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telomere loss


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#1 brokenportal

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Posted 09 August 2006 - 01:27 AM


Which part of sens deals with telemore loss?

I asked somebody to tell me why life extension isnt good or a feasable idea the other day and they said that our cells are programed to die. Ive read about telomeres and done reports on it and everything, but somehow over the years I have lost site of it. People hardly ever bring it up when I talk about life extension because they dont know about it I guess. Anyways, thats when I suddenly realized, Im not sure which part of sens deals with telomeres. What is the answer to somebodies response that our cells are programed to die through telomere loss and so we cant live indefinite life spans?

#2

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Posted 09 August 2006 - 01:48 AM

No part, directly.

(I would tend to agree with your friend: the vast majority of our cells are programmed to die. A few from each generation have the potential to survive (from the germ line))

SENS actually seeks to remove telomerase (the enzyme that repairs telomeres) from all cells to deal with the problem of cancer. To compensate for the inevitable cellular catastrophe that would ensue (stem cells and germ line cells need telomerase) SENS then seeks to have people undergo periodic replenishment with fresh stem cells. This is the indirect way SENS deals with telomere loss.

This particular SENS strategy is the one I have the most issue with.

#3 brokenportal

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Posted 09 August 2006 - 01:54 AM

Which part of sens is that indirect part of removing telemorase to deal with cancer in? Also is there a link where you may have gone over your reasons for having issue with it I could check out? and or, could you sum it up here?

#4

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Posted 09 August 2006 - 07:18 AM

WILT = Whole-body Interdiction of Lengthening of Telomeres.

It had been comprehensively debated:

http://www.imminst.o...f=173&t=7669&s=
http://www.imminst.o...f=173&t=3906&s=
http://www.imminst.o...f=173&t=5434&s=

I would call WILT dead in the water.

#5 ag24

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Posted 09 August 2006 - 07:49 PM

In case it wasn't clear, the way that this approach would deal with telomere loss is that the newly-introduced stem cells would still not have any telomerase genes but they would have had their telomeres extended to youthful lengths in vitro. In case anyone doesn't know, this ("WILT") is also the SENS strategy that I myself have the most issue with, i.e. acknowledge is the most difficult. I continue to encourage and cross-fertilise alternative ideas for dealing with cancer as effectively as we will need to do to achieve escape velocity, and no one will be happier than I if and when something good enough comes along. Where I differ with Prometheus, as covered ad nauseam in these forums, is that he thinks other approaches already on the table (or, at least, much closer than WILT) will be good enough, whereas I prefer to give cancer the respect it deserves and devise a plan B if other therapies go the way of existing ones.

#6 jaydfox

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Posted 09 August 2006 - 07:55 PM

The other area that you differ with Harold (and with a number of others), is that you think that cancer is the only consequence of nDNA damage worth having a strategy to deal with (for a few reasons, such as that you think the other consequences of nDNA damage won't matter in a currently normal lifespan, and you think that other aspects of SENS will partially deal with nDNA damage by default anyway, e.g., restoring methylation states to something more normal just by changing the cell's environment, etc.).

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Posted 10 August 2006 - 03:23 AM

Where I differ with Prometheus, as covered ad nauseam in these forums, is that he thinks other approaches already on the table (or, at least, much closer than WILT) will be good enough, whereas I prefer to give cancer the respect it deserves and devise a plan B if other therapies go the way of existing ones.


I sounds like Aubrey is implying that I do not respect the seriousness of cancer. Ironically, based on his consistent disregard for calls to review the validity of WILT it is Aubrey who appears to place PR above scientifically legitimate, practicable, implementable interventions for cancer.

Firstly, what WILT sets out to do is no more sophisticated than classic cancer treatments involving chemotherapy/radiotherapy followed by a bone marrow transplant. In place of chemo/radiotherapy WILT seeks to eliminate the segment of DNA that encodes the telomerase gene from every single nucleus in the body. In place of bone marrow transplants WILT seeks to supply the patient with periodic infusions of stem cells. Aubrey thinks that the frequency of these stem cell upgrades will have to be every 10 years. Astonishingly he ignores the fact that some cells in the body need to get replenished every 24 hours and without telomerase a cell can only divide for approximately 50 times before it becomes senscent. More disturbingly, he has chosen to completely disergard the consequences of deleting the telomerase gene particularly in light of new functions that have been recently atributed to it. Finally, given that such a fantastical intervention as being able to genetically engineer telomerase out of every single cell becomes possible why on earth would we resort to such unelightened intervention strategies when we have the power to gloablly modify every single cell in the body?

