A dead end on the road to immortality?
Telomeres: the obscure secret of longevity
Probably, even from the moment when our first great-great-grandparents gained consciousness, a person was afraid of death and was looking for ways to prevent or delay it. Ancient man craved solace in the ideas of the afterlife, later alchemists tried to invent potions that would help achieve immortality. With the development of science, scientists sought to understand how our mortality works at the cellular level and even deeper – and whether it is possible to seriously change the age measured to a person. It is about telomeres that they often talk about as a kind of secret of longevity, the very magic lever in DNA that can add one or two decades to our life. Is it so?
Telomeres.
What are telomeres?
The DNA of eukaryotes (organisms whose cells all have a nucleus – unlike prokaryotes, which do not have one) consists of both coding and non-coding sites. And the first is much less than the second. 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 end sections of chromosomes that contain a repeating nucleotide pattern. In most animals, it looks like TTAGGG (the letters denote the 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 unravel, stabilize and reproduce DNA strands, as well as form seed primers. The central role here is played by DNA polymerase, which synthesizes a new nucleic acid chain using an existing one as a matrix.
With each cell division, the length of telomeric sequences is gradually reduced. After reaching the Hayflick limit, the cell can no longer divide normally further.
DNA polymerase has one feature: it is not able to synthesize a DNA strand from the very end. This is a kind of "not a bug, but a feature": thanks to this feature of the enzyme, DNA strands are shortened by a certain length at each division. It would seem that the cells obtained in this 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 up to a certain point: the end sequences of DNA are humbly reduced in size, allowing the genetic data that they frame to be preserved.
The enzyme telomerase.
The best short definition for telomeres is "reverse counter of the number of cell divisions". Each cell can go through about 50 divisions: after that, telomerase protection 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 limit of divisions. Hayflick and his colleague Paul Moorhead set up a simple and visual experiment. Scientists mixed fibroblasts taken from men and women in equal parts; at the same time, male cells have already passed 40 cycles of division, and female cells – only ten. The role of the control group was played by purely male fibroblasts.
Leonard Hayflick.
When the cells in the control culture stopped dividing, Hayflick and Moorhead discovered that the mixed culture was no longer mixed: all male fibroblasts in it died, only female cells remained. Based on this, Hayflick made his conclusion about the life limit of the cells of the human body.
Discovery of telomerase
However, not always and not everywhere the life cycle of a cell is predetermined by telomeres. There is a mechanism that allows you to make a cell virtually immortal, and its name is telomerase.
The existence of telomerase was predicted back in 1974 as a way to explain the absence of aging in some types of cells – both healthy (stem) and pathologically altered cells (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.
Alexey Olovnikov predicted a Nobel Prize-winning discovery. But the Soviet scientist himself was left without a reward.
Together with her graduate student Carol Grader, Blackburn isolated and purified the enzyme, showing that, in addition to proteins, it also includes RNA. By the mid-1980s, a number of experiments showed that organisms with a mutation in telomerase RNAs have accelerated telomere shortening, and the cells of these organisms develop very slowly and eventually stop growing. Elizabeth Blackburn confirmed this phenomenon in tetrachymenes (freshwater infusoria), Carol Grader – on human cells, and another American scientist Jack Shostak – in yeast culture. These three scientists are united by another fact: in 2009, "for the discovery of how telomeres and the enzyme telomerase protect chromosomes," they were awarded the Nobel Prize.
Laureates of the Nobel Prize in Physiology and Medicine for 2009. From left to right: Carol Greider, Elizabeth Blackburn, Jack Shostak.
These discoveries have turned the view on the genetics of aging. Many scientists vied with each other to declare that telomerase is the key to eternal youth, and not just a single cell, but the body as a whole. However, subsequent events have shown that not everything is so simple – and a 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 XX 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 the normal cycle of division is disrupted in most cells and the instability of the genome increases. And those few cells that are able to maintain the activity of the enzyme turn into cancer cells fairly quickly. As a result, three quarters of patients with dyskeratosis do not even live to 30 years.
A child with child progeria.
