Jonah Skulachev: Past, present, future
"The understanding of aging has changed radically"
Mikhail Kirov, Mednovosti
Do attempts to slow down aging contradict the data of modern science? What are mitochondrial antioxidants and why can they defeat age-related diseases? What have the developers of the "cure for old age" managed to achieve today?
Maxim Skulachev, Deputy head of the Ion Skulachev project, director of Mitotech, a company established at Lomonosov Moscow State University, answers these and other questions in an interview with Mednovosti.
– Skulachev's ions have a rather long history. Tell us how this project started.
– It all started in the late 60s, when electricity was discovered in mitochondria. The most important proof of its existence was obtained at Moscow State University, in the group of my father, Vladimir Petrovich Skulachev. To confirm the hypothesis first put forward by the future Nobel laureate Peter Mitchell, they used unusual molecules that have an electric charge, but at the same time can penetrate biological membranes formed by a double layer of lipids. It was assumed that if Mitchell is right and there is a negative charge inside the mitochondria, then positively charged molecules with such properties will be absorbed from the cytoplasm by mitochondria. Which was brilliantly demonstrated in the experiment. David Green, director of the Institute of Enzymology in Madison, was so fascinated by the elegance of the idea of Soviet scientists that he suggested calling these unnatural substances – both charged and fatty molecules – Skulachev ions. That is, this term has a very respectable history, and, I emphasize, it was not proposed by us. By the way, even then, in the early 70s, in one of the articles Vladimir Petrovich wrote about these ions that if you need to introduce something into the mitochondria, then here it is, the ideal delivery vehicle.
– Nevertheless, there was no talk of medical use then?
– Skulachev and his team very quickly took up other theoretical issues: mitochondrial biology and other interesting things. As Vladimir Petrovich himself says, firstly, at that time it was not very clear what exactly needed to be delivered to the mitochondria. Secondly, in Soviet times it was like death to do something practical. For example, in the Politburo of the Central Committee of the CPSU, the word "oxidative phosphorylation" was not pronounced – and that's fine: while you study such obscure subjects, you live on an island of freedom, maybe even more than in the West. But as soon as it comes to practice, new medicines, production lines and the like, a party functionary immediately appears and begins to explain what and how to do. There was no particular desire to get involved with all this…
– But has the situation changed over time?
– By about the end of the 90s, it became clear that mitochondria are not only the "energy station" of the cell, but also the most important source of free radicals that cause harm in a variety of pathologies. And, accordingly, these processes can be stopped if the mitochondria are affected by antioxidants that neutralize free radicals. Again, the idea of using Skulachev ions for this is not ours, it was first proposed by a scientist from Cambridge, Michael Murphy – he decided to simply "sew" some molecule with powerful antioxidant properties to them and thus neutralize the destructive effect of reactive oxygen species. Several such compounds were synthesized, and one of them, MitoQ, seemed promising enough, they tried to make a medicine out of it.
Murphy is well acquainted with Vladimir Petrovich, so we knew about this work. But after getting acquainted with the structure of the substance, Vladimir Petrovich suggested that not the best antioxidant was chosen. MITOQ used ubiquinone, an electron carrier in animal mitochondria. And Vladimir Petrovich believed that plastoquinone would be more effective – a substance that performs similar functions in plants that synthesize oxygen, and in fact there is the largest concentration of free radicals. But Murphy didn't make any changes – the pharmacological project was already launched, investors were found, and with a new compound, a lot of research would have to be redone, so he just took the path of least resistance.
As a result, we decided to "cook" our own mitochondrial antioxidant. The Oleg Deripaska Foundation allocated a small grant for our project – then it was pure charity. And with these funds, several variants of the substance were synthesized in the laboratories of Moscow State University. One of them, SkQ1, turned out to be quite stable and workable, but, most importantly, it surpassed MitoQ in a number of parameters.
– Did you initially intend to stop aging, or were the tasks more modest?
– No, the fight against aging has always been the main goal. That's why Vladimir Petrovich was so afraid that Murphy would bury the whole idea because of his unfortunate choice, that by that moment he had finally come to believe in the programmed nature of aging and in the mitochondrial theory of aging.
Its essence is that since the mitochondria is the dirtiest place in the cell, then if for some reason nature needs to gradually disable the body, disrupting all its vital functions, then there is no better way than slow poisoning with active oxygen forms that are produced in the mitochondria. Not instant death – at first the body copes well with this – but a slow extinction, a decrease in the efficiency of all systems – this is aging.
– And the assumption that this process can be regulated or stopped in principle has not met with protests from the scientific community?
