The Immortality of Elizabeth Parrish

How scientists are looking for a recipe for prolonging life

Alexandra Hristich, Schrodinger's Cat magazine

The article was published on the website of Rossiyskaya Gazeta

Elizabeth Parrish. Photo: bioviva-science.com

In September 2015, Elizabeth Parrish, director of the American pharmaceutical company BioViva, was the first in the world to change her genes to delay old age. With the help of a special virus, she activated the enzyme telomerase in the body. It is known for making human cells immortal. There is a hypothesis that it is possible to prolong youth in this way, and Elizabeth hopes to confirm this on her own experience.

Why are we getting old?

Over time, most cells wear out and the body ages. Why this happens, scientists still do not know. They 've been arguing for decades: are we senile because of breakdowns and mechanical wear of organs or because of an aging program activated by a signal from the brain? But there is also good news: we already know how cells age. When they divide, each chromosome loses a small piece. In the new generation of cells, the chromosomes become shorter. Then even shorter. More…

To prevent new cells from suffering, special repeating fragments – telomeres - are placed at the ends of chromosomes. They do not carry important information, so their shortening does not harm the cells. But inevitably there comes a point of no return: after about 50-70 divisions, the telomeres end – the cell can no longer divide and dies. This number is called the Hayflick limit, after the name of the scientist who discovered this effect (Leonard Hayflick is a professor of anatomy at the University of California, San Francisco). It is believed that the shortening of telomeres is one of the reasons for people's efforts.

Lifestyle can affect telomere length. Smokers and people who do not exercise and often worry are the most unlucky: their telomeres are shorter than those of people who lead a healthy and peaceful life. But alcoholics can breathe easy: alcohol consumption does not affect the length of telomeres in any way. However, the length was measured only in leukocytes.

Forever young

Some cells desperately need to be immortal. For example, stem cells are a kind of suppliers of cells for the whole body. A stem cell can turn into anything. In other words, it is a team of spare parts who are always ready to replace those who have been out of action due to illness or injury. Germ cells also need to be immortal, because they give rise to a new person. There are about 37 trillion cells in an adult. To get this amount, the very first fertilized egg needs to be shared at least 45 times. In principle, the telomere length should be enough for this, but what about tissue renewal? And future children? It turns out that in order for people to grow up and raise children, sex cells need to solve the problem of shortening telomeres.

There is a special enzyme telomerase for this. It lengthens telomeres and allows the cell to divide indefinitely. The fact that such an enzyme exists was guessed by Soviet biologist Alexey Olovnikov back in 1973. After 11 years, scientists from the University of California at Berkeley isolated telomerase from cells. And in 2009 they received the Nobel Prize for this discovery. As Leonard Hayflick put it, "Olovnikov's astute assumption has received experimental confirmation."

Many Russians were offended by the Nobel Committee, although Alexey Matveyevich himself did not comment on its decision, and some time later put forward a new theory, even bolder.

In fact, Olovnikov rejected the telomeric hypothesis of aging and instead proposed the so-called redusomal theory, which assumes shortening of structures (printometer and chronometer) in the so–called "lateral DNA" back in the early 2000s.

He suggested that telomeres are only mute witnesses of aging, and other special DNA molecules cause it. He called them chronometers. According to Olovnikov, chronometers are located in brain cells and are gradually shortened, counting down the time of our life. In other words, chronometers are the physical embodiment of a biological clock. The most extraordinary assumption is that the shortening of the chronometer is affected by the change of phases of the Moon, possibly through its gravitational field. There are no experimental confirmations of this extravagant hypothesis yet.

– Experts traditionally scratch their heads at the sight of my hypotheses, – says Alexey Olovnikov. But he does not despair and thanks experimenters in advance in his articles who will be able to confirm his theory. Just as scientists from the University of California confirmed his guess about the existence of telomerase more than 30 years ago.

One of the causes of aging is the shortening of telomeres. Telomeres are repeating fragments at the ends of chromosomes. After about 50-70 cell divisions, telomeres end, the cell can no longer divide and dies. Photo: depositphotos.com

At the end of the XX century, it became clear that the activation of telomerase in individual cells leads to their immortality. But what does "activation" mean? Strictly speaking, the telomerase gene is present in all cells of the body, but they usually do not suspect its existence, because the gene is turned off. In stem and germ cells, on the contrary, it is turned on, and telomerase lengthens telomeres at the slightest need. It turns out that by artificially turning on this gene, you can make telomerase work in any cell and actually immortalize it. Moreover, with the help of certain viruses, the telomerase gene can be embedded in any cell – even one in which it was not in sight.

This discovery intrigued the whole world. Scientists have a tool that can make cells immortal. Is it possible to immortalize people themselves? There is still no definite answer to this question, but over the years of research, a lot of interesting data has accumulated.

How to grow a long-lived mouse

In the late 1990s, biologists bred genetically modified breeds of mice to study in detail the properties of telomerase. Rodents, for whom she did not work from birth, had many problems with internal organs and aged much earlier than ordinary animals. On the other hand, they had fewer malignant tumors. Other mice that had excessively active telomerase from birth were more likely to have cancer. And they also lived less than usual. Why? The fact is that cancer cells learned to turn on the telomerase gene much earlier than scientists and use this to divide endlessly. Thus, it is much more difficult for a cancerous tumor to appear in the body of a mouse with telomerase turned off than in an animal with an active enzyme.

Another interesting experiment was conducted on a breed of mice prone to cancer from birth: tumors grow very easily in them, almost without resistance from the body. Biologists have turned off telomerase in these mice in the hope that they will get less cancer. The result was the opposite: without the enzyme, rodents became covered with tumors much earlier than their relatives.