Perhaps the most famous disease associated with telomere defects is childhood progeria, or Hutchinson–Guilford syndrome. In this disease, there is a mutation of the LMNA gene responsible for the synthesis of lamin, a protein that is part of the cell nucleus envelope. The defective form of lamin, 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 or five years look like old men: a bird's face, a pointed nose, dystrophic processes in nails, hair and teeth. Such children rarely live at least to adulthood.
Comparative telomere length in patients with a negative prognosis for Huntington's disease, a positive prognosis for it and a diagnosed disease.
Some diseases entail telomere dysfunction, which only further undermines an already weak body. This is Huntington's chorea – an autosomal dominant genetic disease. Its cause lies not in telomeres, but in the gene encoding the huntingtin protein with a function unknown to scientists so far. However, among other things, the development of Huntington's chorea entails a reduction in the length of telomeres. A study conducted by Mexican scientists showed that in patients with symptoms, telomeres were about one and a half times shorter than in healthy people or in patients at an early stage.
As the telomere length decreases, the cell can either die in a normal way, or be reborn into a cancerous one.
Most likely, due to the accumulation of huntingtin in the mitochondria, more reactive oxygen species are formed there, which leads to the development of oxidative stress and damage to telomeres. At the same time, the mutant protein blocks enzymes that are responsible for DNA repair, so defective telomeres remain shortened.
And, of course, talking about telomeres, it is impossible to 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 turning into a mass of constantly proliferating cells. The study of telomerase in the context of cancer inevitably leads to the conclusion that a long telomere length as such does not lead to eternal, or at least to prolonged youth.
Mice are an excellent confirmation of this. Normally, the telomere length in these rodents is noticeably longer than in humans: sometimes four to five times. In some lines of laboratory mice, the length of telomeric sequences can even reach 150 thousand pairs of nucleotide bases (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 combination of proteins and RNA. The main components of this set are the telomerase RNA component TERC and the telomerase reverse transcriptase TERT. TERC is a sequence of nucleotides containing a special site (AAUCC), a matrix on which TERT synthesizes a complementary DNA strand. Joining the so-called 3’-end of DNA (with a free hydroxyl group), telomerase adds one nucleotide to it sequentially.
The two most important components of the telomerase complex are the TERC RNA matrix and the TERT reverse transcriptase enzyme
This matrix section is flanked (framed) by two elements: a 5’-matrix limiting and a 3’-matrix recognizing. The 5’ element is a double-stranded site located directly in front of the RNA matrix: it regulates the addition of nucleotides during reverse transcription and, apparently, serves as a binding site to 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 site.
Secondary structures of TER of various organisms: protozoa Tetrahymena, mammals, as well as humans and yeast Saccharomyces.
The 3’-recognizing element is a single–stranded structure located after the matrix site, which allows the end of the matrix to take a place in the active center of telomerase, stimulates telomerase activity, and also contains a binding site of the N-end of the TERT subunit.
Of the elements of the secondary structure of telomerase RNA, the pseudo-node, or stabilizing hairpin, is most intensively studied. Changes in the stability of the pseudonode lead to a decrease in telomerase activity, which indicates an important biological role of this structural element. The recently obtained results of the study of oligonucleotides that mimic the elements of the structure of the pseudo-node of TER have confirmed that it is the dynamics of the tertiary structure of the pseudo-node that plays an important role in the functioning of telomerase.
As we wrote above, immortality is not required for all cells of the body. 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 "Methuselah mouse" have to do with it?
It is not surprising that almost immediately after the discovery, telomerase was called the enzyme of immortality and began to look for ways to use it, 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 aging and apoptosis – cell death - are triggered.
It is logical that many scientists have seized on the idea that the effect on the function of telomeres is somehow able to help prolong human youth. Just in the 1980s, when the existence of telomerase and its role in cell aging were confirmed, 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.
Survival schedule of one- and two-year-old mice in the experiments of the Blasco group. The survival rate of rodents that received a viral vector with the TERT gene is shown in black, and the viral vector without the corresponding gene is shown in gray. The blue color is the control group.
The use of gene therapy methods aimed at telomeres was a matter of time. However, such an approach caused many concerns. The DNA structure is complex, the cell as a whole is even more complicated. The risk that the experiment will get out of control is very high. Why not turn to a proven method – taking pharmaceuticals? Or turn to methods such as food restriction?