I will propose an alternative that is possible to be engineered with today's technology: it is known that tumorigenic cells have gene expression profiles that are not shared by non-cancer (normal) cells. Therefore it is possible to construct a viral delivery vehicle that contains an apoptosis gene that is driven by one or more cancer specific promoters. In other words this cell suicide gene will be expressed inside a a cancer cell. To make the treatment more specific, the viral delivery vehicle can be targeted only to particular types of cells based on cell surface proteins expressed in the target cancer type.

Yet even the above solution appears unnecessarily convoluted when one considers the recent discovery that cancer resistance is transferable as was recently demonstrated in a strain of completely cancer resistant mice. It is likely that within the human population, individuals exist that are variably resistant to cancer and the transfer of that resistance could be as simple as blood transfusion. Imagine rather than surgery, chemo, radiotherapy, etc. one simply has to find a tissue matched donor for a white blood cell transplant from an individual with a cancer resistant phenotype.

#8 jaydfox

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Posted 10 August 2006 - 03:52 AM

Astonishingly he ignores the fact that some cells in the body need to get replenished every 24 hours and without telomerase a cell can only divide for approximately 50 times before it becomes senscent.

Well, it's not as simple as that, as you have 3-4 intervening generations of cells with varying levels of stemness. 40^3 days is longer than a human lifetime. But wait, there's more!

Besides that, in the intensintes (small intestine?) you have 6 stem cells (or possibly just one!) feeding a colony of roughly 3,000 cells, each of which turns over on a roughly daily span of time. 40^4 cells would last about 2-3 years in this scenario (assuming 4 generations of stem cells dividing 40 times each). 6x(40^4) is 14 years. But most of those intervening layers don't divide anywhere near the 40+ times they theoretically could, some as few as 2-3 times. But this theoretical calculation work can be sloppy. The true number requires more investigation. More hard research. Aubrey might be right. He might be wrong. I honestly don't know and can't fairly guess. But I am concerned about it.

For now, Aubrey's gut (no pun intended) tells him that 10 years will be sufficient, but the evidence is not unequivocal (would be nice if it were). The evidence is open to interpretation, leaving us mere mortals to take the words of experts for granted.

#9 jaydfox

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Posted 10 August 2006 - 04:23 AM

While I'm on the subject of the small intestine, I decided to dig this post up and dust it off:
http://www.imminst.o...ST&f=173&t=5417

what is critical to understand is the total proliferative capability of the ultimate stem cells. The six ultimate stem cells must service three villi, each of which has 3,500 cells. Those cells turn over (ablation through apoptosis and/or release into the small intestine) about once every 1-3 days. This means that 10,500 cells must be replaced on a near-daily basis by only six ultimate stem cells. That works out to about 1,750 cells every 24-72 hours, per ultimate stem cell.

This workload is staggering.


I wrote that a year and a half ago. Needless to say, I don't recall all the details of Potten's work. I'll have to re-read that some time soon, as well as read more recent work, as well as find and re-read Aubrey's rebuttals to it (well, to its implications for WILT and the nDNA strand of SENS in general).

#10 ag24

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Posted 10 August 2006 - 10:20 AM

> The other area that you differ with Harold (and with a number of others), is that you think that
> cancer is the only consequence of nDNA damage worth having a strategy to deal with

Yes obviously - but that's not this thread.

#11 ag24

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Posted 10 August 2006 - 10:21 AM

> Potten's work

The key problem is that inbred telomerase knockout mice get gut ptoblems no sooner than they get skin and blood problems.

#12 ag24

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Posted 10 August 2006 - 10:23 AM

> consistent disregard for calls to review the validity of WILT

There you go again.

