Telomerase activation is the most promising approach to prolonging youth
The most promising medical technology on the horizon today
Josh Mitteldorf, translated by Evgenia Ryabtseva
Studying the biology of telomeres should help to increase people's life expectancy and significantly reduce the incidence of diseases that are currently the main causes of death: heart disease, stroke and Alzheimer's disease. The risk of developing all these diseases increases exponentially as a person ages, and the burden they exert on society will decrease significantly when we learn to influence the work of the biological clock of aging.
It would seem that the Nobel Prize in 2009 was supposed to stimulate the study of telomere biology, but this area still remains a specialized branch of medical research, and only a few biologists seriously perceive its prospects in the prevention and treatment of age-related diseases. The US National Institutes of Health has funds for the study of heart diseases, cancer, as well as Alzheimer's and Parkinson's diseases, but the best investment in this case would be investing in telomere biology research. Many billions of dollars are spent on the study of these diseases, since they are considered "medicine" and are funded by the National Institutes of Health, while the study of telomere biology is considered "science" and is funded by the US National Science Foundation. In 2013, only 123 million dollars were allocated for the study of cell biology, and only a tiny part of this amount was spent on the study of telomere biology. The private sector pays a little more attention to this issue, but they make only short-term investments, whereas in reality it is necessary to conduct targeted research with a long-term perspective.
There is convincing evidence that telomere length variation is one of the main mechanisms of the biological clock of aging. The body knows how to lengthen telomeres, but prefers not to do it. We just need to give him a signal to activate the telomerase gene (an enzyme that restores the length of telomeres) available in each cell. Obviously, the effectiveness of this approach is not guaranteed, but compared with the sluggish progress in the study of individual diseases, it is a very attractive problem, especially considering that its target is quite simple. According to the author, the described perspective is worthy of a breakthrough research project.
Three objections to studying telomerase"Aging is inevitable, because, according to the laws of physics, nothing lasts forever."
This statement refers to the second law of thermodynamics, according to which closed systems developing in isolation lose their order over time. However, living systems are open, consuming energy in the form of food or sunlight and releasing their entropy into the environment. There is no reason why such systems cannot maintain their existence indefinitely. In fact, growth and maturation would not be possible if the mentioned law of physics were extended to open thermodynamic systems. Already in the 19th century, when the laws of thermodynamics were formulated, it became obvious that aging cannot be explained by physical laws and, accordingly, its explanation should be sought in the mechanisms of evolution.- "Evolution was aimed at increasing life expectancy in order to increase the endurance of the body. It is unlikely that any simple intervention in physiology that a person can develop will provide results that surpass what evolution has achieved over millions of years."
In fact, evolution was not aimed at increasing life expectancy, but at providing enough time for reproduction. Aging is a form of programmed death that occurs according to a flexible but inflexible pattern. There are aging mechanisms programmed in living organisms already at the level of the first eukaryotic cells. Telomere shortening has been used to control the cell cycle and has been the main mechanism of programmed cell death for at least a billion years. Many protozoan species do not express telomerase during mitosis (only in the conjugation phase), so their telomeres shorten with each division, which imposes a limit of several hundred cycles of reproduction per cell line. This mechanism is a precursor to telomere aging, which still occurs in human cells and other higher animals. - "Telomerase expression will increase the risk of cancer." There are quite a lot of theoretical justifications around this assumption, which, according to the author, are completely wrong. Malignant cells do express telomerase. However, the suggestion that telomerase expression turns a cell into a cancerous one is fundamentally wrong. A detailed explanation of this relationship is given by two respected experts (Shay and Wright, 2011).
In early studies, the only method of increasing telomerase activity in laboratory animal cells was the introduction of additional copies of the gene encoding this enzyme into their genome. The technology available in the early 2000s did not allow the gene to be embedded in a given region of the chromosome. Embedding occurred randomly. It is known that such manipulations with the structure of DNA increase the risk of developing cancer, regardless of which genes are inserted or removed. Three of these early studies showed an increased risk of cancer in mice [1, 2, 3].
There are no laboratory studies, the results of which would indicate that the activation of its own telomerase increases the risk of cancer. According to modern concepts, telomerase is not a necessary condition for starting the malignancy process, its expression is mandatory only to maintain the growth of most progressive malignant tumors. Recent studies conducted by the laboratory of Robert de Pinho (Robert de Pinho) from Harvard University and the Spanish laboratory of Maria Blasco (Maria Blasco) are devoted to the study of the possibility of manipulating telomerase to reduce the risk of cancer. It should be noted that early studies, based on which concern was expressed about the safety of working with telomerase ten years ago, were conducted by the same scientists.