Yes, such relatively trivial methods can achieve serious results. So, in 2004, Steven Spindler from the University of Riverside in California was able to achieve by limiting the caloric intake of a group of mice that the average life expectancy of rodents was 1,356 days, or about 3.5 years. And this is really a lot – taking into account the fact that usually these animals live on average for about two years.
The percentage of survival of mice depending on age in Spindler's experiments. White mugs are mice that ate with calorie restriction, black mugs are a control group of mice.
It is worth noting that Spindler has not worked with mice since their birth. The scientist took 19-month-old animals (average age by human standards): in relation to humans, it's like taking a person aged slightly over 40 and ensuring that he lives to 90 years.
However, the methods of genetic editing, of course, are much more promising for many reasons. Firstly, the results that can be achieved with their help are more impressive. Thus, Andrzej Bartke, using genetic modification methods, was able to create a mouse that lived for 1819 days – more than five years. For their development, Bartke and his test subject received a special "Methuselah mouse prize", named after the biblical centenarian.
Andrzej Bartke and the mouse.
Secondly, restricting food or taking medications is a job for life. And with the editing of genetic information, everything is simple: once you correct what you need, and you live on. And most importantly, gene therapy has a higher degree of focus than drugs that exhibit a large number of side effects.
The fearless virus prolongs the life of rodents
But no matter how promising the approach of direct influence on genes is, we should not forget about the need to find a golden mean. Yes, short telomeres and inactive telomerase lead to rapid aging, but too active telomerase is a high chance of getting a cancerous tumor. Therefore, the task facing scientists who deal with rejuvenation and gerontology is formulated as follows: how to activate the work of the telomerase complex for a limited time period?
A group of scientists from the Spanish National Cancer Research Center led by Maria Blasco has achieved some success in this. Taking two groups of mice (one and two years old, respectively), the researchers injected them with the TERT reverse telomerase transcriptase gene. An adeno-associated virus (AAV) was chosen as a vector basis for entering this gene into the genome of the modified organism.
Adenoassociated virus (AAV).
It sounds creepy, but do not be afraid: AAV cannot be called a pathogen, it does not cause any symptoms of the disease and provokes a very weak immune response. In addition, although this virus introduces its genes into the host genome, it is very predictable, according to a specific site, and embedding into random sites is vanishingly rare.
FIG. 16a – experimental diagram: yellow – cells of an ordinary mouse, green – fluorescent cells with long telomeres;
b – fluorescent cells in tissues: the upper row is an ordinary mouse, the lower one is a mouse with long telomeres, red color is staining with antibodies to a fluorescent protein;
c is a slimmer mouse with long telomeres next to the control at the ages of 40 and 110 weeks,
d is the dynamics of the weight of mice, gray is control, black is experiment.
Such therapy, as can be seen in the image above, increased the life expectancy of rodents by 24% for one–year-old mice and by 13% for two-year-olds. 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, mice that received an injection of AAV did not have an increase in oncogenic telomerase activity compared to 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 have 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 embryo's existence, and then gradually decreases. By selecting stem cells from embryos to grow in culture and preventing them from differentiating, biologists have ensured that telomerase has provided these cells with telomeres twice as long as in normal healthy mice.
Then such "super cells" were injected into the embryos of ordinary mice. As a result, scientists obtained chimeric rodents: in their placenta and germ membranes there were cells with short telomeres, and the rest of the mouse body consisted of cells with chromosomes elongated due to tail sequences. Subsequent observations showed that in chimera mice, the telomere length at any age was at least a quarter longer than in unmodified "peers". Moreover, telomerase remained inactive in somatic cells.
In the experience of Spanish scientists, mice with longer telomeres were slimmer than their counterparts with short terminal chromosome sequences.
Such chimera mice were noticeably slimmer than their usual relatives, their blood had several times less so-called bad cholesterol (low-density lipoproteins). And the modified mice lived longer: their average life expectancy increased by 13% compared to the control group of animals, and the maximum duration – by 8%. In addition, they also got cancer less often than the mice from the control!
