How to beat aging - a plan of action

Aging is a genetic pathology embedded in each of us. This is HIV 2.0, the inexorable "age-related human involution." I firmly believe that we urgently need to throw all the forces on the search for the means to cure it or at least stop it. Do I have a plan? There is! I will try to explain it below and will be glad to any criticism or alternative suggestions. Only the result is important to me - the extension of human life by at least 50%.



Until now, there are no proven ways to increase a person’s longevity by more than 10%. Over the past decade, many different approaches have been proposed, and all of them are united only by how ineffective they are. Starting from starvation or calorie restriction ( as experiments on primates showed ), metformin ( on diabetics ), rapamycin (on mice or dogs ) and ending with a number of equally weak “geroprotectors”.



An extension of 10% does not suit me personally. I believe that Humanity urgently needs to start developing methods for extending life by at least 50%, otherwise our parents simply will not live to the moment when the mechanisms of aging will be solved completely, and science will finally be able to stop it. Therefore, my minimum task is to develop a therapy capable of extending the life of primates by at least 50%. Moreover, this therapy, the rejuvenating effect of which will be quickly noticeable after its application. Noticeable for any reliable age biomarkers: for example, epigenetic hours or blood biochemical parameters.

Who is guilty?

Whatever we do, I am sure that without gene manipulation, we can not significantly extend our life. Because it is the genes that determine the lifespan: they are given 4 years to the rat, 12 years to the dog, and we are about 80. And it doesn’t depend on whether aging is programmed or not, this is simply an empirical fact.



At the same time, I see a lot of evidence in favor of the fact that it is programmed . Moreover, I believe that it is precisely this peculiarity of the nature of aging that stands behind the fact that all attempts to win or at least slow down aging over the past 50+ years have not been crowned with success.



The aging program, as I see it, is most likely monitored and performed through epigenetic regulation of gene expression. It is known that many organisms have " epigenetic clocks " that highly correlate with both their age and the likelihood of death. However, Nature knows how to roll back or completely reset the epigenetic clock. This is done for each new embryo and is the reason that each new animal is born "young", although all its cells originate from the mother's cell - the cell that is its full peer (after all, the mother's oocytes were formed while she was still in the womb) .



In 2006, Japanese scientists Yamanaka and Takahashi learned how to use these epigenetic mechanisms for nulling age using four transcription factors under the acronym OSKM. These factors return any cell back to its actual embryonic state. Fortunately for us, they do it gradually, and if we stop them before they change the cellular phenotype, we will, in fact, get a rejuvenated original cell.



But can we use OSKM factors in vivo to rejuvenate whole organisms? It turns out, yes. This was demonstrated by the Belmonte group in 2016 : using the weekly induction of OSKM, they managed to increase the lifespan of progressed mice by 33-50% (the blue curve is the treated mice, the other three curves are the control groups):







Thus, my hypothesis is that aging is a genetic program that can be thrown back by periodic induction of any genetic transcription factors (for example, OSKM). Actually, that's my whole plan: to translate this hypothesis into a safe therapy, which will give us a significant, noticeable rejuvenation.

What to do?

To reliably rejuvenate the entire body, we need to roll back the epigenetic markers of most cells of the body, if not every cell at all. Thanks to the work of the Belmonte group, we know that we can do this by delivering OSKM factors (or other transcription factors) to the cell. Nevertheless, the rollback process is a complex task, subject to the “Goldilocks problem”: rolling back too weakly, we will not get a significant rejuvenating effect; rolling away too much, you can get cancer, because the cells lose their phenotype and return to the table, pluripotent state.



After all, the ability to effectively 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 have shown their effectiveness for rejuvenation through partial rollback, and represent a “bird in the hand”, they are far from ideal for safe rejuvenation. I think it is worthwhile to continue the search for safer epigenetic factors of rollback. Perhaps it makes sense to start by checking the remaining 20 factors from the original 24 Yamanaki factors . Also worth checking out are other reprogramming methods developed in recent years.



Finding the best factors is only half the battle. The other half is how to deliver them safely and, ideally, cheaply. The epigenetic aging program is quite stubborn even in the face of weekly kickbacks, as the work of the Belmonte group showed. Therefore, in order to achieve significant rejuvenation in people, it is likely that it will be necessary to activate epigenetic factors of rollback monthly or even weekly (regardless of whether they are OSKM factors or others).



Thus, the most economical way to achieve this goal will be to integrate a special, default inactive gene cassette (containing genes for rollback factors) into almost every patient cell, presumably using lentiviruses or another integrative delivery method. Further, such a cassette will have to be periodically activated by a unique and inert agent that can be developed separately and will make such therapy 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 be determined only by the cost of the induction agent (presumably a small molecule or peptide) - that is, it will be relatively cheap.



