Telomerase does not cause cancer

Josh Mitteldorf, Telomerase does Not Cause CancerTranslated by Evgenia Ryabtseva

The author ranks himself among the growing minority of researchers dealing with longevity issues who believe that telomerase is the most promising and fastest way to significantly increase human life expectancy. It should be noted that almost all scientists specializing in telomere biology (including Andrews, Blasco, de Pinho, Fossel, Harley, West, Wright) came to this conclusion. However, the costs of scientific research devoted to this strategy are limited and the main reason for this is the fear of developing cancer. In 1990, a young Carol Greider first proposed the idea that the reason why the evolution of humans and most mammals led to the appearance of short telomeres is protection from cancer. Independently of her, in 1991, the famous geneticist Ruth Sager proposed a similar hypothesis, accompanied by a more detailed explanation and indirect evidence. It should be noted here that conclusions about the goals of evolution are inevitably indirect.

The idea that increasing the length of telomeres is associated with the risk of developing cancer, based on inconclusive experiments and rooted in an initially erroneous theory, began to live its own life. Currently, in printed works, it is referred to as a self-evident truth, accompanying it only with formal documents and without giving convincing arguments. The author believes that this belief is erroneous, that telomerase activation will actually reduce the ultimate risk of cancer and that the fear of cancer stifles the enthusiasm that the study of telomerase more than deserves.

The relationship between telomerase and cancerIn this case, the driving forces act in opposite directions:

Bad:

1. After malignancy, a cell with telomerase is only able to continue dividing. Therefore, the appearance of telomerase at the disposal of the cell eliminates one of the barriers to the formation of a malignant tumor.
2. In addition to participating in maintaining telomere length, one of the components of telomerase – hTERT – also performs a secondary function, acting as a hormone capable of stimulating malignant growth.

Well:The main means of protecting the body from cancer is the immune system.

1. As we age, the activity of hematopoietic stem cells, which give rise to cells of the immune system, decreases due to the shortening of telomeres. Telomerase rejuvenates the immune system and thus helps the body resist cancer.
2. When the telomere length reaches a critical value, the cell enters the phase of physiological aging and begins to release hormones (or cytokines) that increase the inflammatory status of the entire organism and damage surrounding cells. Telomerase prevents this.
3. When the telomeres of a cell become too short, chromosome fragmentation may occur, which, in turn, may be the cause of malignancy. Telomerase prevents this, too.

The author believes that the three "good" factors far outweigh the risk caused by the two "bad" ones. In animal experiments, everything looks like this and, apparently, the theoretical reasons for concern about telomerase are based on an unreliable theory. Obviously, we will not get an unambiguous answer until we know how telomerase actually affects the human body.

More recently, an article was published with the results of a study by Danish scientists, in which the relationship between telomere length and mortality of members of a very large population was analyzed for the first time. Due to the size of the population, this work provided a very serious argument in favor of the fact that longer telomeres are a predictive factor of longevity.

BackgroundAt the end of the 1980s, the story of the physiological aging of cells acquired clear outlines: the gradual extinction of viability, which is the result of multiple divisions (the Hayflick limit), was explained by the shortening of telomeres.

This process was returned to its original state with the help of the enzyme telomerase, first described in the article by Blackburn and Greider, which took the Nobel Prize committee 25 years to realize its importance.

Each eukaryotic cell is capable of synthesizing telomerase, since the gene encoding it is an ancient and ubiquitous fragment of the genome. (Its age should correspond to the age of DNA replication, since without telomerase, DNA cannot be copied for a long time.) Naturally, the question arises: if the drug is so widespread and easily accessible, why do cells have to enter the phase of physiological aging? Why are telomeres not restored with each cell division using a small amount of telomerase?

The rejection of telomerase looked like a kind of programmed death, whereas the standard evolutionary theory states that programmed death is impossible. According to the standard definition of Darwinian fitness, "longer survival means a longer reproductive period," whereas programmed death is the exact opposite of this. How can programmed death in any way contribute to the maintenance of life?

