Telomeres: the vague secret of longevity

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Telomeres: the vague secret of longevity
Telomeres: the vague secret of longevity

Probably, even from the moment our first great-great-ancestors gained consciousness, a person was afraid of death and looked for ways to prevent or delay it. The ancient man longed for consolation in the idea of ​​the afterlife, later alchemists tried to invent potions that would help achieve immortality. With the development of science, scientists have sought to understand how our mortality works at the cellular level and even deeper - and whether it is possible to seriously change the century measured to a person. It is telomeres that are often spoken of as a kind of secret to longevity, the very magic lever in DNA that can add one to two decades to our life. Is it so?


What are telomeres

The DNA of eukaryotes (organisms, all of whose cells have a nucleus - unlike prokaryotes, which do not have one) consists of both coding and non-coding regions. And the former are much less than the latter. This, however, is not at all strange, because a multicellular organism is an extremely complex structure, and a lot of data is required for its regulation. Telomeres perform one of these regulatory functions: they determine the age of the cell. And here it is worth clarifying: this age is not the time that the cell has existed.

The telomere itself is an extremely simple structure. These are the ends of chromosomes that contain a repeating nucleotide pattern. In most animals, it looks like TTAGGG (letters denote nucleotides: thymine, adenine, guanine, respectively). Such sequences, as already written above, do not encode anything. Their role can be called sacrificial. With each new cell division, its genetic material is copied. A whole complex of enzymes is responsible for this, which untwist, stabilize and reproduce DNA strands, and also form primers. The central role here is played by DNA polymerase, which synthesizes a new nucleic acid strand using the existing one as a template.


DNA polymerase has one peculiarity: it is not able to synthesize a DNA strand from the very end. This is a kind of "not a bug, but a feature": due to this feature of the enzyme, DNA strands are shortened by a certain length with each division. It would seem that the cells obtained by such a process will be defective from a genetic point of view, because important information may be lost. But, thanks to the existence of telomeres, this loss does not occur until a certain point: the terminal DNA sequences humbly decrease in size, allowing the genetic data that they frame to be preserved.


The best short definition for telomeres would be “cell division countdown”. Each cell can go through about 50 divisions: after that, the telomerase defense is exhausted, and this serves as a signal for the onset of apoptosis - programmed cell death. The number of 50 divisions is called the "Hayflick limit" - in honor of Leonard Hayflick, who discovered this division limit. Hayflick and his colleague Paul Moorehead set up a simple and visual experiment. Scientists in equal parts mixed fibroblasts taken from men and women; at the same time, male cells have already gone through 40 division cycles, and female cells only ten. The role of the control group was played by purely male fibroblasts.


When the cells in the control culture stopped dividing, Hayflick and Moorhead found that the mixed culture was no longer mixed: all the male fibroblasts in it died, leaving only female cells. Based on this, Hayflick made his conclusion about the life limit of the cells of the human body.

Discovery of telomerase

However, the life cycle of a cell is not always and not always predetermined by telomeres. There is a mechanism that makes a cell virtually immortal, and its name is telomerase.

The existence of telomerase was predicted back in 1974 as a way to explain the lack of aging in some types of cells - both healthy cells (stem) and pathologically altered (for example, cancer cells). The 45-year-old Soviet scientist Mikhail Olovnikov predicted the existence of this enzyme, calling it tandem DNA polymerase. And seven years later, in 1981, American Elizabeth Blackburn confirmed Olovnikov's theory by isolating this enzyme.


Together with her graduate student Carol Grader, Blackburn isolated and purified the enzyme, showing that, in addition to proteins, it also contains RNA. By the mid-1980s, a number of experiments showed that organisms with mutations in telomerase RNAs experience an accelerated shortening of telomeres, and the cells of these organisms develop very slowly and eventually stop growing. Elizabeth Blackburn confirmed this phenomenon in tetrachimenes (freshwater ciliates), Carol Grader - on human cells, and another American scientist Jack Shostak - in yeast culture. The three scientists are united by another fact: in 2009, they were awarded the Nobel Prize for the discovery of how telomeres and the enzyme telomerase protect chromosomes.


These discoveries have redefined the genetics of aging. Many scientists vied with each other that telomerase is the key to eternal youth, and not just a single cell, but the whole organism. However, further events showed that not everything is so simple - and one single key will not open all the doors. However, more on that later.

