13 replies to this topic

[rahein]

This is good news.

It seems that telomerase is even more a fountain of youth that I had thought. The study mentions that fibroblasts that are taken orally was how the telomerase was administered. I wonder if this is an safe, effective, and a mass producible way of getting a telomerase suppliment. I would start taking it the day it went on the market.

[rahein]

I miss understood what part of the post that Prometheus corrected me on.
They where using the fibroblasts from oral cells, not administering it orally.

[henri]

This additional benefit of telomerase now brings to question how strong its association with cancer really is. In other words, is the presence of telomerase the defining difference between the cancer and normal cell? Of course not. We know that there are other even more important factors that define a cancer cell such as indifference to surrounding cells and the extra cellular matrix, potential for migration and abnormal growth factor secretions and responses. Therefore, telomerase should be lowered on the scale of importance in what constitutes a cancer cell and therapeutic strategies are better off focusing on dealing with the migration (malignancy) potential of cancer cells.

But could cancer cells acquire their combination of properties if telomerase didn't remove the Hayflick's limit?

de Grey states:

"In about 90% of human cancers, however, TERT [the reverse transcriptase part of telomerase] is highly expressed and telomere length thereby stabilised...

In practice, since cancer progression in humans requires many more than two mutations (except some
rare childhood cancers), there are probably at least a few hundred cell generations between the
originating non-mutant cell and the clinically relevant cancer. It is this that makes prevention of
telomere elongation a realistic way to prevent cancers from ever reaching an advanced stage. No human
cell has ever been observed to divide more than 100 times without telomere elongation machinery."

By the way, do mice get metastatizing tumors?

[Mark Hamalainen]

t seems that telomerase is even more a fountain of youth that I had thought.

First of all, that is a highly premature sentiment. And I would strongly advise against taking supplements (assuming they become available) until we know a great deal more.

There are a number of reasons for caution.

DNA repair is impaired in mice with telomere dysfunction (19 , 20).

Following their references it is clear that this statement is only correct in a very specific context.

19. Wong KK, Chang S, Weiler SR, et al Telomere dysfunction impairs DNA repair and enhances sensitivity to ionizing radiation. Nat Genet, 26: 85-8, 2000.

20. Goytisolo FA, Samper E, Martin-Caballero J, et al Short telomeres result in organismal hypersensitivity to ionizing radiation in mammals. J Exp Med, 192: 1625-36, 2000.

That context being late generation tert(-/-) mice. Cells with short telomeres have increased incidence of apoptosis upon irradiation, not too suprising.

The results of the paper itself are more interesting:

The hTERT-induced enhancement of DNA repair was demonstrated in four different ways. First, in NHOF expressing telomerase activity treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the mutation frequency of the replicating pS189 shuttle vector was decreased. Second, NHOF expressing telomerase activity had a higher repair level of exogenous DNA damaged in vitro by MNNG. Third, NHOF expressing telomerase activity showed a faster rate of nucleotide excision repair (NER) in both strands of an endogenous cellular gene. Fourth, NHOF expressing telomerase activity had a higher rate of DNA end-joining activity. The parental primary NHOF and five hTERT-negative clones served as controls.

However, this doesn't mean that telomerase is a fountain of youth. Telomerase enhanced the rate of repair, however it is possible that the normal rate of repair is sufficient under normal circumstances. Speed is not everything, accuracy is important too, telomerase associated repair could be less accurate.

Prometheus:

In other words, is the presence of telomerase the defining difference between the cancer and normal cell? Of course not.

No, but it is a factor. Do the possible benefits of telomerase expression outweigh the increased cancer incidence? Do these benefits really exist in vivo?

Has there been a study in which mice were engineered to overexpress telomerase in all or some tissues?

[John Schloendorn]

Yes. It did not affect induced carcinogenesis, did increase sponatneous mammary carcinomas in aged females, but did not affect many other types of spontaneous cancers.
However, in humans the story might be entirely different (worse outcome) because telomeres are much shorter.

[John Schloendorn]

"Benefits" exist, too, if you call increased angiogenesis a benefit ;-)

[Mark Hamalainen]

I guess the question is: can you reap the benefits without suffering the side effects? Or can we find a cure for cancer that doesn't require WILT?

I've previously suggested engineering tissues to facilitate cancer treatments and replacing our normal tissues, but I didn't offer any specifics. Perhaps it would be a good time for some brainstorming?

[jaydfox]

Harold and I had the WILT debate out with Aubrey and I think Michael Rae. We basically asserted that WILT will likely be unnecessary, for a lot of reasons.

First, timing. By the time we can get WILT working and ready for mass distribution to the public, something better and less drastic will come along within a couple decades at most, meaning that the only people who would likely benefit would be people in their 70's and older, and definitely people in their 80's an older: that's a small market, so I doubt any but the wealthy will get the treatment.

Younger people (60's and younger, but especially 50's and younger) would likely be put at more risk than any possible benefit they could see.

