72 replies to this topic

[ag24]

> Small intestine is an example that frequent divisions of stem cells need not,
> necesserily, lead to frequent cases of cancer.

Right -- this is a very important point, and indeed it can be generalised somewhat. By and large, tissues with constant renewal (gut, blood, skin) are not the most cancer-prone: ones with much slower turnover (liver, lung, breast) are more cancer-prone. (Incidentally, not too much faith should be put in the idea that gut stem cells divide much more often than blood or skin: the evidence for this is rather indirect and the fact that telomerase knockout mice get blood and skin problems just as soon as gut problems contradicts it.) It's indeed clear that having telomerase expression (at low levels) does not actively predispose cells to become cancerous. However, while it's possible that telomerase helps these stem cells not to accumulate mutations, there are quite a few alternative possibilities. One that has had a fair bit of attention over the years is the "immortal strand" hypothesis, which proposes that stem cells partition their DNA at cell division so that the daughter which is set on the path to differentiation has the parent cell's "young" strand (the one synthesised at the previous cell division) as its old strand. I think this hypothesis is more or less dead now because it only works if virtually all stem cell divisions really are asymmetrical (giving rise to one stem cell and one differentiating cell), and we now know that in fact "self-renewing" divisions occur (in which both daughters are stem cells). And that, in fact, is the clue to what I would say is the most straightforward explanation for why continuously renewing cell types are not particularly cancer-prone. Since stem cell numbers can be maintained by doing self-renewing divisions when a nearby stem cell dies, it's possible for stem cells to have really hair-trigger apoptotic responses to DNA damage, which indeed they do. In tissues where cell turnover is slower, cells take more punishment before apoptosing. Why? Well, a rather persuasive answer in my view is "why not?": in other words, those cells can afford to tolerate more damage because they are inherently less cancer-prone than the continuously renewing stem cells. What makes them less cancer-prone? Well, the fact that their telomerase is more thoroughly turned off is a bit of a smoking gun...

I know that what I've given here is only a hypothesis for why cancer should be roughly of equal incidence in continuously renewing and slowly renewing cell types, and not for why it's actually *lower* in the continuously renewing ones. I don't have a good answer to that, but I think the first thing to answer (or at least, to identify the range of possible answers to) is why cancer levels are not much higher in continually renewing tissues than in slowly renewing ones, and I think the above is a satisfactorily economical model.

[nazgul]

Can we produce a telomerase without the mitochondrial forwarding tag? Perhaps just fill in a dummy sequence on that section of the enzyme. Any hack that could extend our useful lifetimes would seem beneficial as researchers looking for a better solution would have more time to conduct further experiments without being slaves to the naturally high turnover rate.

[nazgul]

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

Aging necessarily prevents cross-generational inbreeding spanning more than just a few generations. Sort of an anti-incest device perhaps.

However, I think this is more of a coincidence than a selected for trait. I have a feeling we're to a large extent ad-hoc and that some things that don't make much sense (like our backs being prone to injury or our eyes being so easily misshapen and out of focus. Look at a cephalapod eye vs ours, our blood vessels are on the wrong side of the retina, blocking light, and they flex their eye instead of their lens for focus too, pure accident). I think these things must be looked at as vestigal remnants from our evolutionary past, and are not necessarily the best or even decent designs. Just barely passable over the organisms we were competing with is enough to lock in what is in hindsight a ridiculous mistake. Personnally, I can't wait for a complete overhaul!

[nazgul]

Oops, I meant a lowering of the turnover rate of researchers, and thus an extension of their useful careers, not of the cells that compose the researchers!

Thanks for the links. Looks like I have a lot of reading to do to get up to date on these subjects.

[ag24]

One more time: the default state is a much greater inherent instability in DNA than can be tolerated in the soma, let alone the germ line, so the optimum mutation rate in the germ line will be achieved auomatically just by the diminishing selective pressure to lessen the mutation rate as that rate falls closer to the optimum. No genes or genetic pathways to actively raise the mutation rate are needed. Hence, there is no conflict between the maxim that aging is not selected for and the need for mutation to allow evolution to occur.

The core reason why the notion of a programmed theory of aging is so unpalatable is basically a generalisation of the above. Aging -- physiological decay -- happens by default, and its default rate is much faster than any living organism could tolerate even briefly, let alone long enough to procreate. Thus, we have anti-aging (i.e., self-maintenance) machinery, and longer-lived organisms have more sophisticated anti-aging machinery than shorter-lived ones. The only things we need (hence, will evolve and retain during evolution) machinery for are things that wouldn't happen by default. So salmon have pro-aging machinery that kicks in after reproduction, but that's because they've been selected for a type of aging that would not happen by default, namely very rapid aging triggered by reproduction.

