Visualizing Telomeres
Those of you who follow telomere research in connection with healthy life extension efforts should find this interesting - recent research that extends our understanding of human telomeres and poses a whole new set of questions:
According to Cech, the findings raise important questions about the regulation of telomerase. When telomeric DNA is buried within POT1, telomerase cannot access the DNA to elongate the telomere. "This is something that could keep the cell from making telomeres all day long," he said. "We think this is one level at which telomerase is regulated." Therefore, he said, an important next step will be to determine the cellular mechanism that switches the telomere to the on state so that elongation can occur.
It turns out that human telomere structure is quite different from that of yeast (that researchers had previously been using as a conceptual model for understanding human cellular mechanisms).
One of the engineering methods required for Aubrey de Grey's proposed methodology of reversing aging is lengthening telomeres, since the gradual shortening of telomere length with age is apparently a mechanism by which cancer becomes more common in older people. (On the other hand, rampant lengthening of telomeres is also a good way for cancer to get going, since telomeres control the normal process of cell senescence and turnover in cell populations within the body). How do we work towards lengthening telomeres throughout the body in a reliable, controlled, safe way? Well, we start by determining how human telomeres are structured - as in the work described in this post.
A spot of clarification is needed here. Cells that are able to maintain telomeres at a satisfactory length (typically using telomerase) avoid genomic instability and therefore accumulate mutations more slowly. This has, as Reason alludes to, been suggested by some people to imply that cells which express plenty of telomerase will be less prone to become cancers than normal cells (which get short telomeres and hence genomic instability if they divide a lot). But the more popular view, to which I subscribe, is that cells which don't express telomerase never divide in the body often enough to get critically short telomeres anyway, in anything like a normal lifetime, unless and until they've already acquired most of the mutations needed for becoming cancerous. Quite possibly, the turning-on of telomerase is often the only mutation still required at the time that such a cell reaches this stage, and in that circumstance the whole argument above clearly fails. Hence, my proposal is in fact to delete the telomerase genes from as many of our cells as possible, by a variety of stem cell and gene therapy techniques, and avoiding the side-effects that this would certainly cause in constantly-renewing tissues such as the blood and the gut by periodically replenishing stem cell pools with cells that have been given long telomeres by ex vivo manipulations but still have no telomerase genes. There's more to the proposal than that; the link that Reason gave:
http://www.gen.cam.ac.uk/sens/cancer.htm
explains it in more detail, along with a link to the paper that I and a bunch of experts in the various relevant areas published recently.
Well, I don't know if the following has been proven incorrect( or if not the information could be outdated, I dunno), but if not there may exist a conflict.
"Even telomerase expression, the hallmark of immortal cells, has been found at extraordinarily high levels in all the cells of negligibly aging animals like the American lobster (Homarus americanus) and the rainbow trout (Onchorhynchus mykiss)[9,10]. "
http://www.grg.org/resources/LHayflickChapt.htm
These reports of high telomerase activity in such animals are (as far as I know) still considered reliable, yes. The difficulty in comparing such animals to mammals is that lobsters and trout carry on growing throughout life, which requires all tissues to have at least a modicum of biogenesis (cell division, either from progenitor cells or of mature cells) capacity. This in turn means that cells in all tissues can be allowed to die a good deal more easily than in postmitotic mammalian tissues, as replacement is easy, and that may cause the actual cell division rate to be higher than needed for growth. The anti-cancer defences of such animals may thus be constructed without the aid of systems that turn cell division off really thoroughly. Those animals may therefore have something to teach us about delaying cancer -- but not necessarily, as they live with much lower temperatures and lower oxygen concentration than us, hence lower mutation rates. But their telomerase expression cannot be regarded as in conflict with the idea that lack of telomerase expression is a good anti-cancer mechanism for humans.
Hmm, I was wondering something. Dr. de Grey, I have commented in the past, as you may remember, that one failing of your proposal that I see is that it leads to a situation where, if treatments were stopped, one would have less time left to live given their apparent biological age than if they had not undergone the treatments. Brief example, at age 40 I undergo this comprehensive treatment, extending my likely 40 remaining years to potentially hundreds (conservatively). Then, five years after I undergo this treatment, the treatment becomes unavailable, for whatever reason. My previously 40 remaining years have now become only ten or fifteen. Even if I had 20, it's still less than the 40 I had had.
At least with CR, AGE-breakers, stronger lysosomal enzymes, and protected mitochondrial DNA, etc., there isn't as much a worry that the technique, if initially successful, would reduce my remaining life expectancy if it were to become unavailable (e.g. if I stop CR, stop taking AGE-breaker drugs... I guess the other changes are fairly permanent...).
But, I was wondering about something you said here:
> But the more popular view, to which I
> subscribe, is that cells which don't express
> telomerase never divide in the body often
> enough to get critically short telomeres
> anyway, in anything like a normal lifetime,
> unless and until they've already acquired most
> of the mutations needed for becoming cancerous.
> Quite possibly, the turning-on of telomerase is
> often the only mutation still required at the
> time that such a cell reaches this stage, and
> in that circumstance the whole argument above
> clearly fails. Hence, my proposal is in fact to
> delete the telomerase genes from as many of our
> cells as possible...
