Fight Aging!

Initial coin offerings (ICOs) are driving most of the light and heat in the blockchain world these days. People are raising enormous sums in cryptocurrencies for ventures with somewhere between little plausibility and ordinary levels of startup plausibility. In many ways it looks a lot like the last years of the internet bubble way back when; there are a lot of parallels. The flows of funding may be driven by some combination of people bypassing Chinese currency controls, early holders of Bitcoins and Ether diversifying their holdings within the blockchain ecosystem, and various large investment concerns whose owners have found they can make a quick buck by flipping blockchain tokens, all of which adds fuel to the fire. As I asked earlier this year, if fairly dubious ventures can pull in tens of millions of dollars doing this, why can't we use this to fund thoughtful, legitimate initiatives in rejuvenation research? The challenge here lies in finding a meaningful use for blockchains and network effects in our world of research and development.

Some groups are forging ahead with that effort. I've mentioned Open Longevity's ICO, in which they seek to fund collaborative human trials of various potential pharmaceutical means to slow aging, but for today the focus is on Youthereum Genetics, a newer venture that also seeks to use an ICO as a mechanism to fund research and development. The Youthereum principals are initially intending to work on a means to deliver pluripotency factors involved in the creation of induced pluripotent stem cells to spur regeneration. A demonstration of this was conducted by a research group and published earlier this year, resulting in health benefits for the progeroid mice often used in early stage aging research. This was somewhat surprising as an outcome: haphazardly inducing cells to become pluripotent in a living organism sounds like a rapid short-cut to cancer.

The next steps will be to try this in normal mice, quantify the most useful dose and delivery method, and continue to watch carefully for evidence of cancer as a side-effect. In the best case this may be a road to a regenerative therapy analogous to stem cell transplants, but that remains to be seen. As in so many areas of research where interesting results may or may not lie ahead, the first question is where the funding for that work will be found. The Youthereum team hope that tapping into the blockchain market is the way to go.

I recently had the chance to chat with Yuri Deigin of Youthereum Genetics, and to ask some questions about his aims. As you can tell he is proceeding from a programmed aging point of view - something that I tend to present as standing in diametric opposition to the more mainstream view of aging as accumulated damage. Possibly oversimplifying, this is the question of whether in aging epigenetic change (a program) causes damage, or whether damage causes epigenetic change (a reaction). A programmed aging point of view leads one to intervene in processes that are, to the accumulated damage point of view, secondary consequences only, and attacking secondary consequences just won't be very effective. We are close to the years in which one side or the other will be definitively proven correct, due to the implementation of specific approaches to the treatment of aging as a medical condition.

Nothing is completely black and white, however, and it is interesting to see the development of areas where theorists from either side of this divide will meet in the middle at approaches to therapies that both will consider potentially useful enough to try, but for different reasons. Some classes of stem cell therapies and efforts to achieve similar effects through changes in signaling or reprogramming cells in situ rather than through delivery of cells are a good example of the type. From a programmed aging point of view, these are levers with which to change epigenetic signaling to more youthful levels, while from an accumulated damage point of view, they could be essentially compensatory in nature, like stem cell therapies, but picking the slack to some degree for native regenerative processes that are hampered by damage.

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

I am a Russian-Canadian transhumanist longevity activist, amateur theoretical biologist, and a biotech entrepreneur. Previously, those areas of my life did not intersect, but in the past few months the stars have aligned to prompt me to finally combine my passion and expertise, and channel them into an undertaking I consider the most important in my life: curing aging. Or - getting off the high horse - at least developing some significant life extension therapies for humans, because at the moment there are none. By "significant" I mean something that can prolong our lives by at least 30%. No therapy outside of caloric restriction has been able to achieve this milestone even in mice - not rapamycin (26%), not metformin (14%), not telomerase (24%), not senolytics (26%) or any other 'geroprotector'. And caloric restriction which holds the record for non-genetic lifespan extension (up to 50% in various rodents) failed to produce anywhere near as spectacular a result in primates. In the two macaque studies conducted on CR, at most a 10% median lifespan increase was observed in females and in some groups CR actually shortened lifespan.