An important biochemical marker is 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 somatotropin. 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, 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 intermediaries – insulin-like growth factor-1, or somatomedin. This substance is secreted in the liver in response to stimulation of the somatotropin receptors of this organ and regulates the secretion of somatotropin and somatostatin.
As the experiments of scientists from the University of Gothenburg conducted in 2012 showed, the optimal level of somatomedin, which provides a minimal risk of mortality from all causes, ranges from 105-125 mg/ml. Researchers from the USA came to almost similar conclusions two years later. Their work showed that people aged 50 to 65 years had the lowest risk of death from all causes at this level of IGF-1.
The relationship of mortality from all causes, from cancer and cardiovascular diseases with the level of somatomedin in the blood.
But it is difficult to directly influence the level of the mediator in the blood, so the growth hormone receptor gene was chosen as the final target. GHRKO technology (partial knockout of growth hormone genes) was tested on mice in 2016-2017; experiments have shown that the duration of GHRKO mice is about a third higher than that of wild-type mice. By the way, approximately the same results were shown by rodents who were specially kept on a diet to reduce the level of somatomedin.
Another important biochemical component that can increase life expectancy is fibroblast growth factor FGF-21. This molecule enhances the absorption of glucose by adipocytes, adipose tissue cells. FGF-21 is synthesized in response to a lack of nutrients to help adapt to starvation. Among other things, FGF-21 blocks growth hormones, reducing the concentration of somatomedin.
Well, what about people there?
However, above we write all the time about mice and mice – but what about the increase in life span and the postponement of aging in humans? Haven't you heard about 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 (as well as in other short–lived creatures like worms or flies) no longer work on primates. In particular, it is worth mentioning two rather large studies that started in the USA in the late 1980s. In them, scientists investigated the effect of a 30 percent calorie restriction in the diet on the life expectancy of rhesus monkeys.
The percentage of survival of rhesus monkeys depending on the age of the experimental animals. The red graph shows animals to which calorie restriction was applied, the blue graph shows monkeys from the control group.
In 2017, a review article on these two studies was published in Nature entitled Caloric restriction improves health and survival of rhesus monkeys ("Calorie restriction improved the health and survival of Rhesus monkeys"). But don't look for anything encouraging and supernatural there: the improvement is limited to five percent.
What about telomerase? Perhaps the most famous experiment on this topic is the experience that the American Elizabeth Parrish put... on herself. In 2015, Parrish injected herself with two AAV–based vectors: the first contained the TERT telomerase gene, and the second contained the follistatin gene, a muscle growth stimulator and myostatin antagonist (before that, follistatin had been successfully tested on people with muscular dystrophy). Parrish was inspired by the results obtained earlier by Blasco's group on mice.
Elizabeth Parrish.
After a year of the experiment, the first results were published. Then many of the world's 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 telomeres in her lymphocytes lengthened from an average of 6710 base pairs to 7330 pairs. If we take into account that in the cells of the immune system, the rate of shortening of telomeric sequences is about 30 pairs per year, then we just get those conditional 20 years – although it is certainly not worth extrapolating this to the whole organism as a whole.
As a percentage, telomeres lengthened by only 9%. It should be said here that when measuring the length of chromosomal sequences by quantitative PCR, the error can normally reach 8-10%. This fact immediately caused a certain skepticism towards Parrish and her experiment. However, the researcher stated that the measurement results were confirmed in 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 images 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 could in principle be a positive effect of follistatin therapy. However, even here, many experts have serious doubts about the data.
MRI of Elizabeth Parrish's hips. On the left – before, on the right – after.
Firstly, two years have passed between the pictures, and it is possible that the difference in the images is due only to the fact that a better device has appeared in the researcher's arsenal. Secondly, the difference in the distance between the two legs on the slices is clearly noticeable. Of course, a woman could just put her legs a little wider, especially since try to remember how the procedure took place last time.
Hayflick, Shostak and Olovnikov are not thrilled
In fact, the Parrish experiment cannot be called such: only the subjective feelings of one person and measurements, which cannot even be called experimental, serve as confirmation of any positive results. Of course, this approach does not stand up to any standards. However, the topic is also specific, so it is also impossible not to notice this case.
