How to Beat Aging

Action plan

Yuri Deigin, Geektimes

Aging is a genetic pathology inherent 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 our efforts into finding a means to cure it or at least to stop it. Do I have a plan? There is! I will try to explain it below and I will be glad of any criticism or alternative suggestions. I only care about the result – the extension of human life by at least 50%.

There are still no proven ways to increase human life expectancy by more than 10%. Over the past decades, many different approaches have been proposed, and all of them are united only by how ineffective they are. Starting from fasting or calorie restriction (as shown by experiments on primates), metformin (on diabetics), rapamycin (on mice or dogs) and ending with a number of equally weak "geroprotectors".

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

Who is to blame?

No matter what we do, I am sure that without gene manipulation we will not be able to significantly extend our lives. Because it is the genes that determine the life span: they give the rat 4 years, the dog 12 years, and we are about 80. And it does not depend in any way on whether aging is programmed or not, it's just an empirical fact.

At the same time, I see a lot of evidence in favor of the fact that it is still programmed. Moreover, I believe that this particular feature of the nature of aging is behind the fact that all attempts to defeat or at least slow down aging over the past 50+ years have failed.

The aging program, as I see it, is most likely both monitored and performed through epigenetic regulation of gene expression. It is known that many organisms have an "epigenetic clock" that is highly correlated with both their age and the probability of death. Nevertheless, 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 – a cell that is her full age (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 of age zeroing using four transcription factors under the abbreviation OSKM. These factors return any cell back to its actually 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 weekly induction of OSKM, they managed to increase the life expectancy of progeria mice by 33-50% (the blue curve is the mice receiving therapy, the other three curves are the control groups):

So my hypothesis is that aging is a genetic program that can be pushed back by periodic induction of some genetic transcription factors (e.g. OSKM). Actually, that's my whole plan: to translate this hypothesis into a safe therapy that 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) into the cell. Nevertheless, the rollback process is a difficult task, subject to the "Goldilocks problem": rolling back too weakly, we will not get a significant rejuvenating effect; rolling back too much, you can get cancer, because the cells will lose their phenotype and return to a table, pluripotent state.

After all, it was the ability to effectively return cells back to a pluripotent state that served as the main selection criterion for Yamanaka's selection of 4 OSKM factors from the original 24 candidates. Thus, although OSKM factors have shown their effectiveness for rejuvenation by partial rollback, and represent a "tit in the hand", they are far from ideal for the purposes of safe rejuvenation. I think it's worth continuing the search for safer epigenetic pullback factors. Perhaps it makes sense to start by checking the remaining 20 factors from the original 24 Yamanaka factors. It is also worth checking out other reprogramming methods developed in recent years.

Finding the best factors is only half the battle. The other half is how to deliver them to the body 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 has shown. Therefore, in order to achieve significant rejuvenation in humans, it is likely that epigenetic pullback factors will have to be activated monthly or even weekly (regardless of whether they are OSKM factors or others).

Thus, the most economical way to achieve this goal would be to integrate a special, by default inactive gene cassette (containing genes for rollback factors) into almost every cell of the patient, 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, how the rollback factors will end up inside the cells, although important, is not related to the rejuvenation process itself. We will just need to get the identified factors inside in the best possible way. Such a task is not only in our country – the whole industry of gene therapy is looking for ways to solve it. Today there are already several ways to achieve this: viral vectors (lentiviruses, AAV), mRNA, proteins penetrating into cells. The infamous CRISPR is also looming on the horizon.

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

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

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

As soon as the efficiency and delivery method projects issue the first leader therapy with a minimum acceptable proven prolongation of life in mice (at least 50%), it will be possible to start all the necessary studies for the approval of this therapy by the FDA/ EMA agencies.

Regulatory rules for genetic therapy are just beginning to take shape. Therefore, it would be advisable to have a preliminary pre-IND meeting with the FDA (or apply for the "EMA Scientific council") as early as possible to hear first-hand what experiments these regulatory authorities 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 (a small molecule, unless an already known activator, such as doxycycline, is used).
• Similar considerations apply to toxicology studies.
• Teratogenicity studies will most likely be required both for the combination of the gene cassette and the 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 conduct a study on primates. Of course, life expectancy studies in primates take a lot of time, but it is possible to use already adult/elderly primates, and as the main endpoints of the study to use significant improvements in biomarkers of aging (epigenetic clock and/or improvement of cardiac/pulmonary/renal function, etc.), and not their life expectancy.

A few words about the economy

What I 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 anti–aging therapy.

However, if the main goal is achieved, the financial return will amount to billions, if not trillions of dollars. After all, the size of the market for various "anti-aging" dietary supplements, cosmetic or surgical procedures amounts to billions of dollars, despite the almost complete absence of any anti-aging effect in all these products. As soon as a 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 therapy I propose, in case of scientific success, will be able to generate the first income long before permission for use on humans. Rejuvenation of pets represents a huge market potential with significantly reduced regulatory barriers. And since Yamanaka factors work in so many species, the same therapy (adjusted for gene homology) will be effective in dogs, cats and humans.

Moreover, even before a full-fledged version of therapy for already adult individuals is developed (i.e., even before an optimal mechanism for delivering genes to an adult organism is created), a genetic cassette can be embedded in the embryos of "designer" pets, whose owners can begin experimenting with extending the life of their pets very much early. I think there will be many people who want to buy a dog that will potentially live 40 years, not 12.

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

Resume

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

Alas, all these approaches have either already shown their inadequacy in providing a significant increase in life expectancy, or are doomed to failure soon. The next big wave, in my opinion, is expected in the field of epigenetic rejuvenation. And, I believe that, unlike all the previous ones, this scientific approach has a high chance of success. Fortunately, I'm not the only one who thinks so:

In conclusion, we believe that the proof of concept of in vivo reprogramming for tissue regeneration and the strategies to elude tumorigenesis discussed here represent two initial prerequisites that should encourage further research towards clinical use. They will hopefully build enough confidence to continue on the long road to clinical translation of transient in vivo 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. Don't be silent, write a couple of words in support of this approach, if it seems feasible to you, or speak out against it, if not. And ideally, offer something better. You can do it in person if you don't want to do it publicly.

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

Portal "Eternal youth" http://vechnayamolodost.ru  18.09.2017