[ag24]

Not spontaneous degradation, intrinsically imperfect replication and repair.

Hupermutation in the immune system is evolved lust like semelparity - we need it and it wouldn't happen by default so we hsve machinery for it.

My argument against your hypothetical scenario is not as you say but rather than your scenario would never arise because no selective pressure ever existed to make DNA replication and repair "superbly accurate" in the first place.

But you knew all this, so you're obviously not trying.

[jaydfox]

when radiation levels were higher than they are today.

Isn't this thought to occur every couple million years when the earth's magnetic field reverses polarity? Not sure if the increase is much, but it is predicted.

[zhanguolao]

OK. I only have an undergrad biology degree from 1986, so it is very possible I just don't understand something important with regard to my next statement. If evolution selects for reproductive fitness, then longevity would seem to have no inherent role in the process beyond a certain point. Perhaps the issue of telomere shortening is merely that there was just not any selective pressure for it not to happen. If most humans rarely lived past 40 for most of the history of the species, then it would seem the issue of tumor suppression is just an artifact of no particular meaning. Add to that that telomere shortening does not prevent modern long lived humans from succumbing to cancer as one of the leading causes of death. Maybe telomeres shorten because the pathways that lead to this event just evolved by chance and were efficient enough to do the job of evolution. Again, I reiterate the likely dimness of this post.

[ag24]

The general consensus in the field is that without telomerase suppression we would get (and die of) cancer a good deal younger than we do, quite possibly well before the age of 40. If so, evolution would indeed select for telomerase suppression in order to delay death from cancer -- not indefinitely, as you say, but until an evolutionarily insignificant age.

[rshack]

It appears my posts have been removed. I find this offensive. So much for free discussion.

[John Schloendorn]

It is possible that they were moved to a non-public place due to certain personal tensions that had arisen during the discussion, which we did not want to publicize. If this is what happened, then it was unrelated to the contents of your posts, but rather to the style of the surrounding posts by others. We apologize for this emergency situation, and are working to resolve it.

[netesq]

I've been following this discussion for quite some time, and I'm somewhat perplexed by Aubrey de Grey's objections to taking the results of the telomerase study in question at face value. To wit, if the study in question demonstrates that telomerase is a safe and effective way of rejuvenating senescent somatic cells, does it really matter how and why humans evolved in such a way that telomerase activity came to be suppressed in most somatic cells?

Having taken my fair share of graduate level courses in physical anthropology, I can state with some certainty that there is no such thing as a consensus among the experts when it comes to the how and why of most evolutionary mechanisms. Indeed, there is a great deal of infighting among the experts, so much so that the anthropology department that awarded me my bachelor's degree voted to disband shortly after I decided to transfer there in my third year of undergraduate studies. The anthropology professors changed their minds about disbanding their department when they figured out that no other departments at the university were willing to take them in.

Having read most of the studies linking telomerase activity and cancer, I can say with some certainty that Dr. de Grey is correct in stating that there is a general consensus among the experts that cancer would be out of control in humans but for telomerase suppression. However, the study cited at the beginning of this thread indicates that the general consensus is just plain wrong about this. Indeed, there is a great deal of evidence to indicate that cells with shortened telomeres are much more likely to become cancerous.

Virtually all of the studies linking cancer and telomerase activity deal with malignant tumors being treated with telomerase inhibitors. Once malignant tumors form, artificial telomerase suppression is unquestionably a Good Thing™. Prior to that time, however, natural telomerase suppression is a short-sighted evolutionary mechanism that eventually delivers the old and feeble over to a wide variety of ailments, including cancer, through the adaptive strategy of senescence.

If one views a culture the way that a biologist views an organism, the death of an old and feeble individual is no more significant than the death of a cell, provided there is a younger individual who has been groomed to fill the role of the deceased. Indeed, senescence is a natural form of population control that insures a form of cultural homeostasis. However, speaking only for myself, I'd much rather live longer than have offspring.

Edited by netesq, 28 September 2006 - 03:03 AM.

[apocalypse]

One more time: the default state is a much greater inherent instability in DNA than can be tolerated in the soma, let alone the germ line, so the optimum mutation rate in the germ line will be achieved auomatically just by the diminishing selective pressure to lessen the mutation rate as that rate falls closer to the optimum. No genes or genetic pathways to actively raise the mutation rate are needed. Hence, there is no conflict between the maxim that aging is not selected for and the need for mutation to allow evolution to occur.