Personally, I believe that the reason behind this inability to put a significant dent in aging in the past 50+ years lies in its programmed nature. Over the years, I have seen plenty of evidence in support of this hypothesis with the most convincing being results from parabiosis and young plasma experiments. I think that aging is ultimately controlled by the hypothalamus, just 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 Everitt's. Recent research by Dongsheng Cai and his colleagues provides further evidence for the hypothalamic hypothesis. On the cellular level, aging is most likely both tracked by and executed via epigenetic regulation of gene expression. Several years ago it was first observed that a person's age is highly correlated to his/her epigenetic profile. Later it was recognized that these 'epigenetic clocks' are effective life expectancy predictors, which confirmed that epigenetics is a key component of the aging process. Many organisms were found to have such 'epigenetic clocks' that are highly correlated with both their age and probability of death.

Moreover, Nature knows how to roll back or even completely reset the epigenetic clock. This is done for every new embryo and is most likely the reason why every new animal is born young despite having started as an oocyte cell of the same age as its mother (as mother's oocytes were formed while she herself was still in utero). Finally, experiments with epigenetic rejuvenation which demonstrated that rolling back epigenetics rejuvenates not just individual cells but entire organisms (and prolongs their lifespan) have confirmed that epigenetics is not just a consequence but an important driver or aging. This is where Youthereum Genetics comes in. Based on the recent work of Juan Carlos Izpisua Belmonte's group at Salk, who have shown that periodic induction of OSKM transcription factors can prolong lifespans of progeric mice by up to 50%, we hypothesize that aging can be rolled back by periodic epigenetic rollbacks. Our strategy is aimed at translating this hypothesis into a safe therapy that produces sizable, noticeable rejuvenation in humans.

Why us and why now? In a nutshell, because I grew too tired of waiting for someone else to do it and not seeing anyone step up to the plate. So I put together a team that is capable of designing and overseeing experiments for all the steps involved in first verifying the science behind our hypothesis and then translating it into a therapy should science hold up. The only thing left to do now is a small matter of raising the necessary funding. I am being sarcastic, of course. It is a huge challenge, especially given the amounts required and the associated scientific risks involved. But I am willing to try, even in the face of high odds against.

What is your model for what is going on under the hood in animals transfected with pluripotency factors? Why does it produce benefits?

As I mentioned, I am of the Programmed Aging Witnesses cult. 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 damage that we see the body accumulate with age do so because our cells gradually tone down the volume of various damage repair mechanisms. Our cells do so via epigenetic regulation of various genes upon receipt of endocrine signals that originate in the hypothalamus based on circadian rhythms and some sort of an internal clock. We know there is a clock because we can see how finely tuned the timings of various developmental and cyclical processes are - from embryogenesis to puberty to menstrual cycles.

So my belief is that the body has enough capacity for self-repair to function at the level of a 25-year-old for hundreds if not thousands of years, or maybe even longer. If the germ line can do so for billions of years, periodically generating a new organism from scratch, it seems logical to me that just a fraction of those remarkable bodybuilding abilities should be enough to sustain our bodies for much, much longer periods than we see today. So if we find a way to trick our cells into thinking that we are 25, they will function (and get replenished) at the level of a 25 year old regardless of our chronological age. To do so, they would need to have gene expression profiles (epigenetic profiles) typical of 25-year-old humans. And we know from the work of Hannum and Horvath that the epigenetic profiles of 25-year-olds are quite different from profiles of 45- and 65-year-olds.

So when we induce OSKM factors in cells, what I think happens is epigenetic rewinding that is associated with upregulation of various repair mechanisms. It is an empirical fact that induced pluripotent stem cells experience significant rejuvenation that ameliorates virtually all the famous Hallmarks of Aging: telomeres elongate, laminar defects get fixed, mitochondrial function gets restored and so on. There is a great article about this by Vittorio Sebastiano and Tapash Jay Sarkar of Stanford with plenty of details.