Diseases associated with telomeres and telomerase

Telomerase and telomere dysfunction leads to a variety of pathological conditions and diseases. Most of them were described long before the discovery of the "enzyme of immortality", in the first half of the 20th century. For example, in congenital dyskeratosis due to gene mutations and associated TERT and TERC defects, the telomeres of patients are very short. This leads to the fact that in most cells the normal division cycle is disrupted and the instability of the genome increases. And those few cells that are able to maintain the activity of the enzyme quickly turn into cancerous ones. As a result, three quarters of patients with dyskeratosis do not even live up to 30 years.


Perhaps the most famous disease associated with telomere defects is childhood progeria, or Hutchinson-Guildford syndrome. In this disease, the LMNA gene mutates, which is responsible for the synthesis of lamin, a protein that is part of the membrane of the cell nucleus. A defective form of lamina, the so-called progerin, disrupts many genetic processes, including greatly shortening telomeres. Children's Progeria clearly shows how a violation of the mechanisms of cellular aging is reflected in the body as a whole. Patients already at the age of four to five years look like old people: a bird's face, a pointed nose, degenerative processes in nails, hair and teeth. Such children rarely live to even reach adulthood.


Some diseases lead to telomere dysfunction, which only undermines an already weak body even more. This is Huntington's chorea, an autosomal dominant genetic disorder. Its cause lies not in telomeres, but in the gene encoding the huntingtin protein with a function that is still unknown to scientists. However, among other things, the development of Huntington's chorea also entails a reduction in telomere length.A study by Mexican scientists showed that symptomatic patients had about one and a half times shorter telomeres than healthy people or early-stage patients.


Most likely, due to the accumulation of huntingtin in mitochondria, more reactive oxygen species are formed there, which leads to the development of oxidative stress and damage to telomeres. In this case, the mutant protein blocks enzymes that are responsible for DNA repair, so defective telomeres remain truncated.

And, of course, talking about telomeres, one cannot ignore oncological diseases. Moreover, in this case, the problem is no longer too short, but excessively long telomeres. An important fact: most often, tumor structures arise precisely in constantly renewing tissues, where telomerase activity is high and in a normal state.

This fact suggests that the normal state of our body and how it ages is a natural "golden mean", a way to maintain a balance between aging too quickly and becoming a mass of constantly proliferating cells. The study of telomerase in the context of cancer inevitably leads to the conclusion that the large length of telomeres as such does not lead to either eternal or even prolonged youth.

An excellent confirmation of this is the mice. Normally, the telomere length in these rodents is noticeably longer than in humans: sometimes by four to five times. In some lines of laboratory mice, the length of telomeric sequences can even reach 150 thousand base pairs (in humans, this figure usually does not exceed 15 thousand pairs). This is largely why laboratory mice are a popular model object for studying the mechanisms of tumor formation and treatment.

The mechanics of "immortal pieces"

Telomerase is not a single molecule, but a complex ribonucleoprotein complex. In simpler terms, a collection of proteins and RNA. The main components of this set are the telomerase RNA component TERC and telomerase reverse transcriptase TERT. TERC is a nucleotide sequence containing a special region (AAUTSC), the template on which TERT synthesizes a complementary DNA strand. Attaching to the so-called 3'-end of DNA (with a free hydroxyl group), telomerase adds one nucleotide to it sequentially.


This matrix area is flanked (flanked) by two elements: a 5'-matrix bounding and a 3'-matrix recognizer. The 5'-element is a double-stranded region located immediately before the RNA template: it regulates the addition of nucleotides during reverse transcription and, apparently, serves as a binding site for TERT. Using mutagenesis, it was shown that for the effective functioning of telomerase, it is not the nucleotide sequence itself that is important, but the secondary structure of this region.


The 3'-recognition element is a single-stranded structure located after the template region, which allows the end of the template to take place in the active center of telomerase, stimulates telomerase activity, and also contains a binding site for the N-terminus of the TERT subunit.