In any case, the way the rollback factors will end up inside the cells, although important, but not related to the rejuvenation process itself. We just need to deliver the identified factors in the best way possible. Such a task is not only ours - the entire branch of gene therapy is looking for ways to solve it. Today there are already several ways to achieve this: viral vectors ( lentiviruses , AAV ), mRNA , cell-penetrating proteins . The notorious CRISPR also looms on the horizon.



The most optimal plan I see is a step-by-step, iterative improvement of an already proven approach (induction of OSKM factors with doxycycline; such a cassette with OSKM factors can be delivered to the body using lentiviral carrier available on the market today) and parallel development of ideal therapy (maximally safe and effective factors activated by a unique, inert, patentable agent).



Thus, the research can be divided into three parallel projects:

• develop an optimal dosing regimen using 4 initial factors OSKM
• go back to the original 24 factors of Yamanaki to find safer (not leading to complete de-differentiation)
• create the best means of gene delivery (preferably patentable)

Once the efficiency and delivery method projects have been given the first leader therapy with the minimum acceptable proven life extension in mice (at least 50%), all the necessary research can be started to be approved by the FDA / EMA agencies.



The regulatory rules for genetic therapy are just beginning to form. Therefore, it would be advisable to hold a preliminary pre-IND meeting with the FDA (or apply for an “EMA scientific advice”) as early as possible in order to hear firsthand what experiments these regulatory agencies will require as proof of the safety of the proposed therapy.



Some considerations:

• ADME studies do not make sense in the context of gene therapy, but they will almost certainly be necessary for an activator (small molecule, unless an already known activator is used, such as doxycycline, for example)
• Similar considerations apply to toxicology studies.
• Studies of teratogenicity are likely to be required both for the combination of the gene cassette and activator, and for each of these parts separately.
• Almost all of the above studies can be performed on mice, rats, dogs
• If desired, if the budget allows, it would be cool to do research on primates. Of course, life span studies in primates are time consuming, but adult / elderly primates can be used, and major improvements in biomarkers of aging (epigenetic hours and / or cardiac / pulmonary / renal function, etc.) can be used as the main end points of the study. ), not their lifespan.

A few words about economics

What I have described above is a very unusual plan. His main goal is not to make money, but something much more important: to develop the first really working rejuvenating therapy.



However, if the main goal is achieved, then the financial return will amount to billions, if not trillions of dollars. Indeed, the size of the market for various "anti-aging" dietary supplements, cosmetic or surgical procedures amount to billions of dollars, despite the almost complete absence of any anti-aging effect in all these products. As soon as real anti-aging therapy appears, the demand for it will be very high, as will the willingness of people to pay substantial money for it.



It should be noted that the proposed therapy, in case of scientific success, will be able to generate the first income long before permission for use in humans. Rejuvenation of domestic animals represents a huge market potential with significantly reduced regulatory barriers. And since the Yamanaki factors work in so many species, the same therapy (adjusted for homologous genes) will be effective in dogs, cats, and humans.



Moreover, even before a full-fledged version of therapy is developed for already adult individuals (that is, before the optimal mechanism is created for delivering genes to an adult organism), the genetic cassette can be integrated into the embryos of “designer” pets whose owners will be able to start experimenting with extending the lives of their pets very early. I think there will be many who want to buy a dog that will potentially live for 40 years, not 12.



Theoretically, the same gene cassette can even be embedded in human embryos. If this cassette is proven to be 100% safe, then the ethical issues associated with embedding it in embryos will be almost identical to the ethical issues associated with the ability to embed this cassette to an adult. Moreover, these ethical questions are mitigated by the fact that the inserted genes will not be activated by default until they are activated by a unique activator tool.

Summary

Over the past decade there have been several bursts of activity in the field of anti-aging. Each surge was marked by the emergence of a new approach: mTOR inhibitors, sirtuins, wnt-mediators, telomerase activators, and now senolithics.



Alas, all these approaches either have already shown their inconsistency in ensuring a significant increase in life expectancy, or are doomed to an early failure. The next big wave, in my opinion, is expected in the field of epigenetic rejuvenation. And, I believe that, unlike all previous ones, this scientific approach has a high chance of success. Fortunately, I do not think so alone :

In conclusion, we recommended that you follow the guidelines for in vivo reprogramming. They will hopefully build a cell in vivo cell cell reprogramming for tissue regeneration and rejuvenation.

Let's think together about the most effective and safe therapy that can radically prolong the life of us and our loved ones. If you are well versed in molecular biology or applied genetics, please comment on the above plan. Or if you have friends who are well versed in this, ask them to comment on them. Do not be silent, drop a few words in support of this approach, if it seems to be feasible, or speak out against it if not. And ideally, offer something better. It is possible in a personal, if you do not want to do this in public.



Alas, as often happens, the salvation of drowning people is the work of the drowning people themselves. Therefore, I believe that one should not wait for the weather from the sea. It's time to start working with your hands.



PS: In detail about the experiment Belmonte I tell here: