Details of the development of gene therapy of aging in an interview with "Fight Aging!"

As I have repeatedly said and written ( 1 , 2 ), epigenetic recoil seems to me to be the most promising, if not the only approach that can significantly prolong our lives. Why? Because epigenetics plays a key role in the implementation of the entire development program of the organism, from embryogenesis to thanatogenesis. And while we are not able to stop this process, we can at least try to periodically roll it back. This approach extended the life of properitic mice by 33-50% in the experiments of the Belmonte group.



I believe in this approach so much that I decided to organize a project for its translation from the scientific plane to the applied one. I already described my vision of how to implement this ( 1 , 2 ). I see crowdfunding as the best way to attract funding for such a project. Over the past year, blockchain and cryptocurrency brought the possibility of crowdfunding to a new level, and those projects that previously could not and hope to attract the required amount of funds, with the help of ICO were able to collect even excess amounts for their implementation.



Yes, the peak of fees in the ICO is likely to be over, but seeing how raw projects continue to attract significant amounts of funding, it seems to me that we have every chance of collecting a sufficient amount in order to make significant progress in our task. In detail about all this, our goals and strategies to achieve them, I told the site Fight Aging, which is very respected in wrestling circles. I cite the translation of this interview here.

Interview with Yuri Deygin from Youthereum Genetics: Merging ICO and Yamanaki Factors

Introduction from Reason, the author of the site "Fight Aging!":

Primary coin placements (ICOs) are today the main source of heat and light in the blockchain world. People attract huge sums in cryptocurrency for projects whose credibility ranges from a meager to typical for startups. In many ways, this is very similar to the last years of the Internet bubble of the 90s ; There are many parallels. Such financing flows can be caused by several factors: people who want to circumvent Chinese currency control, early Bitcoin and ether owners who diversify their assets within the blockchain ecosystem, and various large investment funds that have found themselves able to make money on tokens quickly. All this adds fuel to the fire. As I wrote earlier this year, if rather dubious enterprises are capable of attracting tens of millions of dollars to the ICO, why can't we use the same mechanism to finance much more thoughtful and realistic rejuvenation research initiatives? The challenge is finding the right symbiosis of blockchain and network effects for our research and development world.



Some groups are moving forward in this task. I have already mentioned ICO Open Longevity, in which they are trying to attract funding for organizing clinical research on volunteers to test the potential of various pharmaceuticals to slow down aging, but today I want to focus on Youthereum Genetics , a new project that is also going to use ICO as a mechanism to attract funding for research and development. The creators of Youthereum intend to develop a method of delivery to the body of pluripotent factors associated with the creation of induced pluripotent stem cells, in order to stimulate regeneration. A demonstration of the possibility of such an approach was conducted by a research group and published earlier this year; Researchers have shown a positive effect of this approach on the health of progeroid mice , which are often used in primary studies of aging. This was a somewhat unexpected result: trying to return cells to a pluripotent state in a living organism sounds like a quick way to cancer.



The next steps will be to try this approach on normal mice, determine the optimal dose and delivery method, and continue to closely monitor that cancer does not occur. In the best of scenarios, this may lead to regenerative therapy, similar to stem cell transplantation , but this remains to be seen. As in many areas of research, where interesting results may or may not materialize, the main question is where to find funding for this work. The Youthereum team hopes that with the help of crowdfunding on the blockchain, it will succeed.



Recently, I had the opportunity to talk with Yuri Dein of Youthereum Genetics and ask him some questions about his goals. As you can see, it comes from the programmed theory of aging , which I tend to view as the complete opposite of the more common notion of aging as the accumulation of breakdowns . Strongly simplifying, this is a question of whether the age-related accumulation of damage is a consequence of epigenetic changes (program), or is it different damages with time cause epigenetic changes (reaction). The consequence of the programmed aging paradigm is the desire to intervene in those processes that, from the point of view of the aging paradigm as an accumulation of breakdowns, are only secondary consequences, and therefore the impact on them is not effective. We are already close to the moment when one or the other point of view will be finally proved by demonstrating the effectiveness of specific approaches to treating aging as a disease.