Of the elements of the secondary structure of telomerase RNA, the pseudo-knot, or the stabilizing hairpin, is most intensively studied. Changes in the stability of the pseudoknot lead to a decrease in telomerase activity, which indicates an important biological role of this structural element. Recent results of studying oligonucleotides mimicking the elements of the TERC pseudo-knot structure have confirmed that it is the dynamics of the tertiary structure of the pseudo-knot that plays an important role in the functioning of telomerase.

As we wrote above, all cells of the body do not need immortality. Accordingly, telomerase is not active everywhere. The TERC component is transcribed in many cells, but reverse transcriptase is absent in most of them. A fully functional telomerase complex can be found in germ and stem cells.Telomerase activity is also observed in cells that are constantly dividing (for example, intestinal epithelial cells and B-lymphocytes).

How to live longer and what does the "mouse of Methuselah" have to do with it?

It is not surprising that almost immediately after the discovery, telomerase was called the enzyme of immortality and they began to look for ways with its help, if not to reverse aging, then at least to slow it down as much as possible. When telomeres in a cell are shortened to a certain critically short length, the mechanisms of cellular senescence and apoptosis - cell death - are triggered.

It is logical that many scientists have jumped on the idea that influencing telomere function in some way can help prolong human youth. It was in the 1980s, when the existence of telomerase and its role in cell aging was confirmed, that gene therapy methods began to develop. Individual genes were isolated, expression vectors (genetic constructs for transferring information into the cell and its subsequent use) began to be actively created, and gene transfers in mice and other laboratory animals became commonplace.


Telomere-targeted gene therapy was only a matter of time. However, this approach caused many concerns. DNA is a complex structure, the cell as a whole is even more complex. The risk that "prank will spiral out of control" is very high. Why not turn to the tried and tested method of taking pharmaceuticals? Or turn to methods such as dietary restriction?

Yes, such relatively trivial methods can achieve serious results. So, in 2004, Stephen Spindler from the University of Riverside in California was able, by limiting the calorie intake of a group of mice, to achieve that the average lifespan of rodents was 1356 days, or about 3.5 years. And this is really a lot - taking into account the fact that these animals usually live on average about two years.


It is worth noting that Spindler worked with mice far from the moment they were born. The scientist took 19-month-old animals (average age by human standards): for humans, this is like taking a person slightly over 40 and making him live to 90 years.

However, genetic editing techniques are, of course, much more promising for many reasons. First, the results they can achieve are more impressive. So, Andrzej Bartke, using methods of genetic modification, was able to create a mouse that lived 1819 days - more than five years. For their development, Bartke and his experimental received a special "Methuselah mouse prize", named so in honor of the biblical long-liver.


Second, restricting food or taking medication is a lifelong job. And with the editing of genetic information, everything is simple: once you have corrected what you need, and you live on. And most importantly, gene therapy has a higher degree of targeting than drugs, which exhibit a large number of side effects.

A fearsome virus extends the life of rodents

But no matter how promising the approach of directly affecting genes is, one should not forget about the need to find the golden mean. Yes, short telomeres and inactive telomerase lead to rapid aging, but too active telomerase is a high chance of getting a cancer. Therefore, the task facing scientists who deal with the issues of rejuvenation and gerontology is formulated as follows: how to activate the work of the telomerase complex in a limited time period?

Some success in this has been achieved by a group of scientists from the Spanish National Cancer Research Center under the leadership of Maria Blasco. Taking two groups of mice (one and two years of age, respectively), the researchers injected them with the gene for reverse telomerase transcriptase TERT. Adeno-associated virus (AAV) was chosen as a vector basis for the entry of this gene into the genome of the modified organism.


It sounds creepy, but don't be intimidated: AAV is not a pathogen, it does not cause any disease symptoms and provokes a very weak immune response. In addition, although this virus inserts its genes into the host's genome, it is very predictable, at a specific site, and insertion into random sites is vanishingly rare.


Such therapy, as seen in the image above, increased the lifespan of rodents by 24% for one-year-old mice and 13% for two-year-old mice. This is not as impressive as the results obtained by Bartke and Spindler, but it is quite significant. It is also important that in Blasco's experiments in mice that received an injection of AAV, there was no increase in the oncogenic activity of telomerase compared with the control group of animals.

