27 August 2012

Drops from old age

Youth is for sale

Galina Kostina, "Expert" No. 34-2012

In July, Visomitin appeared in pharmacies in Moscow – eye drops from Academician Vladimir Skulachev, the world's first registered drug that penetrates mitochondria. And although the indication for the use of drops modestly indicates the little-known "dry eye" disease to the general public, they were bought by everyone who had heard at least something about the academician's work on a remedy for old age.

In the pharmacy of Moscow State University, the queue was insistently demanding drops: "We heard that they came out, are they under your counter?" In another pharmacy, someone bought a hundred vials at once. "It's good if it's for small–scale commerce," says Vladimir Skulachev. – God forbid he drinks. After all, there is a harmless antibacterial agent in large doses, which is added to all eye drops. This is the same medicine, you need to follow the prescriptions, and not drink as you please!" Clinical trials that took place before the release of Visomitin on the market showed that an incurable disease of the lacrimal gland – dry eye – lends itself well to therapy. More than 60% of the subjects noted a significant improvement in their eye condition. For comparison, some of the subjects used moisturizing drops from a well-known Western company, and the results were three times worse. Clinical trials of drops against cataracts have already passed, they are ending – against glaucoma, the results will be officially announced in the near future, but it is already known that drops are very effective. An old woman, one of the subjects, who went only with escorts, after a couple of months already appeared at the doctor herself and answered the surprised exclamations of the medic: "Son, I can see back!" Stories about dogs, horses, and now old ladies who have seen the light cause skeptics to grin. But they are not averse to trying drops: there will be no harm, but suddenly aging will slow down! The academician himself, dripping his own drops for four years, defeated cataracts in one eye and seriously reversed myopia. And generally looks energetic.

About the clock, the program, mitochondria and plantsIn the first interview with the "Expert" in 2005, Academician Skulachev, talking about his hypothesis of programmed aging and the mechanism through which the program is implemented, cautiously warned: "It may turn out that I am wrong."

But even then he was sure that the product he created would improve the condition of the body. Now Skulachev is much more confident in his hypothesis: science adds more and more facts to his piggy bank. Well, long-term tests of the substance invented by him have already shown their effectiveness.

For decades, Skulachev was engaged in oxygen, its noble functions. And at some point I thought about the almost negligible percentage of harmful, but reactive oxygen species that can spoil DNA. In youth, the body copes with this negligible number of forms and levels their effect. But with age, it becomes more and more difficult to fight. Harmful oxygen is formed mainly in mitochondria – cell organelles that generate energy by burning nutrients with oxygen, and damages DNA, membranes, and proteins in the cell. Many molecules in contact with active forms of oxygen themselves turn into free radicals and also attack these targets. This starts the process of apoptosis – suicide of damaged cells in different organs: the cells are getting smaller, the body is getting senile and can no longer perform the functions inherent in youth. Back in 1957, the famous physicist Leo Szilard, who studied the effect on cells of radiation leading to progeria – accelerated aging, suggested that in old age the body can still be quite good, only the cells in every muscle, in every organ are getting smaller. "It seems that the self–destruction of cells is faster than their replacement," says Skulachev. "It's like in a factory, when the plan remains the same, and the number of workers is constantly decreasing."

The more he did his research, the more he came to the conclusion that aging is not an accumulation of breakdowns in the body, as most gerontologists believe, but a genetic program. After all, there is a genetic program of cell death – apoptosis, why not be a program of death for the whole organism? It would be logical from the point of view of evolution. With the help of apoptosis, nature culls bad and superfluous cells, and with the help of phenoptosis (the aging program of the body) – individuals who have fulfilled their functions of transferring the genome to a new generation. Some scientists suggest that up to a certain time in the history of all living organisms could be immortal. However, according to the famous biologist August Weisman, the unlimited existence of individuals has become a luxury without any benefit to nature.

According to the supporters of this hypothesis, one of whom is Vladimir Dilman, who first made this assumption, and then Alex Comfort, who developed the idea, the "big biological clock" is responsible for the aging program, counting the life span and triggering the aging processes in different organs at different times. It is not yet known what a "big clock" is, although "small" ones that count the circadian rhythms have already been discovered. But the "big clock" just has to be! Otherwise, how can we explain the stages of human development from infancy that are completely determined by time: first growth, then its cessation, puberty and menopause, age-related changes in hormone levels, etc. Alas, the "big clock" has not yet been detected.