However, there is nothing black and white, and it is interesting to see the development of areas where theorists on both sides of this gap will meet in the middle of approaches to aging therapy, which both sides will consider to be potentially effective, but for different reasons. Some classes of stem cell therapy and efforts to achieve similar effects by changing endocrine signals or reprogramming existing cells inside the body are a good example of such approaches. From the point of view of programmed aging, these are levers with which you can return epigenetic expression to younger levels, while from the point of view of damage accumulation, they can be compensatory in nature, such as stem cell therapy, i.e. which are usually answered by internal regenerative processes, which the accumulation of damage over time interferes with the efficient performance of its work.

Interview:

Why Youthereum Genetics, and why now? Who are you and how did this organization come about?

I am a Russian-Canadian transhumanist , anti-aging activist, theoretical self-taught biologist and biotech entrepreneur. Previously, these areas of my activity did not overlap, but in the past few months, the stars have come together in such a way as to encourage me to finally combine activism and career experience, and send them to the area that I consider the most important in my life: the search for a cure for aging . Or - if you reduce the degree of pathos - at least, begin to develop at least some methods of significant life extension for people, because today there are none at all. By “significant” I mean something that can extend our life by at least 30%. No therapy, with the exception of calorie restriction, reached this level even in mice — neither rapamycin (26%), nor metformin (14%), nor telomerase (24%), nor senolytics (26%), or any other geroprotector . The very same calorie restriction , which holds the record for non-genetic life extension (up to 50% in various species of rodents), on primates could not demonstrate the same impressive results. In two studies on macaques, OA gave no more than 10% of the median increase in life expectancy for females, and in some groups, OA even reduced life expectancy.



I believe that the reason for our inability to achieve at least some significant breakthrough in slowing aging over the past 50 years lies in its programmed nature. Over the past few years I have seen a lot of evidence in support of this hypothesis , and the most convincing to me are the results of experiments on parabiosis and transfusion of young plasma . I think that aging is ultimately controlled by the hypothalamus , like all other aspects of ontogenesis . This concept dates back to the 1950s and is described in detail in the works of Dilman, Frolkis and Averitt . Recent studies by Dongsheng Cai and his colleagues provide additional evidence for the hypothesis of the key role of the hypothalamus. At the cellular level, aging is most likely monitored and performed by epigenetic regulation of gene expression . A few years ago it was first noted that a person’s age correlates with his epigenetic profile. It was later shown that these “epigenetic clocks” are effective predictors of life expectancy, which confirms the key role of epigenetics in the aging process. It has been found that many organisms have epigenetic clocks that are highly correlated with both their age and the likelihood of death.



In addition, nature can roll back or even completely reset the epigenetic clock. This is done for each embryo and, most likely, is the reason that every new animal is born young, despite the fact that it originates from an egg cell of the same age as its mother (since mother’s eggs were formed when she herself was still in the womb ). Finally, experiments with epigenetic rejuvenation, which demonstrated that the roll back of epigenetics rejuvenates not only individual cells, but whole organisms (and prolongs their lifespan), confirmed that epigenetics is not just a consequence, but an important driver of aging. This was the reason for the creation of Youthereum Genetics. Based on the recent work of the Juan Carlos Ispisua Belmonte group from the Salk Institute, which showed that the periodic induction of OSKM transcription factors could prolong the lifespan of progressive mice by 50% , we adhere to the hypothesis that aging can be reversed by periodic epigenetic recoils. Our strategy is aimed at translating this hypothesis into a safe therapy that can provide people with a significant, noticeable rejuvenation.



Why us and why now? In a nutshell, because I got tired of hoping that someone else would still not see this one appear. Therefore, I decided to put together a team of like-minded people who are able to design and control the execution of those experiments that are necessary for all steps related to the scientific testing of our hypothesis and its subsequent translation into therapy, if science passes this test. The only thing left to do now is a trifle: to attract the necessary funding. I, of course, joke. This is a daunting task, especially considering the required amounts and scientific risks. But I am ready to try, even despite the high risk of failure.

What is your understanding of what is happening “under the hood” in animals that have introduced pluripotency factors? Why does this benefit?

As I have already mentioned, I am a member of the Witnesses of the Aging Program sect. At least that's what some opponents of programmed aging call us. I believe that most, if not all forms of various intra-and intercellular damages, whose accumulation we observe with age, accumulate due to the fact that our body gradually reduces the effectiveness of various damage repair mechanisms. Our cells perform this reduction by epigenetic regulation of various genes after receiving endocrine signals , which originate in the hypothalamus based on circadian rhythms and certain internal clocks. We know that such a clock exists, if only because we can see how precisely the various developmental and vital processes are synchronized — from embryogenesis to puberty and menstrual cycles.

