Discussing Telomerase and Cellular Senescence

It think it's something of a given that, somewhere, a scientific study exists to apparently disproves any given consensus view of human biological processes. Half are wrong, of course, but that still leaves the uncomfortable truth that a complex, incompletely understood biological system can be accidentally coaxed into confounding almost any reasonable expectation. This is one reason why looking at a single study is never all that useful, and why it usually takes a great deal longer to change a scientific paradigm than to run any given study. No one ever said science was an easy or clear-cut business.

With that in mind, I'll direct your attention to a discussion on telomerase and cellular senescence - in the context of building better regenerative medicine for the replacement of age-damaged tissue in the elderly - over at the Immortality Institute forums:

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.

This is, for me at least, an entirely unexpected result. Take a look at the original paper and see what you think. Many other studies seem to confirm that increasing the number of cell divisions by altering telomere shortening rates - through the use of telomerase - and thus pushing back cellular senescence will give you cancer, and lots of it:

Without the enzyme [called telomerase] that 'regenerates' telomeres (the ends of DNA), stem cells lose functionality and the organism rapidly ages, while it acquires cancer resistance. ... the lack of telomerase causes a severe defect in the fundamental functions of stem cells. ... in genetically modified mice that did not express telomerase, stem cells lost their functionality and became unable to regenerate the damaged epithelial tissue. On the whole, these mice aged more rapidly than normal mice. But, there was a very interesting side effect: without telomerase, mice showed a marked cancer resistance. ... Further experiments on telomeres structure showed that every time the shortening process is altered, the result is either 'early aging and cancer resistance' (if shortening is boosted), or 'aging inhibition and more cancer occurrence' (if shortening is reduced)."

Cellular senescence or cancer - pick one, it seems. Senescence serves as a cancer suppressing mechanism by removing older, more damaged cells from operation. These accumulating senescent cells still cause harm and contribute to age-related degeneration, but that's presently the lesser evil when compared to the level of cancer that would exist without cellular senescence.

So what is going on in this study? It seems to show that pushing off cellular senescence leads to less cancer, even though it was accomplished in much the same way as leads to more cancer in other studies. If I had to hazard a guess (as opposed to pointing out that you can't go far wrong with more research), I'd suggest looking into in vitro versus in vivo differences in cellular biochemistry. We know that a number of cellular processes can run quite differently in culture rather than in an organism; perhaps this is one of them. That is a pity, given the possibilities, but there you have it - there is no free lunch.

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The purported trade off between cancer and cellular senescence is a great oversimplification of the various cellular processes at work. To wit, most cancer cells are cells that have (1) undergone a deleterious mutation in their DNA coding, thereby making them pre-cancerous cells and then (2) undergo a *second* mutation where telomerase production is stimulated, thereby making said pre-cancerous cells into immortal cancer cells. Most pre-cancerous cells simply kill themselves off without undergoing the second mutation. Moreover, stem cells are categorically different from specialized cells, not to mention the fact that cellular senescence in mice is qualitatively different from cellular senescence in human beings. Being able to turn telomerase production off and on is the key: Off with cancerous cells; on with healthy but aged cells, thereby rejuvenating said healthy cells. The latter can even be done in vitro.

Posted by: David Prenatt at September 21st, 2006 2:12 PM

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