The core reason why the notion of a programmed theory of aging is so unpalatable is basically a generalisation of the above. Aging -- physiological decay -- happens by default, and its default rate is much faster than any living organism could tolerate even briefly, let alone long enough to procreate. Thus, we have anti-aging (i.e., self-maintenance) machinery, and longer-lived organisms have more sophisticated anti-aging machinery than shorter-lived ones. The only things we need (hence, will evolve and retain during evolution) machinery for are things that wouldn't happen by default. So salmon have pro-aging machinery that kicks in after reproduction, but that's because they've been selected for a type of aging that would not happen by default, namely very rapid aging triggered by reproduction.-ag24

Hmmm, yet(as pretty much all of us know) even single mutations confer substantial life extension in some organisms, without obvious detrimental consequences(with regards to the individual), and don't manage to predominate in the populations of said organisms... this alone would seem to be a good example of even such subtle antiaging use of present machinery being selected against. Also within some social species, there exist vast(orders of magnitude) differences in organism lifespan, organisms with the same genome yet being made such that they die much much sooner than their genetic potential can actually achieve, intraspecies modulation of the aging process. With the further evolution of multicellular organisms we saw the power of selection at the level of groups, how a group cooperating and specializing, could at the cost/loss of the individual cells(in time most such cells lossing their ability to spread their genes outside the organism) could outcompete those that did not do so. The same was seen with solely sexual reproduction at the cost of the individual and the amount of genetic material it was able to pass, the species prospered.

We have seen how not only at the cellular level can programmed death and limitations on the ability to pass genes to future generations occur, but at the level of multicellular organisms, with the use of sexual reproduction and in some organisms with subgroups having the reproductive potential. So as far as I see it, and as I've said previously, it wouldn't be out of the question for there to be even more things that compromise the individual but improve the survival of the species.

OK. I only have an undergrad biology degree from 1986, so it is very possible I just don't understand something important with regard to my next statement. If evolution selects for reproductive fitness, then longevity would seem to have no inherent role in the process beyond a certain point. Perhaps the issue of telomere shortening is merely that there was just not any selective pressure for it not to happen. If most humans rarely lived past 40 for most of the history of the species, then it would seem the issue of tumor suppression is just an artifact of no particular meaning.  Add to that that telomere shortening does not prevent modern long lived humans from succumbing to cancer as one of the leading causes of death. Maybe telomeres shorten because the pathways that lead to this event just evolved by chance and were efficient enough to do the job of evolution. Again, I reiterate the likely dimness of this post.-zhanguolao

Fitness begins to decrease long before an advanced age is reached, and some of the antiaging mutations/mechanisms seen in other organisms seem to prolonged healthspan(which begins decaying progressively long before an advanced age is reached.) and sometimes increases in resistance(e.g. resveratrol endurance increase in mice, improved stress resistance in mutants, etc.).

Virtually all of the studies linking cancer and telomerase activity deal with malignant tumors being treated with telomerase inhibitors.  Once malignant tumors form, artificial telomerase suppression is unquestionably a Good Thing™.  Prior to that time, however, natural telomerase suppression is a short-sighted evolutionary mechanism that eventually delivers the old and feeble over to a wide variety of ailments, including cancer, through the adaptive strategy of senescence.

If one views a culture the way that a biologist views an organism, the death of an old and feeble individual is no more significant than the death of a cell, provided there is a younger individual who has been groomed to fill the role of the deceased.  Indeed, senescence is a natural form of population control that insures a form of cultural homeostasis.  However, speaking only for myself, I'd much rather live longer than have offspring.-netesq

Adding to that, the senescent cells seem to me more like entrenching disfunctional cells at their post, so as to inhibit their replacement by efficient cells while increasing tissue dysfunction in a gradual manner, and appear to be detrimental to the organism.
Here's an old quote I posted some time ago:

Senescent human fibroblasts stimulate premalignant and malignant, but not normal, epithelial cells to proliferate in culture and form tumors in mice. In culture, the growth stimulation was evident when senescent cells comprised only 10% of the fibroblast population and was equally robust whether senescence was induced by replicative exhaustion, oncogenic RAS, p14ARF, or hydrogen peroxide. Moreover, it was due at least in part to soluble and insoluble factors secreted by senescent cells. In mice, senescent, much more than presenescent, fibroblasts caused premalignant and malignant epithelial cells to form tumors. It could be suggested that, although cellular senescence suppresses tumorigenesis early in life, it may promote cancer in aged organisms....

promote cancer

[henri]

tl;dr, but, what's the point since the stem cells in our bodies already express all the telomerase they need (and cancer arises from them)?

[telomolecular]

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...

--------------------
My website: http://www.sens.org/

>> The explanation is simple. The human cell is designed to die in a punctual way, not live as long as possible, that's why critical telomere shortening is observed in 97% of all premalignant tissues. The transient lengthening of telomeres will prevent the cellular crisiss that cause almost all cancer. Nature would not employ telomere shortening as a tool to prevent cancer if this tool was the cause of 97%. Instead we have to view cancer as a useful biological asset meant to happen in a highly planned way to regulate the ideal lifespan of the huma organism in the ecosystem. Every organism has a different ideal lfiespan and therefore, the cell degrades in different ways according to different programs.