Therefore, I am convinced that our body has a sufficient capacity for regeneration in order to function at the level of 25 years of age for hundreds, if not thousands of years, and maybe even longer. If the germline can do this for billions of years, periodically creating a new organism from scratch, it seems logical to me that even a small part of these fantastic bodybuilding abilities should be enough to sustain our bodies for a much longer time than we see today. Therefore, if we find a way to deceive our cells and make them think that we are 25, then they will also function (and regenerate) at the level of a 25-year-old organism, regardless of our chronological age. To do this, they will need to have gene expression profiles (epigenetic profiles) characteristic of 25-year-olds. After all, we know from the works of Hannum and Horvath that the epigenetic profiles of 25-year-olds are completely different from those of 45- and 65-year-olds.



Therefore, when we activate OSKM factors in cells, I think that an epigenetic rollback occurs in them, causing an increase in various recovery mechanisms. After all, it is an empirical fact that induced pluripotent stem cells show significant rejuvenation, which improves almost all known signs of aging : telomeres are lengthened, laminin defects are repaired , mitochondrial function is restored , and so on. Vittorio Sebastiano and Tapash Jay Sarkar from Stanford write about this in detail in their excellent article .



However, it is not at all necessary to believe in programmed aging in order to see the potential of epigenetic rejuvenation in order to prolong life. For example, Aubrey de Gray , who is one of our advisors, also believes that epigenetic rollback has therapeutic potential, although Aubrey is a staunch opponent of the hypothesis of programmed aging. In his opinion, the ability to rejuvenate an aging organism by reactivating the regulatory pathways associated with early life stages does not in any way contradict the idea that aging is not programmed and is the result of the imperfection of the “anti-aging apparatus” of our organisms, and not the presence of an active aging mechanism. . I would be happy to be refuted in relation to the underlying mechanisms of epigenetic rejuvenation, so long as it provides us with a comparable life extension with what was shown in Belmonte's work.

Conversely, will not this approach lead to an unacceptable level of cancer risk? This is always one of the main concerns for such manipulations.

Absolutely right, teratomas are probably the biggest danger of this approach. In fact, before Belmonte showed that there was a certain Goldilocks zone for the induction of OSKM factors, which prolongs life without the occurrence of teratomas, the risk of cancer of this approach was considered prohibitively high for its therapeutic applicability. Apparently, this risk is not so high. The trick is to roll back the cells only a little, not enough to cause their dedifferentiation , and do it so often to prevent (or at least slow down) the accumulation of age-related damage that occurs as a result of the inexorable reduction of repair mechanisms. with age.

How does this fit in with your understanding of aging? What do you expect from this and other approaches in the coming years? Where would you expect the biggest victories to appear?

This is fully consistent with my understanding of aging. The reason why I was so happy to hear about the results of Belmont back in February is that, before I found out about them, I assumed that if we ever learn to periodically roll back epigenetic changes, then this could give us a good " hack ”(hack), able to significantly slow down aging, until we completely deciphered its mechanisms and learned to stop them. Thus, I think that epigenetic rejuvenation is precisely the area in which one can expect the greatest success in the near future. Another important area that we also plan to explore in the Youthereum, albeit in a separate scientific track, is an attempt to decode the hypothalamic signals released by it in the exosomes . We consider this direction to be very important, especially in the light of the last article of Dongsheng Cai, in which it was shown that 16-month-old mice showed signs of rejuvenation after a single injection with exosomes isolated from cultured stem cells of the hypothalamus neurons .

Tell us about your vision of how to direct cash flows from the blockchain sphere towards the realization of something useful in the field of life extension. A lot of ICOs look like a clumsy attempt to screw the blockchain onto something completely logically unrelated to it. What is your difference?