However, this scientific gap did not prevent Skulachev from engaging in that stage of the program during which, in his opinion, the mechanism of aging is carried out – the accumulation of harmful forms of oxygen and the destruction of cells. It would be logical to stop this lawlessness with the help of special antioxidants that neutralize toxic oxygen. The creation of such a substance was facilitated by the discovery of Vladimir Skulachev in collaboration with biophysicist Efim Lieberman, made back in 1969. Scientists have discovered that some cations (positively charged ions), using the difference in electrical potentials between the cell and its environment, easily penetrate into the cell. But much faster they are drawn into the mitochondria, where the potential difference is three times higher than in the cell. Therefore, cations can be used as "electric locomotive molecules" that can be loaded with antioxidants. And mitochondria will swallow this construction according to all the laws of physics. This discovery has already been used by a scientist from Cambridge, Michael Murphy. He attached to the cation the antioxidant that sits in our mitochondria – ubiquinone. Skulachev then thought: not that! The fact is that ubiquinone can be both an antioxidant and a prooxidant. Moreover, the range between "anti" and "pro" is very small. Skulachev later used plastoquinone from plants in his design, a much more powerful antioxidant than ubiquinone, which has a hundred times greater gap between "anti" and "pro". This is how the antioxidant Skulachev – SkQ1, addressed to the mitochondria, turned out. Sk is the Skulachev ion-"electric locomotive", and Q is the plastoquinone.

For saleThe design had to be tested, animal testing had to begin.

The project required decent funds. And Skulachev was lucky. Its first investor was the famous Russian entrepreneur Oleg Deripaska. First, the scientist received a grant from the Deripaska Foundation, and then money for an investment project that began in 2004. The Mitotechnology company was created for the project. Research was in full swing, and so was funding, until the crisis of 2008. Deripaska was not up to a non-core, albeit socially tempting project. And it was difficult to slow down Mitotechnology sharply, the company already had three hundred employees, including abroad. "No one left, although there was no salary and it was not expected in the near future," Skulachev states an amazing fact. "Everyone believed in the idea–it seemed so obvious that there was bound to be a new investor." So far, the scientists were supported as best they could by the Rector of Moscow State University Viktor Sadovnichy. With his submission, at one of the conferences at the university, there was a significant meeting between Skulachev and the head of Rusnano, Anatoly Chubais. "The first slide of my presentation was crossed by a bold red stripe on which it was written: For sale," says Skulachev. Chubais became interested, but warned that the discussion of the project and the expertise in the state corporation could take so long that the case would probably stall. After thinking about it, he offered to meet with a private investor – his former colleague at RAO UES Alexander Chikunov. By that time, Chikunov had created the Rostock group, which included a fund designed to invest breakthrough projects that were significant for humanity, moreover, did not promise immediate commercial returns. So in 2009, the project "Jonah Skulachev" received the support of the Rostock Foundation, and the new company "Mitotech" continued its work. Chikunov was fascinated by the academician and his ideas. Skulachev, in turn, is the support at such an important moment and the investor's enthusiasm for noble projects. Cooperation with the Rostock Foundation was also important for a successful connection with the Rusnano Corporation, which requires a co-investor for each project. Rostock financed the Skulachev project for a year and a half, exactly until the fall of 2010, when the agreement with Rusnano came into force and Mitotech received the first tranche from the corporation – 95 million rubles. And then Alexander Chikunov decided that he had done his job. I must say, it was an unexpected decision for scientists, but, whatever it was, they are grateful to him. "He really helped us in a critical situation," said the CEO of Mitotech Maxim Skulachev. – Now, perhaps, he will support other interesting projects." Chikunov, although he stopped financing the project, remained among the co-owners of Mitotech.

Scientists had to urgently look for a new investor: not only because expensive clinical trials of drops had already started, but also because the agreement with Rusnano required it. They were lucky again. One of the graduates of Moscow State University, the owner of an IT company, became interested in the project. He agreed to take over the investor's baton. The project agreed by Rusnano assumed investments in the amount of 1.4 billion rubles from the corporation and the co-investor. Before that, about $24 million had already been invested in it. For this money, many scientific groups worked, including foreign ones, an experimental certified production was built, a modern vivarium was opened at Moscow State University, several series of clinical trials were conducted, drug trials were launched in the USA and Great Britain. By Russian standards, investments are significant, although a representative of big pharma can spend more than a billion dollars on one medicine. But on the other hand, it "beats" them fast enough. "We are already earning money, too," Vladimir Skulachev laughs. – The first batch of drops was swept off the shelves in a few days. We are now certifying the next batch." The cost of a bottle of drops is about 500 rubles, and the initial proceeds from the sale – in just five days – half a million rubles. But this is just the beginning!