In another interesting experiment, scientists managed to "improve" telomeres without increasing oncogenic activity in the body of mice. Spanish researchers created rodents with elongated telomeres using an original technique. The authors drew attention to the fact that the highest telomerase activity is observed in stem cells in the first days of the existence of the embryo, and then gradually decreases. By selecting stem cells from embryos for growing in culture and preventing them from differentiating, biologists have achieved that telomerase provided these cells with telomeres twice as long as in normal healthy mice.

Then these "supercells" were injected into the embryos of normal mice. As a result, scientists obtained chimeric rodents: in their placenta and embryonic membranes there were cells with short telomeres, and the rest of the mouse organism consisted of cells with chromosomes elongated due to tail sequences. Subsequent observations showed that in chimera mice, telomere length at any age was at least a quarter longer than in unmodified "peers". Moreover, telomerase in somatic cells remained inactive.


Such chimera mice were noticeably slimmer than their usual relatives, their blood contained several times less so-called bad cholesterol (low density lipoproteins). The modified mice also lived longer: their average lifespan increased by 13% compared to the control group of animals, and the maximum duration increased by 8%. In addition, they also had cancer less often than mice out of control!

An important biochemical marker - somatomedin

Of course, telomerase is not the only target of genetic therapy that can affect the aging process. For example, growth hormone, also known as growth hormone. Scientists came to a similar idea after it turned out that there is a certain level of this hormone in the body, which corresponds to the maximum life expectancy. If the level is higher or lower, then the risk of death from all causes increases.

Numerous experiments have shown that it is more convenient to act not on somatotropin itself, but on one of its mediators - insulin-like growth factor-1, or somatomedin. This substance is secreted in the liver in response to stimulation of the growth hormone receptors of this organ and regulates the secretion of growth hormone and somatostatin.

As shown by the experiments of scientists from the University of Gothenburg, conducted in 2012, the optimal level of somatomedin, providing the minimum risk of mortality from all causes, ranges from 105-125 mg / ml. Researchers from the United States came to almost the same conclusions two years later. Their work showed that in people aged 50 to 65 years, it was with this level of IGF-1 that the lowest risk of death from all causes was noted.


But it is difficult to directly affect the level of the neurotransmitter in the blood, so the gene for growth hormone receptors was chosen as the final target. GHRKO (Growth Hormone Genes Partial Knockout) technology was tested on mice in 2016-2017; experiments have shown that the duration of GHRKO mice is about a third longer than that of wild-type mice.By the way, about the same results were shown by rodents, which were specially kept on a diet to reduce the level of somatomedin.

Another important biochemical component that can increase lifespan is fibroblast growth factor FGF-21. This molecule enhances the uptake of glucose by adipocytes, adipose tissue cells. FGF-21 is synthesized in response to a lack of nutrients to help adapt to fasting. Among other things, FGF-21 blocks growth hormones, decreasing the concentration of somatomedin.

Well, what about the people?

However, above we all the time write about mice and about mice - but what about an increase in life span and a delay in aging in humans? Have you heard of any results? Moreover, the budgets of the world's leading organizations studying the fight against aging amount to tens of millions of dollars a year.

For some reason, techniques that give good results in mice (and also in other short-lived creatures like worms or flies) no longer work in primates. In particular, it is worth mentioning two fairly large studies that started in the United States in the late 1980s. In them, scientists investigated the effect of 30 percent calorie restriction in the diet on the lifespan of rhesus monkeys.


In 2017, a review article on these two studies was published in Nature entitled Caloric restriction improves health and survival of rhesus monkeys. But don't look for anything hopeful or supernatural there: improvement is limited to five percent.

What about telomerase? Perhaps the most famous experiment on this topic is the experiment that the American Elizabeth Parrish performed … on herself. In 2015, Parrish injected herself with two AAV-based vectors: the first contained the telomerase TERT gene, and the second contained the gene for follistatin, a muscle growth promoter and myostatin antagonist (previously, follistatin had been successfully tested in people with muscular dystrophy). Parrish was inspired by the results previously obtained by Blasco's group on mice.


After a year of the experiment, the first results were published. Then many world media were full of headlines in the style of "a woman rejuvenated herself by 20 years." Why exactly 20? A study of Parrish's chromosomes showed that the telomeres in her lymphocytes lengthened from an average of 6710 base pairs to 7330 pairs. If we take into account that the rate of shortening of telomere sequences in the cells of the immune system is about 30 pairs per year, then we just get the same conditional 20 years - although it is certainly not worth extrapolating to the whole organism as a whole.