We are not going to pretend that our project is aimed at improving the blockchain infrastructure. Not at all, we are simply a decentralized biotechnology project that collects money, primarily for research. In other words, we are users of the blockchain technology, not its developers. We plan to use the blockchain to eliminate any intermediaries between us and those who are ready to provide us with funding, as well as to ensure that the rights of our project sponsors to the treatment methods that we are developing do not depend on the unpredictability of various government regulatory restrictions - current or future . In our opinion, these are the two main advantages of decentralization. Thus, we consider ICO only as a more effective crowdfunding mechanism, even if this causes rejection of the blockchain in some purists. At the same time, I absolutely do not understand their snobbery, since the adoption of the blockchain technology for the implementation of real, rather than virtual projects, actually means recognition by the market of the benefits of the technology created by them, and significantly expands its potential user base.

How is Youthereum Genetics different from Open Longevity, who are also trying to launch ICO?

While Mikhail Batin from Open Longevity and I agree that in order to create a radical therapy for life extension as soon as possible, we need to involve as many people as possible, we disagree on what kind of intervention can provide such a radical life extension. I do not think that any therapy that exists today, including any clinically approved medications, can extend our life by more than 10%, not to mention 30%. Therefore, in my opinion, conducting clinical studies of a diet simulating fasting (FMD) or statins to check whether they can significantly prolong our lifespan is of little use. On the other hand, epigenetic rejuvenation has, in my opinion, the potential to prolong our life by 30% or even much more. That is why I decided to invest my personal time and money in this approach.

If everything goes well, and you have a lot of money, and even positive results on animals in using pluripotent factors as therapy, what next?

I will try to answer this question starting with our research plan. We intend to subdivide it into 3 parallel research directions: (1) the development of an optimal dosing regimen using OSKM factors; (2) search for safer factors of epigenetic recoil, which do not lead to complete dedifferentiation; (3) the creation of better means of gene delivery, preferably patentable. So, our key hypothesis is as follows: in order to reliably rejuvenate the entire body, we need to periodically roll back the epigenetic hours of most cells in the body, if not all of the cells. Thanks to the work of the Belmonte group, we know that this is possible through the delivery of OSKM factors (or other factors) into the cell. However, this is a difficult task: if you roll back too little, then we will not get a significant effect, and if too much, then we risk causing cancer, because the cells lose their phenotype and again become pluripotent . After all, the ability to return cells back to a pluripotent state was the main selection criterion for Yamanaka’s choice of 4 OSKM factors from the original 24 candidates. Thus, although the OSKM factors are effective and represent a “bird in hand”, they are far from ideal for our purposes.



We want to find better, safer epigenetic rollback factors; we plan to start by revising the remaining 20 factors from the original 24 Yamanaki factors, and also try to use the Oct4 factor exclusively, since there is evidence that it alone is capable of rolling back epigenetics and, as a rule, is the main “guardian of epigenetic gates”. However, finding factors is only half the problem. Deliver them safely and ideally cheaply - the other half. The epigenetic aging program is stubborn enough even in the face of weekly kickbacks, as evidenced by Belmonte’s work, so achieving meaningful rejuvenation in people is likely to require a monthly or even weekly induction of the epigenetic rollback factors (regardless of whether they are OSKM factors or others). The most cost-effective way to achieve this goal is to integrate a special, default inactive, gene cassette containing the genes for rollback factors into virtually every cell of the patient. Such a cassette would be activated by a unique and usually inert agent, which must be developed separately and will make this approach patentable. Today, such cassettes are activated, for example, by tetracycline or doxycycline . With this approach, the cost of weekly induction of anti-aging factors will depend only on the cost of the induction agent (presumably a small molecule or peptide ) - that is, it will be relatively inexpensive.



Thus, we see the most optimal research plan as a gradual, iterative improvement of the already proven approach - the induction of OSKM factors by doxycycline; Such a cassette with OSKM factors can be delivered to the body using lentiviral carrier available on the market today. At the same time, the development of an ideal therapy will be carried out: with the safest and most effective factors activated by a unique, inert, patentable agent. Patentability is critical in order to interest Big Pharma in licensing this therapy after reaching the IND stage . If the project successfully reaches the IND stage, we believe that large pharmaceutical companies will be very interested in licensing this therapy and starting clinical studies - first to prevent atherosclerosis , Alzheimer's disease , diabetes or other age-related diseases that other anti-aging drugs are being tested against today, since aging itself is still Not classified as a disease by the World Health Organization (WHO) . Accordingly, our plan is to bring the therapy to the IND stage, and then allow Big Pharma to do what it does best: validate this therapy clinically. According to our estimates, it will take 5-6 years to reach the IND stage if everything goes well.



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