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Telomerase Therapies and Cancer Risk

To date progress in the development of stem cell treatments has been accompanied by a markedly lower risk of cancer than was expected at the outset. The characteristic decline in stem cell activity with age is believed to be an evolutionary adaptation that reduces cancer risk: there is a balance between on the one hand the risk of cancer due to over-active damaged cells, and on the other hand the failure of tissues and organs due to loss of maintenance activities on the part of stem cells. It is the responsibility of stem cells to deliver supplies of fresh, fit cells as needed to replace those that have become damaged, worn, or have reached the inherent limits imposed on replication of somatic cells. That supply tapers off in old age, however, as stem cells gather damage and spend ever more time quiescent rather than active.

Despite the comparative lack of cancer resulting from stem cell therapies, there is still every reason to expect that caution should attend the development of any therapy that spurs greater regeneration in old tissues. The cells in those tissues have a higher load of nuclear DNA damage, and thus a greater cancer risk attends their activity. Yet in practice it isn't working out to be as great a risk as expected, or at least not so far based on the data gathered to date. Why this is the case is an interesting question with no solid answer at this time.

The replication limits of somatic cells depend in part on telomere shortening. Telomeres are repeated lengths of DNA at the ends of chromosomes. A little of that length is lost with each cell division, and very short telomeres trigger cellular senescence or programmed cell death. In comparison stem cells retain long telomeres, and thus the ability to continually create new daughter somatic cells with long telomeres to deliver into the tissues they support. This maintenance of telomere length in stem cells is achieved through the activity of telomerase, an enzyme that adds repeated DNA sequences to the ends of chromosomes.

Based on all of the above, it is not unreasonable to expect that more telomerase activity in more cells would mean a greater risk of cancer. It would mean cells being more active, and older, more damaged cells being more active. In mice, however, this is not what happens. The risk of cancer actually falls, even as life span is lengthened: researchers believe there is increased stem cell activity and tissue maintenance, but not enough time in even the extended mouse life span for the other shoe to drop and cancer risk to catch up. A firm and comprehensive analysis of what exactly is going on inside these mice is probably still a few years away, however. Nonetheless, the picture painted above suggests that we should be cautious about extrapolating a beneficial balance of time and cellular activity in mice to indicate that telomerase treatments would be similarly great for humans. The span of time is different, our telomere biology is different, and the balance of aging and cell activity is different.

On the other hand, the medical community seems to be doing pretty well with stem cell treatments that are just another way of spurring increased cell activity and tissue maintenance in old, damaged tissues. Enhanced telomerase activity seems worthy of further investigation for all the same reasons that stem cell therapies were worthy of clinical development. I don't see telomerase therapies as a treatment for aging per se, however. The approach of increased telomerase activity doesn't address the underlying issues that cause stem cell decline, but instead forces damaged cells to get back to work by overriding the normal reactions of an aged biochemistry. In the view of aging as accumulated cellular damage, stem cell failure with age is an evolved reaction to an increasingly damaged tissue environment. The best way forward is to repair that environment, not override the signals. As first generation stem cell treatments have shown, however, it is possible to achieve beneficial results by taking this path, even while failing to address the root causes of aging. Benefits are good, but we shouldn't let them distract us from the end goal.

Telomerase does Not Cause Cancer

I am one of a growing minority of life extension scientists who believe that telomerase may be our most promising, near-term path to a major boost in the human life span. Notably, almost all the scientists who specialize in telomere biology have come to this opinion. But research investment in this strategy has been limited and the main obstacle has been fear of cancer. Back in 1990, a young Carol Greider was the first to float the idea that the reason that man and most other mammals have evolved with short telomeres is to help protect against cancer. Independently in 1991, senior geneticist Ruth Sager proposed the same hypothesis with more detail, citing circumstantial evidence. Inference of evolutionary purpose is of necessity indirect.

The idea that lengthening telomeres poses a danger of cancer took a life of its own, based on marginal experimental data and firm grounding in a theory that is fundamentally flawed. It is now taken for granted in publications, and only token documentation and no reasoning is provided when this view is asserted. I believe that this concern is misplaced, that activating telomerase will actually reduce net cancer risk, and that the fear of cancer is damping the enthusiasm that telomere science so richly deserves.

I have written a technical article on this subject. There are forces at work here in opposite directions:

(Bad #1) Once a cell becomes cancerous, it can only continue to grow if it has telomerase. So giving the cell telomerase removes one barrier to malignancy.

(Bad #2) Secondary to its role in growing telomeres, the telomerase component hTERT also functions as a kind of growth hormone, that can promote malignancy.

(Good #1) The body's primary defense against cancer is the immune system. As we get older, our blood stem cells slow down because their telomeres are too short. Telomerase rejuvenates the immune system, and helps the body fight cancer before it gets started.

(Good #2) When telomeres in a cell get too short, the cell goes into a "senescent" state, in which it spits out hormones (called "cytokines") that raise inflammation throughout the body and damage cells nearby. Telomerase protects against this.

(Good #3) When telomeres in a cell get too short, the cell's chromosomes can become fragmented and unstable, and this can lead to cancer. Telomerase protects against this.

I believe that the three "goods" far outweigh the risk from the two "bads". In animal experiments this seems to be the case, and I think that the "theoretical" reasons for concern are based on discredited theory. Of course, we won't know for sure until we have more experience with humans.

It's a modestly long post, and worth reading. Bear in mind the author is coming at this from a programmed aging point of view, however. In this perspective, aging is not an accumulation of cell and tissue damage that leads to dysfunction, but is rather an evolved program of dysfunction that causes cell and tissue damage. In the programmed aging view, the right approach to treating aging is to alter levels of proteins to make the cellular environment more youthful in appearance, at which point damage will be repaired. In the aging as damage viewpoint, tinkering with the cellular environment has only limited utility and the right approach is to repair damage. Given sufficiently good repair, the reactions to damage will cease and the tissue environment will become more youthful in operation and appearance.

Comments

There seems to be more than a dose of wishful thinking about the idea that telomerase will reverse aging. Particularly as Good reason #1 that it will prevent immune system failure due stem cell loss due to short telomeres is incorrect as far as I have read (reason states that teleomere length is maintained in stem cells).

Posted by: Jim at April 25th, 2015 9:06 AM

@Jim Telomerase has been shown to rejuvenate T-Cells restoring them to function. I will try to find the paper that showed this and link it for you. Telomeres would certainly help improve gene expression via TPE so they will more than likely be of benefit to the system. There are a number of studies that show positive results from elongation of Telomeres so I don't think Josh is being entirely wishful here. Have a read of some of the papers by Shay about Telomeres if you havent already you might be surprised to see what things they do influence.

Posted by: Steve H at April 25th, 2015 12:21 PM

Also Stem cells do not necessarily maintain Telomere length and based on my reading appear to ultimately shorten which leads onto poorer gene expression via the TPE effect and epigenetic drift.

http://www.ncbi.nlm.nih.gov/pubmed/17876321

There are a fair few other papers around that indicate even stem cells loose telomere length. Restoring them could therefore be a reasonable approach to restoring efficient function and addressing some of the damage.

Posted by: Steve H at April 28th, 2015 8:14 AM

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