The following answer seemed obvious: the death of malignant cells = the life of an animal. Perhaps the physiological aging of cells appeared as a component of the body's defense mechanism against cancer. At the same time, it is known that cancer cells do not enter the phase of physiological aging and continue to divide indefinitely. That is, they acquire the ability to restore telomerase activity. Subsequently, as a result of studying samples of many types of cancer, it was confirmed that more than 80% of malignant cells express this enzyme.

On the way to malignancy, normal cells go through many transformations. One of them is to restore telomerase activity. Perhaps telomerase is a "bottleneck", and blocking its activity protects the human body from cells that would otherwise get out of control and turn into cancerous.

This explanation did not contradict the standard evolutionary theory, but was very anthropocentric in nature. It was soon found that due to the absence of telomerase, the cells of all animals, including those who have never had cancer, enter the phase of physiological aging. This was the first prerequisite for understanding that this simple explanation is only one part of the story. Even some of the simplest organisms (ciliated infusoria) refuse telomerase and enter the phase of physiological aging. The very concept of cancer does not apply to them in any way.

The truth is that telomere shortening is an ancient form of programmed death. It works the same for both protozoa and mammals. Evolutionary theorists will have to complicate the simplistic theory describing the action of natural selection.

What really causes cancer?It is true that the restoration of telomerase activity is one of the mandatory stages of progression from a normal cell to a malignant one.

However, this only matters if it is a stage limiting the rate of progression.

Each multi-stage process consists of fast and slow stages, and the speed of the process as a whole is determined by the speed of the slowest stage. The acquisition of telomerase activity by a cell will accelerate its transformation into malignant only if it is the slowest stage limiting the speed of the malignancy process. The most convincing evidence at our disposal is that some other stage is limiting the speed, since in practice the acquisition of telomerase activity does not seem to increase the risk of cancer. This was demonstrated by a group of researchers from the University of Texas, working under the leadership of Woody Wright and Jerry Shay in 1999.

(What is the speed-limiting stage in this case? The author believes that it is the intervention of the immune system. Apparently, every day there is a malignancy of several cells from billions of cells of the human body. However, the immune system exercises continuous control and destroys tumors in the bud.)

Limited proof of the hypothesisSeveral studies in mice have revealed an increase in the incidence of cancer with increased telomerase expression.

Transgenic female mice with additional copies of the telomerase gene developed breast tumors, whereas control group mice developed tumors of other organs, but not of the breast. The introduction of additional copies of the telomerase gene into thymocytes (thymus stem cells) led to an increase in the incidence of T-cell lymphoma. Similarly, overexpression of telomerase in skin stem cells increased the incidence of skin cancer. In a genetically modified mouse model susceptible to the development of endocrine gland cancer, telomerase inactivation significantly reduced the incidence of tumors.

All authors of studies on mice note an incomprehensible feature of the results obtained: mice are initially characterized by pronounced telomerase expression, and their telomeres never reach a critically short length. According to the standard hypothesis, the restriction of telomerase activity should serve the body by suppressing tumors when they reach a size determined by the length of telomeres. Therefore, any relationship between telomerase and the initiation of cancer formation must be due to some other mechanism unknown to date.

Laboratory mice do not belong to animals whose lifespan is limited by telomere shortening, so the evolutionary theory based on the restriction of telomerase activity cannot be applied to them at all. The results described above are interesting and indicate that telomerase plays other roles in metabolism. Perhaps, among other things, it performs the function of a growth activator. However, the results of experiments on mice cannot be cited as evidence of a standard hypothesis that applies to humans, dogs, horses and other animals (but not to mice).

An unexpected line of research has shown that telomerase, in addition to maintaining telomere length, performs other functions. Its TERT component can act as a growth hormone, and in fact, all the real pro-tumor activity of telomerase is due to the hormonal activity of TERT, and not to the "immortalization" provided by an increase in telomere length.