What if, rather than deleting telomerase capability from all our cells, we delete it from all post-mitotic cells, or if I'm using that phrase incorrectly, from all the cells which don't and won't have a need for telomerase?
I realize that this still leaves open the possibility of developing cancer in stem cells and other regenerating tissues. And this also leaves open the possibility of subversion of telomerase-enabled cells by neighboring cancer cells.
But would it at least have a very significant impact on cancer? Given that cancer is assumed by the NIH to be treatable as a chronic disease in the next decade, wouldn't a significant (30%? 80%?) reduction in potentially fatal cancers be a happy medium, rather than requiring periodic treatments?
Perhaps I'm just overestimating the cost in time, money, resources, etc. of periodic visits for everyone (assuming SENS becomes available in something quite less than a "lifetime" to "everyone").
I agree with your view on the shortcomings of WILT as a cancer therapy. Unfortunately, there is a pretty thorough consensus now that most cancers do indeed start from strem cells, partly because they have to have telomerase only mildly suppressed and partly because they accumulate mutations as a result of the large amount of cell division. I wish I had a better plan than WILT, but I don't. The "chronic disease" concept is absolutely bizarre in my view - I can't see how anyone who knows anything about natural selection could find it remotely plausible.
It seems I'd forgotten the low temperature/low oxygen characteristic of negligibles found so far.
Still what of those who even when exposed to substantial carcinogen loads, manage to live well off into their eleventh decade? I've heard there are individuals who're said to be very resilient against cancer and who never develop it in their lifetimes despite exposure to a substantial number of carcinogens.
That is true, and indeed it is borne out by the well-known non-monotonicity in the incidence of cancer with age, i.e. the proportion of people of age N that die of cancer is higher than at age N-1 up to N=90 or so but thereafter it is lower than at age N-1. This basically says that there is more heterogeneity in the population with regard to cancer susceptibility than with regard to all other causes of death taken together. The bad news about this heterogeneity is that it is to a large extent genetic (since cancer resistance and susceptibility run in families) and worse, that the damage may be done early, i.e. it may not be a lifelong low mutation rate so much as cancers being initiated more rarely during growth/development and growing more slowly thereafter. The evidence for this latter point is still weak- it needs to be explored much more thoroughly.
> The "chronic disease" concept is absolutely bizarre in my view...
Bizarre? Perhaps. I think the point could be taken from another point of view: aging. At this point, we could think of it as a disease (we as in a majority of the anti-aging community). Once we reach the cusp of actuarial escape velocity (assuming we reach it incrememntally, rather than simply jumping past it), then aging becomes a "chronic disease", something that continues to gnaw at you with its static mortality rate, but grows no worse. A worthy goal, even if it falls far short of eliminating aging-related diseases. After all, I view it as a stepping stone: once acheived, it buys more time for many of us, especially those who are not in a "high" mortality class, such as those in the 60's and up.
But we keep pushing forward, towards reducing our mortality rates with time, not just keeping them static.
With cancer, much the same could be said. Assuming that cancer does become a "chronic disease" by 2015, this should not mean we assume that one will have this malignant but not fatal cancer for life. It's just on hold, pending better medical developments.
If we achieved the other 6 of 7 aspects of SENS by 2030 (per your SAGE crossroads debate), that would be 15 years after cancer had become merely a "chronic" and not necessarily a fatal disease. And I assume that the chronic cases would be today's fatal cases, and the rest would actually go into remission.
In that 15 years, we've got time to turn many of those "chronic" cases into curable cases. At any rate, another 30-40 years should suffice to obviate the need for WILT, when cancer is curable 99% of the time. It would seem a shame to subject a generation to WILT when the successive generations wouldn't need it.
On the other hand, I guess in 30-40 years gene therapy and stem cell techniques would be sufficiently trivial to undue the WILT procedure, so perhaps I'm getting worked up for nothing?
Aubrey, with enough persistence one day perhaps I'll persuade you that it's a mistake to apply cross species comparisons of the telomere. Telomeres help dictate which program should be running in a cell, and different species have vastly different programs which help that species adapt to its particular biological imperatives. This is why for example, the elongation of aging telomeres in a mouse fribroblast does not have the same in vitro outcome as the elongation of aging telomeres in human fibroblasts. The telomere has much less impact on cancer and aging in short-lived species because the cell is not designed to resist transformation. In humans, there is evidence that the telomere helps prevent transformation when it is full, and that as it becomes shorter the cell becomes increasingly and correspondingly unstable. Abnormal telomere shortening is seen in 97% of premalignant tissues, whether normal somatic cells or those that express low levels of telomerase, meaning, that all cells definitely do divide enough to lead to telomere induced chromosomal instability which is the main precursor of most cancer. I don't believe it is a scientifically substantiated view, whether popular or unpopular, to suggest that most cells don't divide enough to achieve critical telomere shortening. All cell lines seem to encounter critical telomere shortening around the same time, and more frequently dividing cells offset cellular instability by elongating the telomere just enough to reach crisis about the same time as less frequently diving cells.