– Yes, in the late 90s and early 2000s, such theories were perceived as complete madness. At that time, research in the field of aging was considered something indecent for a biologist. I regularly had to deal with misunderstanding: what is there to study at all? After all, it would seem that the "wear" of the body is a completely understandable phenomenon. Here we can draw a parallel with the work of another Nobel laureate – Aaron Chehanover. He discovered the process of ubiquitination, that is, the controlled degradation of proteins in the cell. Before that, everyone studied how proteins are synthesized. And the question of where they go then seemed self–evident - well, they are digested somehow, probably… But why some squirrels live for minutes and others for years, no one was interested for a long time, although this is no less important process. Chehanover, by the way, is very interested in our project. He believes that a kind of mitochondrial renaissance is taking place now. Until recently, it was believed that the functions of mitochondria were exhaustively studied in the 70s, but now we see a lot of new publications about their role in various pathological processes, including those associated with age-related diseases. The understanding of aging has also changed radically. Now it is no longer heresy to struggle with age–related changes, to look for methods that allow them to be controlled. For example, the US National Institute of Aging systematically collects information about potential geroprotectors, offering everyone to test the geroprotective properties of any new compound in their laboratories. And more recently, the very concept of geroprotection was considered almost anti-scientific.
Moreover, there is already more or less reliable data on some methods that allow slowing down age-related changes. For example, restriction of nutrition – its effectiveness has been proven on a large number of laboratory animals. In the USA, many years of research on rhesus monkeys - models as close to humans as possible – are now being completed. The results are somewhat contradictory, but there is no doubt that the reduced calorie intake protected these animals from senility – the difference can be seen with the naked eye. There are a number of chemical compounds that are trying to be used for the same purpose. One of the latest findings is rapamycin, which has shown impressive results in experiments on mice. So we and our theory of mitochondrial aging are no longer heretics and not crazy in the scientific community.
– How many molecules with anti-aging potential are you currently studying?
– Working – about a dozen. Their properties can be varied by changing the length of the molecule, attaching different antioxidants to it, adding methyl groups, etc. By the way, we have discovered several natural "Skulachev ions" – substances with a very similar structure that are used by some plants to fight microbes.
As a rule, the more powerful the antioxidant properties, the less stable the molecule, and vice versa, so you have to choose. But this is the scientific part of our work. In order to put any of these compounds into the clinic, a huge amount of research on pharmacokinetics and toxicology is needed – to which organs it is distributed, how it is excreted from the body, etc. This is quite difficult, and most importantly not very interesting from the point of view of science, but everything must be done if we want to make medicines. Only one compound, SkQ1, plastoquinonyl–decyl-triphenylphosphonium, has passed the full cycle of research so far. Under question is its rhodamine-containing analogue SkQR1. This substance has a number of interesting features, in particular, it works much better in the laboratory with kidney damage, but I can't say yet whether we have enough resources to bring it to the clinic.
– At what stage are the studies of the most studied substance, SkQ1, currently at?
– The substance at a concentration of 250 nmol /l has passed the clinical trials necessary for registration in the Russian Federation and has been put on the market – this is the drug Visomitin, used for dry eye syndrome. However, on our initiative, clinical trials of the drug are continuing. In addition, we have every reason to hope that in the very near future we will receive permission to conduct clinical trials of SkQ1 in the USA.
– How well has the security of this connection been studied?
– Significantly better than any other new drug. All the data on toxicology have been collected, the lethal dose has been determined – it is tens of thousands of times higher than the therapeutic one. It is known that SkQ1 has no accumulation effect with prolonged use – it is very quickly excreted from the body. Moreover, it cost us a lot of effort to trace all these processes precisely because the therapeutic doses of the substance are very small, and they can only be registered with the help of rather complex and expensive equipment.
The main question, of course, is that SkQ1 blocks apoptosis, the self-destruction of the cell triggered by reactive oxygen species. On the one hand, this is good, because it is believed that we age due to the fact that the number of apoptoses per unit of time in tissues increases. But on the other hand, apoptosis is the main anticancer defense, this mechanism allows you to reject and destroy cells in time that begin to divide uncontrollably. Accordingly, since the substance blocks this process, it should cause cancer. But it's all about the details. There are several mechanisms of apoptosis. And our substance affects only one "branch" of this process, mediated by active forms of mitochondrial oxygen. And this type of apoptosis, fortunately, is not involved in any way in the protection against cancer. By the way, one of the first studies of SkQ1 was conducted by Vladimir Nikolaevich Anisimov from the Petrov St. Petersburg Institute of Oncology. And he found that SkQ1 not only does not cause cancer, but also slows down their development somewhat. Of course, this is not an antitumor drug, but it has also had such an effect.
The end of the first part of the interview. The approximate date of publication of the second part is January 28.Portal "Eternal youth" http://vechnayamolodost.ru