What do the patriarchs of genetics think about Parrish? One of the "fathers" of telomerase, Jack Shostak, who received the Nobel Prize for his work on explaining the mechanisms of chromosome protection, generally called Parrish's approach unscientific, and compared her to a fraudster who wants to fool people and extort money from them for an untested, and possibly dangerous drug.
Leonard Hayflick, whose discovery began the study of cellular aging and telomeres, was also not thrilled. The discoverer of the limit of cell divisions was not harsh in his statements, but he does not have any special hopes about the rejuvenation experience. "Since ancient times, people have been experimenting, trying to delay old age. But for various reasons, no one has achieved success yet," Hayflick sadly sums up. – 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 successful intervention is close to zero. Everything in the universe is getting old."
But Alexey Olovnikov, the man who put forward the very idea of the existence of telomerase, responded intricately about the American. In an interview with the publication "Schrodinger's Cat", the scientist said that he admired Elizabeth's courage, and noted two components of her act: "courage and a desire to promote her company." Here you will not immediately understand where the irony is, and where – really admiration.
The Promises of William Andrews
To this day, Elizabeth Parrish remains the only customer of the startup BioViva who has used their products. No news about the clinical trials of the product (successful or unsuccessful), no information about new customers appeared on the Network. A woman who has decided to rejuvenate herself remains the only one of her kind.
Nevertheless, BioViva has already got its first real competitor – Libella Gene Therapeutics. Its representatives are also going to introduce viral vectors with the telomerase gene to patients. In addition, the first clients of the company should actually become participants in the first clinical trial of the products. Speaking of customers: in the fall of 2019, a representative of the company stated that they already have two potential buyers who were supposed to receive their injections at the beginning of this year. Meanwhile, in order to use Libella Gene Therapeutics products, you need to be a very, very rich person or find a serious sponsor: such therapy costs a million dollars. However, the company's representative Jeff Mathis claimed that a 79-year-old man and a 90-year-old woman had already paid for this treatment. However, since December last year, no news has been heard from the company; however, its website is still working, and no one is suing them for their million yet. Perhaps all the 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 their main reason is the founder of the company and its leading researcher William Andrews. On the account of this respectable man with glasses and a tie, there are already several unfulfilled loud promises. So, back in 2017, Andrews promised to deploy telomerase trials for rejuvenation technologies (which, as we already know, did not happen). A year earlier, William, being an employee of another company, talked about plans to build a clinic for rejuvenation services in Fiji. By the way, the very company where Andrews worked at that time was BioViva.
William Andrews is a man famous for mostly unfulfilled promises.
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 developments. It is understandable: no sensible results have been obtained on monkeys or humans yet, and it is generally unknown whether it makes sense to continue poring over vectors with the TERT gene. At the same time, it is unlikely that many people will be able to pay a million dollars, and, accordingly, their number in any case will not be sufficient to draw any specific and statistically significant conclusions. Visual MRI images of the hips are original, but, alas, the effectiveness of therapy does not confirm.
Biopirates and Scientific Robin Hoods
If cost is one of the main obstacles for a drug, is it possible to make it cheaper? And we are talking here not only about efficiency, but also about the possibility of conducting quite 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 such a problem under the leadership of Gabriel Lisina. However, their interest is not directed to the means for rejuvenation, but genetic therapy as such. In particular, last year Lisina and his colleagues created a "pirated version" of a drug to correct protein lipase deficiency. This is a very rare genetic disorder in which the body is unable to break down complex fats, as a result of which they accumulate in the blood, in organs and under the skin. To cope with protein lipase deficiency, you can use a strict diet with a number of additional restrictions – or "tweak the genome settings".
Usually (as far as it is applicable to a rare disease), protein lipase deficiency is treated with Glybera, the first–ever gene therapy method that is 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 created an analogue of the drug called Slybera (a subtle wordplay is hidden here: sly means "tricky" in English). And the cost of this analogue is only seven thousand. The difference is almost 143 times!
In these containers is Glybera, a drug worth a million dollars.