Physiological aging is toxicWhen human cells enter the phase of physiological aging, usually due to the fact that their telomeres have shortened as a result of numerous divisions, they do not just weaken and die (as do protozoa that have entered the phase of physiological aging).

Instead, they become toxic to the body and release signaling molecules that stimulate inflammation and the entry of other cells into the phase of physiological aging. This condition is known as the secretory phenotype associated with physiological aging (SASP, from the English Senescence-Associated Secretory Phenotype). In other words, aging cells turn into toxic monsters that have a powerful effect that aggravates the aging process. Van Deusen demonstrated that to increase the lifespan of mice by 25%, it is enough to induce the death of cells that have entered the phase of physiological aging.

From the point of view of metabolism, this toxicity is completely illogical. Perhaps it is an evolutionary adaptation and should be considered as an adaptation that favors the death of the organism. That is, mammalian cells and protozoa enter the phase of physiological aging for the same reason: this is the mechanism of regulation of life expectancy that has arisen in the course of evolution.

The realization of this first of all resolves the paradox that led to the emergence of the hypothesis of Greider and Sager. Both authors were thinking within a limited evolutionary model, in which the evolution of programmed death is not considered at all. The inertia of this model continues to be the driving force behind the idea that "free cheese only happens in a mousetrap," that is, evolution has already done everything possible to increase life expectancy, and that we are trying to influence its choice at our own risk. If we decide to abandon this model, then many parts of the big picture will fall into place, including adaptations that favor the development of the community by neglecting the interests of the individual, and in particular programmed death.

At the same time, it opens up the possibility that increasing the length of telomeres is really "free cheese".

Experiments on animals in which life expectancy was increased with the help of telomeraseThe nematodes Caenorhabditis elegans are the least expected example in which telomere length would have an impact on life expectancy.

Adult worms have a set of cells that ensure their vital activity during their short life, the duration of which in laboratory conditions at a 20-degree temperature is 15-20 days. In the body of adult worms, there is no replacement of old cells with new ones, respectively, there is no shortening of telomeres, nor cellular aging. It would seem that in this case telomerase has absolutely nothing to do here. Therefore, the results of a Korean study were completely unexpected, demonstrating that an increase in telomere length using a mechanism other than telomerase activity extended the life of worms by 19%.

In experiments conducted in 2008 on a cancer-resistant mouse line, Maria Blasco from the Madrid Laboratory increased the life expectancy of animals by 40% by introducing an additional copy of the telomerase gene into their genome. These results also surprised the authors, since it was generally assumed that mouse cells have a large amount of telomerase and their telomeres never shorten to a critical length.

A subsequent study by the same group of scientists showed that the introduction of an additional telomerase gene with the same success increases the life expectancy of ordinary mice and does not increase the risk of cancer. Inspired by the results, the authors expressed enthusiasm about the potential of therapy based on increasing telomerase activity.

As part of a study conducted in 2011, Ronald DePinho laboratory staff deprived mice of their characteristic abundance of telomerase by knocking out the gene encoding it. As a result, the mice developed a pronounced age-related deterioration in health, including atrophy of muscle tissue, brain atrophy and loss of cognitive functions. The restoration of telomerase activity not only stopped the progression, but also provided a significant improvement in the condition of the muscles and brain.

A new review on the relationship between telomere length and mortalityMost recently, the results of a Danish study were published, in which 65,000 people were monitored for 15 years.

According to the authors' main conclusion, telomere length is a powerful predictive marker of longevity even when adjusted for factors such as age, smoking, physical activity, blood cholesterol, body mass index and alcohol consumption. People with the longest telomeres are at the lowest risk of developing cancer. This article is a new rich source of statistical conclusions, and the author plans to devote his next publication to them.

For links to publications in scientific journals, see the original article.

Portal "Eternal youth" http://vechnayamolodost.ru15.05.2015