If cancer's so easy to fix, you would be better employed getting cancer researchers to implement your suggestions than posting your musings (and misrepresentations of my musings) here. Go away and get on with it.

#13

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Posted 11 August 2006 - 09:15 AM

I can't keep up with anyone in this topic.


Adam, the following pic shows the symptoms associated with dyskeratosis congenita which is associated with reduced telomerase function. Note the similarity with the aging phenotype.

Attached Files



#14 ag24

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Posted 11 August 2006 - 11:38 AM

> Dyskeratosis congenita (DS) sufferers have reduced telomerase activity as opposed to the
> WILT model which would entirely stop all activity.

Is this supposed to be an attempt to correct me? Did I not just say "DKC is not a telomerase knockout"?

> Note the similarity with the aging phenotype.

And your point is? It's not exactly surprising that stem cell depletion without the periodic replenishment suggested in WILT has widespread degenerative effects.

> The value of using mouse telomerase negative models to extrapolate in human physiology
> is questionable since it takes 5 generations of telomerase negative mice before symptoms
> associated with telomere shortening begin to appear.

If that were so, why do you think anyone works with such mice? If you have a SPECIFIC argument why the non-requirement for telomerase in normal-telomere-length mice invalidates my SPECIFIC argument about gut stem cells, kindly state it, rather than waving your hands.

Telomerase activity in autosomal dominant DKC is 50% (it is a heterozygous knockout of the RNA component of telomerase), and it only has early onset in the children of people who had it with adult onset, in other words it's due to telomere shortening in the germ line ("anticipation").. In X-linked DKC (which has childhood onset), activity is about 20%. (Check out refs by Inderjeet Dokal for all the above.) Thus, a true knockout should not be all that much worse than X-linked DKC -- bad enough to be prenatal lethal though. The fact that DKC has childhood onset does not challenge this and likewise does not tell us that we would need the replenishment more often than the once a decade that WILT proposes, because DKC sufferers had telomerase insufficiency throughout prenatal life, when stem cell division was far more frequent than in adulthood.

This - is - all - in - the - WILT - papers (or papers cited therein)..... as prometheus knows perfectly well, thus yet again demonstrating that he cares more about quixotic attempts to prove he's a good "fighter" than about not wasting my time. Prometheus, had you considered that John's encouragement to you to write up your thoughts might be a gentle way of telling you that that way you might find out the difference between fighters and scientists?

#15

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Posted 13 August 2006 - 09:57 PM

Gosh, I'd never thought of that!

Unbelievable.

Not every reader of this topic is a cell biologist familiar with the mitotic behavior of stem cells. It is all too easy for a non-biologist to assume that because 50 population doubings = 2^49 cells there would be sufficient cell numbers despite no telomere maintenance.

#16 ag24

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Posted 13 August 2006 - 10:27 PM

Interewsting (though unsurprising) to see you carefully omitting any mention of transit amplifying cells, thus encouraging such people instead to make the opposite mistake of thinking that 50 doublings = 51 cells....

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Posted 13 August 2006 - 10:37 PM

Interewsting (though unsurprising) to see you carefully omitting any mention of transit amplifying cells, thus encouraging such people instead to make the opposite mistake of thinking that 50 doublings = 51 cells....

50 asymmetrical stem cell doublings will result in only 50 stem cells. This is the reason telomere maintenance is essential for stem cells.

You should take this opportunity to explain how 6 stem cells and 20-30 transit amplifying cells (according to the recent model) can sustain a region > 12,000 cells with a daily turnover. Be mindful to explain that contact inhibition and other restrictions on differentiation ensure that only 6 SC and 20-30 TC may exist at anyone time per crypt.

#18 ag24

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Posted 13 August 2006 - 10:48 PM

No, I don't need to explain any such thing, because I've dealt with this in detail in the WILT papers and this and previous threads -- as everyone else here remembers, despite your best efforts.

Just for you though, 50 asymmetrical stem cell doublings results not in 50 stem cells but in one stem cell and 50 progenitor (transit amplifying) cells. I have a feeling you can take it from there, if you so choose.




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