species has really good maintenance machinery, so good that all individuals of the species are long dead from extrinsic causes (starvation, predation etc) before they have any problems with aging, but this machinery consumes a lot of energy throughout life, then mutations that slightly break that machinery will have no effect on lifespan (because they'll just bring the age at which aging matters down to closer to the age at which everyone is dead from extrinsic causes, but not below that age) but those mutations will sometimes also make the maintenance machinery consume less energy (because it's doing less). Therefore, that energy will be available for reproduction, so the individuals carrying the mutation will outcompete the ones that don't -- in other words the mutation is selected for. Note that reproductive lifespan doesn't enter into this argument: it is sometimes included in such discussions but it shouldn't be, because reproductive lifespan tracks total lifespan in evolution.

As an aside, my contention is that one doesn't actually need the energy component of the above argument to make it work -- that even if there is no gain in available energy from mutations of the sort I just described, they'll still accumulate, just because there's no selection against them. But that's not the disposable soma theory. Actually, to be scrupulously accurate, the above isn't the disposable soma theory either... the trade-off argument above was first advanced by Edney and Gill in the late 1960s, a decade before Kirkwood. Kirkwood repeated it, but he also added a totally new idea that really is the disposable soma theory, namely that maintenance in the germ line will be selected to be much better than in somatic tissues because somatic tissues only have to keep going for one organismal lifetime.

Since these ideas were first raised there has been a steady stream of ingenious theories describing how "programmed aging" can be selected for, i.e. how machinery that accelerates aging can evolve and be maintained by selection. I think they're all bunk, as do most mainstream gerontologists, but I don't dismiss the concept out of hand forever -- that would be a trifle hypocritical, perhaps...

Which allows me to drag this thread back to its title. My last answer to Prometheus was to point out that he seems to need to propound programmed aging in order to defend his thesis that telomerase stimulation in humans might be protective both against cancer and against other aspects of human. I haven't seen an answer to that yet.

#23

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Posted 19 June 2006 - 12:24 PM

My last answer to Prometheus was to point out that he seems to need to propound programmed aging in order to defend his thesis that telomerase stimulation in humans might be protective both against cancer and against other aspects of human. I haven't seen an answer to that yet.


My interpretation of the data is that there is a sense of biological intent in having telomerase supporting genomic stability via two radically different mechanisms: classic telomere maintenance and the newly reported role of ROS-mediated apoptosis. In fact this new role threatens to upend the widespread thinking that explained the inhibition of telomerase expression in somatic cells as selected to prevent cancer. A more fitting explanation would be that its expression is inhibited to conserve energy since that level of genomic purity is not essential in somatic cells. Furthermore, telomerase only presents as a cancer threat if its ability to be exported from the nucleus and imported to mitochondria is compromised and therefore the pathway associated with its phosporylation, export and import should be investigated both in a diagnostic and therapeutic context.

I don't think that answers your question -- but it was you that brought up programmed aging when you said, "In other words, your argument seems to rely on "programmed aging" - right?".

My argument on the misinterpretation of telomerase can stand solely on the new report but it does lay a challenge for you to rationalize WILT.

#24 jaydfox

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Posted 19 June 2006 - 01:53 PM

Luckily, by the time WILT (as a whole) is technically feasible, the status and role(s) of telomerase (bad, indifferent, or possibly good) will have been much better determined, and if necessary, WILT proper can be discarded, leaving the WILT scaffolding for all its usefulness.

#25 John Schloendorn

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Posted 19 June 2006 - 05:51 PM

by the time WILT (as a whole) is technically feasible

Technical feasibility isn't decreed by fate. The question here is, how heavily should we invest today, in order to make it technically feasible...
(Although I will agree that some WILT scaffolding techniques will get developed "by default", we need to ask how heavily we should invest to develop those that won't.)

#26 jaydfox

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Posted 19 June 2006 - 06:32 PM

Technical feasibility isn't decreed by fate. The question here is, how heavily should we invest today, in order to make it technically feasible...
(Although I will agree that some WILT scaffolding techniques will get developed "by default", we need to ask how heavily we should invest to develop those that won't.)

In the past, I thought we should focus less effort on WILT proper and more on nDNA repair. It makes sense to me, and I still think that WILT proper will never become a mainstream medical protocol.

However, I wouldn't necessarily want to "hinder" the development/research of WILT (and WILT proper). That doesn't mean I won't criticize it from time to time.

At any rate, I'm one small voice among a great many, and I don't have any medical or graduate school training, so I don't see myself having any significant sway.

#27 John Schloendorn

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Posted 19 June 2006 - 11:03 PM

Caston,
How would aging selectively reduce inbreeding, while not affecting other breeding? Neither you nor this site offer any explanation.

#28

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Posted 20 June 2006 - 12:05 AM

Since these ideas were first raised there has been a steady stream of ingenious theories describing how "programmed aging" can be selected for, i.e. how machinery that accelerates aging can evolve and be maintained by selection. I think they're all bunk, as do most mainstream gerontologists, but I don't dismiss the concept out of hand forever -- that would be a trifle hypocritical, perhaps...


I don't see why the notion of a programmed theory of aging is so unpalatable. We have a programmed theory of development that is incontestible. If we look at cell death we see in apoptosis a remarkably organised sequence of events (compare with necrosis). Aging in a tissue and organ level seems to be similarly organised. We do not see limbs dropping off or organs liquefying spontaneously.

Whilst there are numerous compensatory mechanisms to mitigate for cell/function loss there seems to be an underlying pressure that drives aging relentlessly which in humans commences around the age of 20. Yet if we take the same cells destined for senescence and death and culture them in vitro, under the right condtions their fate is altered and their lifespan is extended dramatically (the challenge remains to do this in vivo). The only explanation is that restrictions exist in vivo that do not in vitro (and can thus be lifted). Another word for restriction: program.

We can accept that a program exists to conserve energy yet the notion that the same program contributes to aging is controversial, which of course is way past hypocricy and bordering on absurdity.

#29 caston

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Posted 20 June 2006 - 02:57 PM

John: If you went back in time and met a female relative of yours like a aunt, mother or even grandma when they were the same biological age as you there is a chance you might find them attractive.

Remember back to the future part I where McFly's mum tried to crack onto him when he went back to the 60's?

Also a stronger and wiser unaging animal could enforce breeding dominance in a pack which could already be mainly comprised of its own off-spring. This pack would be weaker (due to inbreeding) and eventually defeated by a pack comprised of "fresh" animals.

I've been reading that first pdf that Opales linked to and it does talk about Weismann. I have a bit of catching up to do. I e-mailed J. Coetzee about his site and the theory and gave a link to this forum topic. I think the biggest thing though is a distinction between aging and terminal aging but then again Medawar says they almost never get to the stage where they show signs of declining function.

~"And evolution typically extends a species reproductive lifespan in tandem with it's total life span."
http://www.msnbc.msn.com/id/10879638/


I had a question that I moved to the
Telomerese ang aging thread

Edited by caston, 01 July 2006 - 08:07 AM.


#30 1966

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Posted 04 July 2006 - 08:14 PM

Making a work in social medicine, I learned that cancer of small intestine is not very frequent.
However, epithelial cells in the small intestine live only a few days, and must be replaced by divisions of stem cells in the small intestine. Stem cells are associated with activated telomerases.
But, in spite of frequent divisions of stem cells in the small intestine. carcinomas of the small intestine are not frequent (comparing, for instance, to stomach; however, stomach is, perhaps, more exposed to external detrimental influences, than the small intestine is).
Small intestine is an example that frequent divisions of stem cells need not, necesserily, lead to frequent cases of cancer.




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