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 (e.g., Andrews, Blasco, de Pinho, Fossel, Harley, West, Wright). 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. (e.g., “The senescence response is widely recognized as a potent tumor suppressive mechanism.” [ref]) 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, and in this and next week’s columns, I’ll take the opportunity to summarize the situation as I see it.
Relationship of Telomerase to Cancer
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.
(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.
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.
The topic is timely, as last week a Danish study appeared in the Journal of the National Cancer Inst, tracking a huge population for the first time, and relating their telomere length to their mortality risk. Because of its size, this study gave a sound foundation to the thesis that longer telomeres portend a longer life.
In the late 1980s, the story of cellular senescence took shape: The gradual loss of viability that comes from multiple cell replications (the Hayflick Limit) was explained by shortening telomeres. The process was reset by an enzyme, telomerase, first reported in a paper by Blackburn and Greider, the importance of which the Nobel Prize committee took 25 years to recognize.
Every eukaryotic cell knows how to make telomerase—it’s an ancient and ubiquitous piece of the genome. (It has to be as old as DNA replication, because without telomerase, DNA can’t be copied for long.) It was natural to ask the question: with the remedy so widely and easily available, why should cells ever have to become senescent? Why isn’t the telomere maintained with application of a little telomerase every time the cell divides?
Withholding telomerase looked like a kind of programmed death, and standard evolutionary theory said that programmed death is impossible. “More survival, more reproduction” was the standard definition of Darwin’s fitness, and programmed death was just the opposite. How could programmed death be, in some way, pro-life?
The answer that seemed obvious was: death of cancer cells = life of the animal. Maybe cellular senescence was permitted to occur as part of a protection against cancer. It was known that cancer cells do not senesce; they can go on reproducing forever. So cancer cells must have learned how to unlock telomerase. Later, different human cancers were surveyed, and it was confirmed that well over 80% express telomerase.
Normal cells go through many transformations in order to become malignant. One of these is to unlock telomerase. Perhaps telomerase is the bottleneck, and the lockdown of telomerase helps to protect us from cells that otherwise might go rogue and turn into cancers.
This explanation was consistent with the standard evolutionary theory, but it was a very human-centric answer. It was soon learned that cells senesce for want of telomerase in all kinds of animals, including those that don’t get cancer at all. This might have been an early warning that the simple answer was not the whole story. Even some protozoa withhold telomerase and suffer cellular senescence (ciliates). The very notion of cancer does not apply to single-celled protozoa.
The truth is that telomere attrition is an ancient mode of programmed death. It functions that way in protozoans, and it functions that way in mammals. Evolutionary theorists are going to have to expand the simplistic, one-gene-at-a-time theory about how natural selection works.
What really causes cancer?
It’s true that acquiring telomerase is one necessary step in the progression from a normal cell to a cancer cell. But this only really matters if it is the rate-limiting step.
In every multi-step process, there are fast and slow steps, and the rate of the process as a whole is controlled entirely by the rate of the slowest step. Adding telomerase capacity to a cell will only cause the cell to progress toward cancer more rapidly if telomerase was the slowest step, the rate-limiting step. The best evidence we have is that some other step is rate-limiting, because in practice, adding telomerase does not seem to increase cancer risk. Already in 1999, a study from the UTexas lab of Woody Wright and Jerry Shay demonstrated that
(What is the rate-limiting step? My money is on evasion of the immune system. I believe that of the trillions of cells in our bodies, a few become malignant every day, and that the immune system is constantly looking out for cancers and nipping them in the bud.)
Limited evidence for the hypothesis
Some studies in mice have found an increase in cancer incidence when telomerase was overexpressed. Female mice with extra (transgenic) copies of the telomerase gene developed breast tumors, while control mice had cancers in other organs, but not breast [ref]. Transgenic telomerase targeted to thymocytes (stem cells of the thymus) resulted in an increased incidence of T-cell lymphoma [ref]. Similarly, telomerase overexpression in skin stem cells increased the rate of skin cancer [ref]. In a mouse model genetically engineered to be prone to endocrine cancers, disabling telomerase dramatically reduced the frequency of tumor formation [ref].