In percentage terms, telomeres have lengthened by only 9%. It should be said here that when measuring the length of chromosomal sequences by the method of quantitative PCR, the error in the norm can reach 8–10%. This fact immediately caused a certain skepticism in relation to Parrish and her experiment. However, the researcher said the measurements were confirmed by two independent laboratories.

A year later, Parrish issued a press release with the results of gene therapy. In it, in particular, she published an MRI of her thighs. Allegedly, a comparison of pictures taken in 2015 and 2017, respectively, showed a decrease in the so-called marbling of muscles, that is, a decrease in the amount of fat deposits inside the muscles. This, in principle, could be a positive effect of follistatin therapy. However, here, too, many experts had serious doubts about the data.


Firstly, two years have passed between the images, and it is possible that the difference in the images is due only to the fact that a better apparatus appeared in the researcher's arsenal. Secondly, the difference in the distance between the two legs in the sections is clearly visible. Of course, a woman could just put her legs a little wider, especially since try to remember how the procedure was carried out last time.

Hayflick, Shostak and Olovnikov are not happy

In fact, Parrish's experiment cannot be called such: only the subjective sensations of one person and measurements, which cannot even be called experimental, serve as confirmation of any positive results. This approach, of course, does not stand up to any standards. However, the topic is specific, so it is also impossible not to notice this case.

What do the patriarchs of genetics think of Parrish? One of the "fathers" of telomerase, Jack Shostak, who received the Nobel Prize for his work on explaining the mechanisms of protection of chromosomes, generally called Parrish's approach unscientific, and he herself compared her with a fraudster who wants to fool people and lure them out of money for an unverified, and possibly dangerous a drug.

Leonard Hayflick, whose discovery began the study of cellular aging and telomeres, was also not thrilled. The discoverer of the limit of cell division was not harsh in his statements, but he does not harbor any special hopes about the experience of rejuvenation. “Since ancient times, people have been experimenting trying to delay old age. But for various reasons, no one has yet achieved success, '' Hayflick sums up sadly. “Moreover, we do not have the means to determine the effect. For centuries, people have believed that their knowledge of biology is enough to understand how to defeat aging. But since this process is the result of the second law of thermodynamics, the probability of a successful intervention is close to zero. Everything in the Universe is aging."

But Alexey Olovnikov - the man who put forward the very idea of ​​the existence of telomerase - spoke about the American woman intricately. In an interview with Schrödinger's Cat, the scientist said that he admired Elizabeth's courage, and noted two components of her act: “courage and desire to promote her company”. Here you will not immediately understand where the irony is, and where is really admiration.

The promises of William Andrews

To this day, Elizabeth Parrish remains the only customer of the startup BioViva to use their products. No news of clinical trials of the product (successful or unsuccessful), no information about new customers appeared on the Web. A woman who has decided to rejuvenate herself is still one of a kind.

Nevertheless, BioViva already has its first real competitor - Libella Gene Therapeutics. Its representatives are also going to inject viral vectors with the telomerase gene into patients. In addition, the first customers of the firm must actually become participants in the first clinical trial of the product. By the way, about customers: in the fall of 2019, a company representative said that they already have two potential buyers who should have received their injections at the beginning of this year. Meanwhile, in order to use the products of Libella Gene Therapeutics, you need to be a very, very rich person or find a serious sponsor: this therapy costs a million dollars. However, firm spokesman Jeff Mathis claimed that a 79-year-old man and a 90-year-old woman had already paid for the treatment. However, since December last year, no news has been heard from the company; however, her website is still up and running, and no one is suing them for their million. Perhaps all agreements are in force, and as soon as the coronavirus wave subsides in the world, experiments will resume.

However, there are certain doubts about this, and the main reason for them is the founder of the company and its leading researcher, William Andrews. On account of this respectable man with glasses and a tie, there are already several unfulfilled high-profile promises. So, back in 2017, Andrews promised to deploy telomerase trials for rejuvenation technologies (which, as we already know, did not happen). And a year earlier, William, while an employee of another company, talked about plans to build a clinic in Fiji for rejuvenation services. By the way, BioViva was the very company Andrews was working in at the time.