Theoretically, the approach used by Lisina when creating Slybera can also be applied to a telomerase preparation. Slybera was created according to the scheme already described by us earlier: based on a viral vector. The sequence of a gene – be it a protein lipase gene or a telomerase gene – can be found in open databases. Biohackers took the sequence of a healthy gene from open articles that were published during the development of Glybera, and sent it to a commercial laboratory synthesizing DNA to order. As a result, it turned out to be a ring DNA molecule with the right 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 be much worse at penetrating cells, and the genes it contains will be less actively expressed. Among other things, a cheaper drug is in fact not so cheap: not so many people who need gene therapy can take and lay out seven thousand out of their pocket just like that.
It's not the length that matters, but the speed: it also works for telomeres
Recently, there are more and more works that indicate that the length of telomeres in itself does not correlate with life expectancy. One of these was published last August in the journal Aging Cell. 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 were over 60 years old at the end of the study.
The faster a species' telomeres shorten, the less on average it lives.
For 7.5 years, the 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. It was found that longer telomeric sequences are 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 change in telomere length with age in different animals.
The most interesting thing is that scientists have not found a significant link between life expectancy in people with long telomeres. That is, if your telomeres are longer than normal, you are likely to face fewer problems with the cardiovascular system, but you are more likely to get cancer. And how long you will live depends, apparently, on other factors.
Correlation of telomere length (horizontal axis) with the probability of developing cancer (upper diagram) and coronary heart disease (lower diagram).
But still there is at least one important parameter of telomeres, which is clearly related to 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 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, the researchers measured the rate of contraction of the end sections of chromosomes in nine different animal species: domestic goat, house mouse, bottlenose dolphin, red flamingo, Sumatran elephant, white-headed barn owl, Auduen seagull, reindeer and human. Scientists considered the correlation of the speed 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 out of the average for a certain type of parameters did not affect the life expectancy of the animal in any way. But the rate of telomere contraction predicted this parameter quite well. According to the authors, this confirms the hypothesis that life expectancy depends on when telomeres shorten so much that chromosomes 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 it is not possible to guarantee to increase a person's life span to 100, 120 or 150 years, there may be ways to improve the quality of life in recent years – even if a 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.
Three-dimensional structure of the p16 protein.
The main cause of the development of a group of senile pathologies is called systemic chronic inflammation, which 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 the removal of cells carrying one of the markers of SC 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 senescent cells are the main cause of aging, and set a clear direction for the search for anti-aging drugs among "senolytics" capable of selectively removing SC 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 whose membrane such a protein is expressed are senescent. Most of them are completely different structures of the immune system – macrophages responsible for the removal of senescent cells from the body. Thus, it can be assumed that not only the accumulation of SC occurs with age, but also the disruption of the immune system, which is able to remove SC independently at a young age, preventing the development of inflammation.
A diagram of the processes that take place in senescent cells.
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 only corrected the course of development of anti-aging drugs towards a better characterized target and a greater understanding of the processes occurring in an aging body.
The definition of "chronic inflammation" as a connecting thread between all age-related diseases has become a major achievement in the process of developing a cure for old age. For the first time in the history of gerontology, most specialists representing various fields of aging science come to an agreement. This concept has extremely important consequences not only because it helps to name the common cause of all senile ailments, but also because it allows you to identify the target for therapy – cells that accumulate with age.
Useful lessons
More 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 point the way to a long life: it only helps us to know our limits, to understand that the life span is sandwiched between early aging and uncontrolled tumor formation.
The attention of scientists is gradually shifting to other ways to combat aging and prolong life. Senescent cells, various diets, medications – there are still a lot of not fully understood ways to add years to a person. What will happen to the telomere? Perhaps, for some time, it will turn from a hope for humanity into a toy for scientists: strange, but in some ways it's not bad.
Less speculation will allow it to be "just" an important element for biological, biochemical and genetic research again. Not everyone who read the article to the end was easy (and, let's admit, even interesting) read the section about the mechanics of work. Sometimes areas that are "overheated" by universal interest need some peace in order to become part of pure science again from a target for hopes and scammers. Of course, it's a pity if this road to immortality turns out to be a dead end in the end. But what can you do: many useful lessons can be learned from the experience of working with telomerase. It is quite possible that in a year or ten years a new discovery in the field of chromosomal genetics will blow up 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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