All authors of the mouse studies note a puzzling aspect of their results: telomerase is already abundantly expressed in mice, and telomeres are never critically short. According to the standard hypothesis, telomerase rationing should serve the body by halting tumors when they reach a size determined by beginning telomere length. Any association of telomerase with initiation of cancer must be by a different mechanism, not yet understood.
Lab mice are not among the species whose life spans are limited by telomere attrition, so the evolutionary theory about telomerase rationing ought not to apply to them at all. These results are interesting, and suggestive that telomerase plays other roles in metabolism, perhaps as a growth promoter; but results in mice cannot be cited as evidence for the standard hypothesis that applies to humans, dogs, horses, etc, (but not to mice).
A surprising line of research has indicated that telomerase has other functions besides maintaining telomeres. A telomerase component called TERT can act like a growth hormone [ref, ref, ref], and in fact, all the credible pro-cancer activity of telomerase comes from the hormonal activity of TERT, and not from “immortalization” via telomere extension.
Cellular senescence is toxic
When human cells become senescent, usually because their telomeres have eroded with too many replications, they do not simply languish and die (like senescent protozoans). Instead, they become toxic and send powerful signals out into the body that promote inflammation and further increase cell senescence. This is called SASP, for Senescence-Associated Secretory Phenotype. Not to mince words, the cells become toxic monsters that have a powerful pro-aging effect. Van Deusen has shown that life span of mice can be extended 25% just by inducing senescent cells to die [ref].
There is no metabolic logic behind this toxicity, so I think it is probable that it is an evolutionary adaptation, and it must be seen as a pro-death adaptation. I cite this as evidence that the reason for cell senescence in mammals is the same as the reason for cell senescence in protozoans: it is an evolved mode of regulated life span.
Once you realize this, it resolves the paradox that led to Greider and Sager’s hypothesis in the first place. They had been thinking within a limited evolutionary model in which evolution of programmed death has no place. The inertia of that model continues to be the driving force behind the idea that “there can be no free lunch”, that evolution has already done her best to maximize human life span, and that we tinker with her choices at our peril. If we are willing to discard that model, then a lot of the “big picture” in evolution starts to fall into place, including adaptations that favor the community at the expense of the individual, and programmed death in particular.
And the possibility opens up that lengthening telomeres may indeed be a “free lunch”.
Animal experiments in which life span was increased with telomerase
Lab worms would be the last place you’d expect telomere length to effect life extension. This is because adult worms are endowed with a set of cells that last them through their short lifetimes of 10 days or so. There is no cell replacement in adult worms, hence no telomere shortening, hence no cellular senescence, nothing for telomerase to do. So it was quite a surprise in 2004 when a Korean study showed, using not telomerase but a different means of lengthening telomeres, that life span was extended 19%.
Using a cancer-resistant strain of mice in a 2008 study, Maria Blasco’s Madrid laboratory was able to extend life span of mice by 40% by adding an extra copy of the telomerase gene. Again, this is surprising because it was thought that mice already have plenty of telomerase, and that their telomeres never shortened to a critical level during a lifetime.
An updated study from the same group showed that their care in using cancer-resistant mice was unnecessary. Introducing an extra telomerase gene increased life span in normal mice as well, and cancer rates did not go up. Blasco expresses her enthusiasm for the potential of telomerase therapy in this article. She writes explicitly about the relationship between cancer and telomerase here, in an article that has been a source for my own views.
In a 2011 study from the Harvard laboratory of Ronald dePinho, mice were deprived of their usual abundance of telomerase by knocking out the telomerase gene. The mice were followed until they experienced dramatic age-associated deterioration, including muscle atrophy, brain atrophy, and cognitive impairment. Restoring telomerase, they found that both muscle and brain tissues were remarkably rebuilt, not merely preserved.
A New Survey of Telomere Length and Mortality
Last week, a Danish study was published that tracked 65,000 people over 15 years. The bottom line was that telomere length robustly predicts longevity, even after factoring out the effect of age, smoking, exercise, blood cholesterol, BMI, and alcohol consumption. People with the longest telomeres had the lowest cancer rates. This is a rich new source of statistical inferences, and I’ll write a full column on the study next week.