Reason number two is the cost of such therapy.Since potential participants in clinical diseases are called clients and are obliged to pay for the procedures themselves, obviously, there were no sponsors who would like to invest in the company's development. This is understandable: no sensible results have yet been obtained, either on monkeys or on humans, and it is generally not known whether it makes sense to further pore over vectors with the TERT gene. At the same time, many people are unlikely to be able to shell out a million dollars, and, accordingly, their number in any case will not be sufficient to draw any specific and statistically significant conclusions. Visual images of MRI of the thighs are original, but, alas, they do not confirm the effectiveness of therapy.

Biopirates and Scientific Robin Hoods

If cost is one of the main barriers to a drug, can it be made cheaper? And we are talking here not only about efficiency, but also about the possibility of conducting sufficiently massive tests. If they show the complete uselessness of the created medicine, then in the process they can at the same time indicate the path along which to move.

Biohackers are working on this problem under the leadership of Gabriel Lisina. True, their interest is not directed towards rejuvenation agents, but genetic therapy as such. In particular, last year Lisina and his colleagues created a “pirated version” of the drug for correcting protein lipase deficiency. This is a very rare genetic disorder in which the body is unable to break down complex fats, causing them to accumulate in the blood, organs and under the skin. To cope with the deficiency of protein lipase, you can use a rigid diet with a number of additional restrictions - or "tweak the genome settings."

Typically (as far as rare disease is concerned) protein lipase deficiency is treated with Glybera, the first ever gene therapy method approved for use in clinics in the EU and the United States. At the same time, the cost of an injection of Glybera is the same as that of the drug offered by Libella Gene Therapeutics: one million dollars. Lisina's team has created an analogue of the drug called Slybera (a subtle play on words is hidden here: sly means "cunning" in English). And the cost of this analogue is only seven thousand. The difference is almost 143 times!


In theory, the approach used by Lisina to create Slybera can be applied to a telomerase preparation. Slybera was created according to the scheme already described by us earlier: on the basis of a viral vector. The sequence of the gene - be it the protein lipase gene or the telomerase gene - can be found in open databases. Biohackers took the healthy gene sequence from open articles that came out during the development of Glybera and sent it to a commercial DNA synthesizer lab. The result is a circular DNA molecule with the desired gene, which the authors of the project propose to use as an alternative medicine.

We have already said about the advantage of this approach: the cost of the pirated version of the drug differs from the official product by many orders of magnitude. However, the disadvantages may still be more significant. It's just that the DNA molecule will penetrate cells much worse, and the genes it contains will be less actively expressed. Among other things, a cheaper drug in fact is not so cheap: not so many people who need gene therapy can take and lay out seven thousand just like that out of their pocket.

It's not length that matters, but speed: works for telomeres too

Recently, more and more studies have appeared that indicate that telomere length itself does not correlate with life expectancy. One of these was published last August in Aging Cell magazine. Scientists analyzed the length of telomeric sequences in 379,758 people, whose biological information was taken from the UK Biobank research database. At the same time, about 261 thousand subjects at the time of the end of the study were over 60 years old.


For 7.5 years, researchers tested the links between genetically determined telomere length and aging-related health outcomes. In the course of the work, 13 genetic variants associated with a longer telomere length in peripheral leukocytes were identified. Longer telomeric sequences were found to be significantly associated with a lower risk of coronary heart disease. But the risk of developing cancerous tumors at the same time increased markedly - which, however, is not surprising.


The most interesting thing is that scientists did not find a significant connection between life expectancy in people with long telomeres. That is, if your telomeres are longer than normal, you are likely to face less problems with the cardiovascular system, but more likely to develop cancer. And how long you live depends, most likely, on other factors.


Still, there is at least one important telomere parameter that is clearly associated with life expectancy. We are talking about the rate of shortening of these end sections of chromosomes. As shown by the work of Spanish scientists, published in the publication Proceedings of the National Academy of Sciences, this indicator allows you to estimate the life span of a creature more accurately than the absolute length of telomeres, changes in heart rate or body weight.