[jaydfox]

Just so no one else gets confused by telomolecular's post, note that everything before the ">>" is quoting one of Aubrey's posts from the first page of this thread, and everything after the ">>" appears to be telomolecular's answer.

[John Schloendorn]

The transient lengthening of telomeres will prevent the cellular crisiss that cause almost all cancer

That's a bit of a hypothesis there. I hope you can figure out a way to test it.

we have to view cancer as a useful biological asset meant to happen in a highly planned way to regulate the ideal lifespan of the huma organism in the ecosystem

Where is the selective pressure to "regulate the ideal life-span" by age-related cancers in early ecosystems? It seems that in the ancenstral or medieval ecosystems where the traits in question were presumably selected, barely anyone lived to the age where most cancers manifest.

[enki273]

For the same reason cells produce the minimum quantity in all things. Economy!

Who ever heard of a non-pathological biological system that squanders resources?

That is correct, but it is an argument that can be applied on almost anything to explain why it is not seen in a greater amount. There is always some selective pressure involved. For example, the fact that there are 20 different amino acids but 64 possible codons does not mean that nature is wasteful, but is a logical necessity. On the other hand, animal species who produce a great amount of offspring which mostly dies serve a purpose even if expenditure and wins do not seem to be in an appropriate relation.
Therefore, I feel only a specific explanation can be fully convincing; referring to an overall natural economy is correct, but not very goal-directed.

[apocalypse]

Here's a recent and interesting related news article:

"Evolution, it seems, has determined which species are allowed to express telomerase in their somatic cells in order to maintain a delicate balance between cells that live long, and cells that become cancerous. But while most scientists believed an organism's lifespan determined whether it was at a higher risk of cancer, Gorbunova has revealed evidence that it is not our long lifespan that puts us at risk, but our much-heavier-than-a-mouse body mass...

For over a year, Gorbunova collected deceased rodents from around the world and had them shipped to her lab in chilled containers. She analyzed their tissues to determine if the telomerase was fully active in them, as it was in mice, or suppressed, as it is in humans. Rodents are close to each other on the evolutionary tree and so if there were a pattern to the telomerase expression, she should be able to spot it there.

To her surprise, she found no correlation between telomerase and longevity. The great monkey wrench in that theory was the common gray squirrel, which lives an amazing two decades, yet also expresses telomerase in great quantity. Evolution clearly didn't see long life in a squirrel to be an increased risk for cancer.

Body mass, however, showed a clear correlation across the 15 species. The capybara, nearly the size of a grown human, was not expressing telomerase, suggesting evolution was willing to forgo the benefits in order to reign in cancer...

Gorbunova points out that these findings raise another, perhaps far more important question: What, then, does this mean for animals that are far larger than humans? If a 160-pound human must give up telomerase to thwart cancer, then what does a 250,000-pound whale have to do to keep its risk of cancer at bay?"

news article

[telomolecular]

Cell degradation in general is a biological tool. Protein production that is important in resisting ROS for example closely parallels telomere shortening, as does cell metabolism, signaling, and DNA repair, all tools essential in combating neoplasia. This is perhaps why the telomere is less relevent in mice, because their ideal biological lifespan is short and there is no pressing need to prevent transformation, so it is allowed to happen very quickly. Evolution made a heck of a mistake if it employed telomere shortening as a means of preventing cancer, since cell crisis is caused by telomere shortening, and cell crisis is the cause of almost all cancer. Having addittional apoptosis triggers would be a far superior evolutionary trait to fight cancer, and this would be a simple modification that "would" happen if it was beneficial. The onset of cancer as well as the general slowing and aging of the cell corresponds closely with telomere shortening and seems to fit well with the prompt evacutation of the human organism from its ecosystem.

"It appears that the telomere shortening frequently observed in large advanced tumors has already occurred before it can be detected by standard diagnostic tools, when cellular changes characteristic of early precancer can only be seen through a microscope by a pathologist," says Angelo M. De Marzo, M.D., Ph.D., senior author and associate professor of urology, pathology and oncology at Johns Hopkins. "Therefore, intervention strategies aimed at preventing, or even reversing, telomere shortening may be effective in lowering cancer incidence. And assessing telomere length may provide a new direction for cancer prevention studies, and lead to improved early diagnosis of precancerous lesions."

In any event, cancer and telomeres is an increasingly less important argument since our group has been able to reconstitute dysfunctional p53 and pRB function in vivo, which eliminates tumor formation in all circumstances. You'll hear more about this over the next few years.