Also, the risks involved with missing reseeding operations mean that we could take people with 30-40 years left and put a ten-year ticking time-bomb into their gut, blood, and skin systems. Pragmatically speaking, the risks seems to outweight the benefit, except as I said, for the very old.

By the time we have WILT ready to roll, cancer will be a treatable disease, meaning it will at most be a chronic impediment, but non-lethal, for the majority of its sufferers. At that point, just getting people to hold on for something better than WILT would be a better option, again except for the very old.

Finally, I should point out that about 90% of the WILT proposal will probably end up in the "better" treatment I speak of. It will build on the "WILT scaffolding", as I called it, but use a cell ablation strategy other than "WILT proper". Such a cell ablation strategy might rely on a retuning of tumor suppressors, DNA repair and maintenance, and pharmaceuticals (such as periodically using telomerase-inhibitors). It's too early to tell, but we know that other mammals have done a much better job than humans, without deleting their telomerase genes. WILT proper is just too drastic to be pragmatically applied to the entire population. I foresee a subset of wealthy 70+ year olds getting the therapy, but I don't see it ever being applied to the general public.

[Mark Hamalainen]

By the time we have WILT ready to roll, cancer will be a treatable disease, meaning it will at most be a chronic impediment, but non-lethal, for the majority of its sufferers. At that point, just getting people to hold on for something better than WILT would be a better option, again except for the very old.

I think its dangerous to assume that cancer will be treatable before WILT is ready. Do you have any specific reasons to think that will necessarily be true? I don't necessarily disagree, I just think we should cover all our bases and develop WILT proper as well. It may find more specific uses, such as being a built in failsafe for engineered tissue therapy for specific organs (not the whole body as WILT proposes).

[jaydfox]

No doubt. But we shouldn't put all our hopes on WILT proper. We'll most likely have to develop the WILT scaffolding no matter what, and WILT proper will have its uses, as you say.

However, we need serious high and low level discussions of alternatives to WILT proper, and the current SENS platform didn't include such. Which was the message Harold and I were trying to convey. Research WILT proper, and research the WILT scaffolding, but keep in mind that the two are quite separate for the most part, so don't discuss it as a package deal.

It's not a package deal. I think we got the message across, as newer versions of the SENS website discuss delivery methods a little more separately, but there's still no acknowledgment of a need to pursue alternatives to WILT proper. But then again, any specific SENS platform needn't consider this. As of this time, de Grey's SENS platform is the only comprehensive such platform I'm aware of, and hence it needs to have such backups and alternatives to provide comprehensive strength against the rebuttal from biogerontologists that we're all holding our breath waiting for (anybody pass out yet?).

As for cancer, I've seen many projections from high level "experts" that we'll have cancer under control by 2015, which is ten years away. That's less than half the minimum timeframe for having the full WILT therapy available for even the mega-rich, so even if we double the ten year timeframe to twenty years, I think that's a reasonable guess. As de Grey points out, this is just to control individual cancers. The cancer incidence rate will likely remain unaffected, so people will eventually be dealing with multiple cancers. So even getting to such a "chronic illness" stage will only buy people a decade or two, but it's more than the current few-year prognosis for the elderly (37% don't survive the first five years, and most of the survivors are typically not elderly).

I still would support using WILT on 80-year-olds, maybe even 70-year-olds. But we need a therapy we can apply on 60-year-olds and younger, and WILT is not that therapy.

[Mark Hamalainen]

Fighting off/holding back those individual cancers seems like lifting people up higher and higher off the ground before and eventual and inevitible fall. Reading the discussions you've had on alternatives to WILT, they all sound like they will only augment this problem in the end. Eventually (30+ years from now) we will need WILT or something as powerful as it. I've suggested chromosome synthesis to maintain information content and massive tissue replacement with built in suicide mechanisms to facilitate cancer treatment and subsequent tissue therapy. However, this does not help us with the brain, whereas WILT might (once we achieve efficient gene therapy). Any other suggestions?

[apocalypse]

Fighting off/holding back those individual cancers seems like lifting people up higher and higher off the ground before and eventual and inevitible fall.  Reading the discussions you've had on alternatives to WILT, they all sound like they will only augment this problem in the end.  Eventually (30+ years from now) we will need WILT or something as powerful as it.  I've suggested chromosome synthesis to maintain information content and massive tissue replacement with built in suicide mechanisms to facilitate cancer treatment and subsequent tissue therapy.  However, this does not help us with the brain, whereas WILT might (once we achieve efficient gene therapy).  Any other suggestions?-osiris

I believe that if we can add/deliver gen mods to provide additional measures against cancer dev. and we can safe and precisely deliver massive amounts of genetic information to individual cells in-situ at sufficient time intervals, wilt should not be necessary. I also think such a thing is probably technically possible in less than 50yrs.

[Mark Hamalainen]

I believe that if we can add/deliver gen mods to provide additional measures against cancer dev. and we can safe and precisely deliver massive amounts of genetic information to individual cells in-situ at sufficient time intervals, wilt should not be necessary.

Oh is that all? damn, you make it sound so easy... [sfty]