In this study, scientists measured the rate of contraction of the terminal regions of chromosomes in nine different species of animals: the domestic goat, house mouse, bottlenose dolphin, red flamingo, Sumatran elephant, griffon vulture, Audouin's gull, reindeer, and humans. Scientists considered the correlation between the rate of telomere shortening in mononuclear blood cells of the listed species with life expectancy, body weight and metabolic rate (the latter was calculated by heart rate).

As in the previous study we mentioned, the extent to which the length of telomeres was knocked out of the average for a certain type of parameters did not in any way affect the life span of the animal. But the rate of contraction of telomeres predicted this parameter quite well. As the authors note, this confirms the hypothesis that life expectancy depends on the moment at which telomeres are shortened so much that chromosomes will lose important genetic information.

New object of interest

Now the interests of gerontologists are gradually shifting from telomerase and life extension as such to other biological mechanisms and indicators. If you cannot guarantee to increase a person's life span to 100, 120 or 150 years, perhaps there are ways to improve the quality of life in recent years - even if the person will live "only" 80 years.

It's no secret that the last years of life often become a real torment. A huge number of cardiovascular, metabolic, autoimmune, malignant and degenerative diseases develop with age. Of course, many researchers have tried to find a way to prevent this. However, for a long time the reason for the development of this complex remained unclear.


The main reason for the development of a group of senile pathologies is called systemic chronic inflammation that develops with age. Among the numerous candidates for the role of the causative agent of chronic inflammation, the theory of senescent cells (SC) has received the greatest scientific support. In 2011, a breakthrough was made in this area when a team led by James Kirkland and Jan van Dursen from the Mayo Clinic showed that removing cells carrying one of the CK markers in mice - the so-called p16 protein involved in the control of the cell life cycle - leads to partial rejuvenation of individuals.

The results of subsequent studies confirmed that it is senescent cells that are the main cause of aging, and set a clear direction for the search for anti-aging drugs among "senolytics" capable of selectively removing SCs from the body, which are considered a "source of decrepitude."

Subsequently, a more detailed study of the problem of “senolytics” showed that while all SCs carry the p16 marker, not all cells on the membrane of which such a protein is expressed are senescent. Most of them are completely different structures of the immune system - macrophages, which are responsible for removing senescent cells from the body. Thus, it can be assumed that with age, not only the accumulation of SC occurs, but also the impairment of the functioning of the immune system, which is capable of independently removing SC at a young age, preventing the development of inflammation.


The fact that at least some of the cells considered to be SC turned out to be macrophages does not contradict the theory of "chronic inflammation" and in no way changes the importance of the results of previous studies. The new data has only adjusted the course of anti-aging drug development towards a better characterized target and a greater understanding of the processes occurring in the aging body.

Defining "chronic inflammation" as the link between all age-related diseases was a major advance in the development of a cure for aging. For the first time in the history of gerontology, most experts from various fields of the science of aging come to an agreement. This concept has extremely important implications, not only because it helps to identify the common cause of all age-related ailments, but also because it allows you to identify the target for therapy - cells that accumulate with age.

Useful lessons

Until recently, telomeres were considered the main way to prolong human life. Today, it seems, the “first telomeric winter” is coming: everything that could be done with the help of the “enzyme of immortality” has already been done. Obviously, telomerase does not indicate the path to long life: it only helps us to know our limits, to understand that life span is sandwiched between early aging and uncontrolled tumor formation.

Scientists' attention is gradually shifting to other ways to combat aging and prolong life. Senescent cells, various diets, medications - not fully understood ways to add years to a person are still very many. What will happen to the telomere? Perhaps, for a while, from a hope for humanity, it will turn into a toy for scientists: strange, but in a sense, this is not bad.

Less speculation will allow it to again be “just” an essential element for biological, biochemical and genetic research. Not everyone who read the article to the end found it easy (and, let's face it, even interesting) to read the section on the mechanics of work. Sometimes areas "overheated" by the general interest need some rest in order to become part of pure science from a target for hopes and scammers. Of course, it is a pity if this road to immortality turns out to be a dead end in the end. But what can you do: there are many useful lessons to be learned from the experience with telomerase. It is quite possible that in a year or ten years, a new discovery in the field of chromosomal genetics will explode the scientific world and raise a new wave of interest in telomeres and their features. But for now, it seems, recipes for old age need to be looked for elsewhere.

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