There have also been a large number of studies demonstrating that (a) telomerase expression does not increase the risk of cancer in laboratory animals and (b) short telomeres are associated with a very high risk of cancer. According to the author, the use of telomerase activators will significantly reduce the likelihood of developing cancer. This will happen, firstly, due to the destruction of pro-inflammatory cells, which are potentially carcinogenic due to shortened telomeres, and secondly, due to the rejuvenation of the immune system, which protects the body from the development of cancer. Last year, the author published an article devoted to this issue (J.J.Mittendorf, Telomere biology: Cancer firewall or aging clock?, Biokhimiya, 2013, Vol. 78, No. 9, pp. 1345-1353; translation into Russian is available in the "paper" edition of the journal "Biochemistry").
Why can we expect a significant increase in life expectancy from telomere lengtheningThe answer to this question is obvious, so let's formulate it in a different way: what factors indicate that an increase in telomere length will have a very powerful effect on various aspects of the biology of aging?
A) Telomere shortening is an ancient mechanism of agingProtists are the first unicellular eukaryotes that appeared on Earth a billion years ago (their structure is much more complex than the structure of bacteria that appeared about 3 billion years earlier).
Protists have linear DNA and, accordingly, the need for telomerase. Since protists reproduce by simple division, one would assume that these cells should not "age" or even that the concept of aging does not make sense for their cell cycle. However, the cell lines of protists can age, and with some this actually happens. This is based on the oldest known mechanism of aging, which consists in abstaining from using telomerase.
As an example, paramecia (infusoria-shoes) can be cited. Reproduction of paramecia consists in cell division and DNA replication in the absence of telomerase expression. As a result, each cell division shortens its telomeres. Paramecia can enter into conjugation, which is a primitive form of sexual exchange of genetic information. The cells of the two paramecia merge and exchange DNA, after which they separate. Telomerase expression is characteristic exclusively for the conjugation process. Therefore, any cell line that does not enter into conjugation dies out after several hundred generations. This prevents the occurrence of excessive homogeneity of cell colonies. Thus, it can be argued that the age of the aging mechanism is a billion years, and some of its genetic components were preserved and transmitted through all the transformations of multicellular life forms. William R Clark has written several books on this subject that are in the public domain [1, 2].
C) Human telomeres shorten with ageThis fact became known more than 20 years ago.
C) People with short telomeres are at risk for premature mortalityThis fact was established by Richard Cawthon (2003) and described in an article that surprised specialists involved in the study of this issue.
After all, if the whole complexity of the aging process is the shortening of telomeres, why shouldn't the body solve this problem by expressing telomerase? This would strengthen the individual endurance of organisms. Why didn't evolution use such a simple technique? (The answer to this, of course, is that natural selection favors aging for the sake of maintaining demographic stability. Most evolutionary biologists do not consider this driving force of evolution.) Kauton demonstrated that 25% of 60-year-old study participants who had the longest telomeres had a twice lower risk of death than 25% of participants with the shortest telomeres. Kauton had access to a unique database containing preserved blood samples from 20 years ago. As far as the author knows, for 11 years (at the time of writing this article) no one has been able to reproduce or refute the results obtained by Kauton.
D) When analyzing data taking into account the age factor, people with short telomeres are at risk for the development of various diseases, especially diseases of the cardiovascular system
This relationship was revealed not only in the original study of Kauton, but also in a number of other studies [1, 2]. The relationship between telomere length and the risk of dementia [1, 2], as well as diabetes mellitus [1, 2] has also been demonstrated.
F) When analyzing the results taking into account age, animals with short telomeres are also at high risk of early deathThis has been demonstrated in studies on several bird species [1, 2, 3] and baboons.
Already in 2003, it was found that the telomeres of individuals of long-lived species shorten more slowly than the telomeres of representatives of species with a short lifespan.
F) Small studies in mice have demonstrated the ability of telomerase stimulants to rejuvenate the body of animals
(It is believed that mice are a much less effective target of this strategy compared to humans, since, apparently, human aging is much more dependent on telomere shortening than mouse aging.)