Mitotech plans – in case of success of a number of clinical trials for the treatment of eye diseases – to start negotiations with bigpharma. In the meantime, the innovative company has a commercial product from the "dry eye", clinical trials of drops against cataracts have ended (the data are being processed, but it is already clear that the drug is highly effective), clinical trials of drops against glaucoma are continuing, and in the fall, trials of drops against age-related macular degeneration (retinal damage) will begin. If all these fairly common and poorly or even incurable eye diseases succumb to Skulachev's drops, it will be a success that will undoubtedly interest large pharmaceutical companies. By the way, Mitotech is preparing a decent basis for such agreements not only in Russia: preclinical testing of drops ends in the USA.

From heart attack, diseased joints and baldnessDrops by drops, but everyone is waiting for a universal pill from old age from Skulachev.

A couple of years ago, he showed grayish-brown pills – the first prototypes of pills for old age. Since then they have been improved, now the substance in them is more stable. In a few months, Mitotech is going to apply to the Ministry of Health for permission for clinical trials of tablets. "While these will be safety tests, volunteers will take part in them," says Maxim Skulachev. The company has not yet decided on further tactics. "There are two ways we can go," says Vladimir Skulachev. – Clearly work out eye diseases and enter the world market with these indications or start testing for one of those age-related diseases that covers millions. Most likely, it will be some kind of cardiovascular disease." The company has a year to come to a definite decision.

Although the pill, which will carry the substance throughout the body through the blood, theoretically has a systemic effect, tests will be carried out according to specific indications. The enumeration of diseases peculiar to the elderly and senile age will take more than one page. These are cardiovascular, autoimmune and related to the weakening of immunity, as well as neurodegenerative, hormonal changes. Animal experiments have already begun. In particular, in experiments on mice and rats, it was shown that SkQ1 reduces the area of myocardial infarction and stroke, relieves cardiac arrhythmia, saves from death in kidney infarction. In the tested mice, baldness, graying, and the development of osteoporosis were inhibited. The females did not stop estrous cycles, and the males did not lose sexual motivation. SkQ1 also significantly inhibited age-related degeneration of the thymus (the organ responsible for the production of immune system cells). It is known that in humans, the thymus begins to age at a young age, weakening the immune system.

Thus, the Mitotech company is able to create a whole line of unique innovative drugs that can become very attractive products for the global pharma. In parallel, scientists will conduct further research that would help to convincingly show that aging is a program that can be canceled. One of the directions of scientific activity is the search for a substance that could be a measure of age (by analogy with radiocarbon 14C, according to the content of which various biological remains are dated). "It should be a substance that changes with age not biologically, but chemically," explains Vladimir Skulachev, "for example, some amino acid. It is known that in mammals, all amino acids in proteins have the form of the L isomer. If an amino acid solution is placed in a sealed ampoule, then after a short time there will be equally L and D isomers. But the problem is that it will happen in 250 years. However, quite recently we had one crazy idea on which substance it would be possible to measure age, and we will check it."

The company's scientific plans include testing the mechanism associated with cell death due to the action of free radicals. The research will be conducted in collaboration with Nobel Prize-winning biochemist Aaron Chehanover from Israel. The hypothesis is this: cells die due to apoptosis, which is caused by free radicals. The body, like the factory director, will first save not on workers, but on the service apparatus. According to Vladimir Skulachev, the body begins to save on those molecules that control the quality of proteins, as a result of which breakdowns begin to accumulate in the cells. "It dawned on me that this hypothesis reconciles two contradictory points of view on aging," says Skulachev. – If this is true, then aging is a program that leads to the accumulation of errors! And when there are too many of these errors accumulated, nothing can cure them, even our SkQ. In a very old rat, SkQ does not cure blindness." This study is also important from the point of view of when to start treating senile diseases in order to be young at one hundred years.

Portal "Eternal youth" http://vechnayamolodost.ru27.08.2012

Found a typo? Select it and press ctrl + enter Print version