It's not entirely clear why this is happening. One theory is that if telomerase doesn't work, stem cells lose their telomeres and age. But stem cells make immune system cells, our main defenders against tumors. Cancer fighters come out of old stem cells so-so. Another version is that as soon as the DNA molecules lose their telomeres and bare their ends, the cell wants to somehow connect them. But gluing random DNA molecules is not the best idea, it leads to mutations and increases the likelihood of cancer.

What will happen to a person if you turn off his telomerase? Such an experiment, of course, can not be staged, but it is possible to study diseases associated with the improper operation of the enzyme. One of them is called congenital dyskeratosis. It manifests itself in premature aging: patients get gray hair and teeth fall out early, they often get cancer and rarely live to 50 years.

Rejuvenate the old man

To understand whether the inclusion of telomerase can reverse aging, special mice were needed. They were arranged in a tricky way: scientists turned off their telomerase gene, but it could be turned on by feeding the animals a special substance. Initially, these mice aged rapidly: they had senile disorders of the testicles, spleen, intestines and brain earlier than normal individuals, and their sense of smell worsened. The inclusion of telomerase rejuvenated the animals: their internal organs began to work better, mice began to recognize odors more accurately.

The most impressive results were obtained in 2012 by scientists from the Spanish National Center for Cancer Research. They experimented on the most ordinary mice. The individuals were of two ages: adults, that is, those who turned one year old, and elderly, two-year-olds. Researchers infected rodents with a virus that activates telomerase. As a result, elderly mice began to live 13% longer, and adults – as much as 24%. Remarkably, the incidence of cancer has not increased.

44-year-old American Elizabeth Parrish decided to repeat this experience for herself. BioViva is an American pharmaceutical company, which she heads, founded in 2015 and is engaged in the development and patenting of gene therapy methods. Two main projects are a gene design with telomerase and a design with a myostatin inhibitor (a protein that causes muscle atrophy – Elizabeth injected herself and her). Clinical trials confirming the safety of these methods have not been conducted.

Researchers infected laboratory mice with a virus that activates telomerase, an enzyme that lengthens telomeres and allows the cell to divide indefinitely. As a result of the experiment, elderly mice began to live 13% longer, and adults – by 24%. Photo: depositphotos.com

The injection of the virus was done in a certain laboratory outside the United States, its name was not made public. A weakened AAV virus (adenoassociated virus) was used, having previously inserted a telomerase gene into it. The virus is introduced into the 19th chromosome in blood cells, and as a result, telomerase is constantly expressed in them. According to the official website of BioViva, in April 2016, six months after the injection, Elizabeth's telomere length increased by 9%, which corresponds to tissue rejuvenation for 20 years. The telomere length was measured by the independent company SpectraCell in Texas. It sounds encouraging, but it is hardly worth taking this result as proof of the rejuvenating power of telomerase. Firstly, the measurement of telomere length has a large error – as much as 8%. Secondly, testing of real medicines is a more complex process.

At a minimum, a control group and a large number of subjects are needed. This was told to us by Maria Blasco, the head of the group of Spanish scientists who set up the initial experiment with telomerase activation:

– Any new therapy, including gene therapy, must be approved by regulatory authorities and obtain appropriate permits for clinical trials. After all, clinical trials should guarantee patients safety and the maximum chance of success. Our group is testing telomerase therapy on mouse models in order to then conduct valid clinical trials and reliably evaluate the benefits for patients.

"Schrodinger's Cat" asked the scientists who discovered the mechanisms of cellular aging to comment on Parrish's act. Here 's what the Nobel Prize winner for the discovery of telomerase Jack Shostak said:

– I don't approve of such tricks. This is a completely unscientific approach to a complex problem. His only goal is to fool gullible people and extort money from them for a "medicine" that can be very dangerous.

Leonard Hayflick was also unenthusiastic about Elizabeth's act:

– I do not support experiments on myself in the absence of rational explanations. Since ancient times, people have been experimenting, trying to delay old age. But for various reasons, no one has achieved success yet. Moreover, we have no 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.

Hayflick added that he does not understand the very idea of searching for eternal youth:

– I would not like tyrants, dictators and murderers to live longer.

But Alexey Olovnikov speaks less categorically about Elizabeth:

– I admire her courage. There are two components in Parrish's act: courage and a desire to promote his company BioViva.

Anyway, the troublemaker herself is determined. She plans to patent her rejuvenation method, but in the meantime she is traveling the world in search of a company that will agree to conduct real clinical research. This summer she visited Moscow, where she held a press conference. Elizabeth said that with her experiment she wanted to speed up the clinical trials of anti-aging gene therapy. According to her, scientists have already found a way to prolong youth, and she sees no point in hiding it.

But in fact, scientists are still afraid to repeat this experience in humans and argue about whether telomerase activation can prolong life at all. Enthusiasts consider this enzyme to be a real elixir of youth, because if the results of the experiment are the same as in mice, people will live as much as 18 years longer. Skeptics fear cancerous tumors and other side effects. They compare the activation of telomerase with the coloring of gray hair, bearing in mind that even if the telomeres lengthen, it will not necessarily eliminate the cause of cell aging. And does the rejuvenation of cells mean the rejuvenation of the body as the sum of these cells? Over time, we will find out the answers to all these questions, but for now, the most interesting thing remains for us to look for them.

Portal "Eternal youth" http://vechnayamolodost.ru  21.10.2016