The first such experiment was conducted in 2008. Spanish researcher Tomas Loba (Tomas-Loba) from the laboratory of Maria Blasco has created genetically modified mice that are both resistant to cancer and have an additional copy of the telomerase gene expressed in some tissues, for which the expression of this gene is not typical even in mice. The life expectancy of these animals was 18% higher than that of cancer-resistant mice with only the usual telomerase gene.
However, it was soon found that the precautions taken regarding the risk of developing cancer might have been unnecessary. Another researcher from the same laboratory Bernardes de Jesus (Bernardes de Jesus, 2011) published data according to which he managed to increase the lifespan of mice using a commercially available product TA-65 (commonly known as cycloastrogenol) without increasing the risk of developing cancer. Cycloastrogenol is a weak telomerase activator, compared to synthetic compounds developed by Sierra Sciences specialists. Its activity is comparable to that of a number of other plant extracts. However, researchers in Maria Blasco's laboratory demonstrated that short-term TA-65 therapy provided elongation of even the shortest telomeres of mice. This was accompanied by an improvement in a number of health indicators, including tissue sensitivity to insulin.
Subsequently, the Blasco laboratory worked with a more powerful (though more dangerous) method of telomerase induction – infection with a modified retrovirus embedding the telomerase gene into the nuclear DNA of infected cells. "The introduction of a therapeutic adenoassociated broad tropism virus expressing the mouse TERT gene to mice aged 1 and 2 years had a pronounced effect on the health and endurance of animals, including such indicators as tissue sensitivity to insulin, the severity of symptoms of osteoporosis, neuromuscular coordination and several molecular biomarkers of aging" (Bernardes de Jesus et al., 2012). At the beginning of therapy at the age of 2, the life expectancy of mice increased by 13%, and at the beginning of therapy at the age of 1 year - by 24%. At the same time, there was no increase in the incidence of cancer.
The most outstanding example of rejuvenation is the achievement of the laboratory of Robert de Pinault from Harvard University. As a rule, mouse cells (unlike human cells) express telomerase throughout life. The researchers created modified mice that do not have a normal (permanently active) version of the telomerase gene. Instead, the animals had a telomerase gene that could be activated or inactivated using a chemical compound added to animal feed. As these mice aged, they developed many severe symptoms of degeneration of the seminal glands, spleen, intestines, nervous system and other organs. The progression of these symptoms not only stopped, but also reversed with the activation of telomerase in the later stages of animal life. The effect on the nervous system turned out to be particularly interesting, since, unlike intestinal and skin cells, nerve cells function throughout the life of the body and do not need constant renewal due to stem cells. Despite this, senescent mice with an inactivated telomerase gene had decreased sensory sensitivity and learning ability. Activation of telomerase completely restored these disorders.
Researchers at Stanford University and Geron conducted experiments with "skin" grown from human cells in the laboratory. They found that the infection of cells with a modified retrovirus, which embeds the telomerase gene into their genome, provides artificial skin with the restoration of elasticity, softness and texture characteristic of the skin of a young organism.
G) In addition to performing the main function of telomere lengthening, telomerase acts as a kind of growth hormoneThis hypothesis was proposed in the 90s of the last century and received convincing confirmation in the form of results obtained by scientists at Stanford University [1, 2, 3, 4].
As part of this work, a line of mice with altered telomerase was created, in which there was no component necessary for the synthesis of telomeres. Despite this, the ability of telomerase to induce the growth of animal hair has been demonstrated. The ability of telomerase to affect the hormonal signaling mechanism known as Wnt has also been shown. Other functions of telomerase are discussed in the article Cong and Shay (2008).
H) On the example of one person, it has been demonstrated that taking large doses of plant-derived telomerase activators provides rejuvenationRecently, the author has been in a relationship with a physicist from Kansas, who has been taking huge doses of telomerase-activating herbal preparations and dietary supplements for six years and claims that this has improved his appearance and well-being, as well as positively affected his physical abilities.
It may be interesting to study the problem on the example of one case. Jim Green comments on the experiment on his own body in his blog.
ConclusionsAccording to the author, telomerase activation is the direction that opens up the most promising opportunities to increase human life expectancy over the next few years.
Research in this area is very slow due to lack of funding and lack of attention.
Portal "Eternal youth" http://vechnayamolodost.ru
23.005.2014