That said, one doesn't have to believe in programmed aging to see the potential of epigenetic rejuvenation for life extension purposes. In fact, Aubrey de Grey, who is one of our advisors, despite being a staunch opponent of the programmed hypothesis, also believes epigenetic rollback holds therapeutic promise. In his view, the ability to rejuvenate the aged body by reactivating early-life pathways does not in any way conflict with the idea that aging is unprogrammed and results from the gaps in our anti-aging machinery rather than the presence of actively pro-aging machinery. I would be more than happy to be proven wrong on the underlying mechanisms of epigenetic rejuvenation as long as it provides us with a lifespan extension comparable to that seen in Belmonte's work.

Conversely, why won't this treatment produce an unacceptable level of cancer risk? That is always a concern in this sort of thing.

Absolutely, teratomas are probably the biggest concern of this approach. In fact, before Belmonte showed that there is a Goldilocks zone of OSKM induction that extends lifespan without producing teratomas, cancer risk of this approach was thought to be prohibitive for its translation. Apparently, it isn't. The trick is to roll the cells back ever so slightly to prevent them from de-differentiation, but to do so often enough to prevent (or at least slow down) the accumulation of age-related damage that results from the relentless downregulation of damage repair mechanisms with age.

How does this fit together into your view of aging? What do you expect from this and other efforts in the years ahead? Where would you expect the biggest wins to emerge?

This fits my view of aging like a glove. In fact, the reason I got so excited about Belmonte's results back in February was because before I learned about them, I hypothesized that if we ever learn to roll back epigenetic changes, doing so periodically can provide us with a good enough "hack" to significantly delay aging until we completely decipher its mechanisms and learn to stop them for good. So epigenetic rejuvenation is precisely where I think the biggest gains in life extension could emerge. One other important area that we also plan to explore at Youthereum, albeit in a separate research track, is trying to decode hypothalamic exosome secretions. We think that Dongsheng Cai's latest paper, which showed that 16-months old mice exhibit signs of rejuvenation after a one-time injection with hypothalamic exosomes isolated from cultured hypothalamic neuronal stem cells, is really onto something.

Tell us about your take on how to merge the flow of funds in the blockchain market with the goal of doing something useful in longevity science. So much of what is going on in the ICO space seems a very clumsy effort to bolt one thing, the blockchain, onto another completely unrelated thing that has no logical connection to the blockchain. How are you different?

We are not trying to pretend that we will contribute something to the blockchain infrastructure. We won't, we are a decentralized biotech crowdfunding project that is raising money first and foremost for scientific research. In other words, we are users of the blockchain technology, not its developers. We plan to use it to eliminate any middlemen between us and our funding contributors, and to ensure that all our backers' rights to the therapies we plan to develop are not affected by various governmental red tape - current or future. Those are the two main benefits of decentralization, in our opinion. So we view ICOs as just a more efficient crowdfunding mechanism, even if that makes some blockchain purists cringe. I am not sure why they would cringe, though - by embracing the blockchain paradigm and bringing real-world projects into their realm we are actually validating their technology and greatly expanding its potential user base.

How does Youthereum Genetics differ from Open Longevity, who are trying their own hand at an ICO?

While Mikhail Batin of Open Longevity and I agree that we need more people to do everything possible to develop radical life extension therapies ASAP, we differ on what kinds of interventions could actually produce such life extension. I believe that no therapy that exists today, including any clinically approved drugs, can prolong our lifespans by more than 10%, let alone 30%. So in my view, conducting clinical trials for the Fasting-Mimicking Diet (FMD) or use of statins to see if they have the potential to prolong lifespan is not very useful. Epigenetic rejuvenation, on the other hand, does, in my view, have the potential to prolong our lifespans by over 30% or even much, much greater. That is why I am betting so much of my time and money on it.

If this all goes swimmingly well, and you are buried in funds, with decent animal data on the use of pluripotency factors as a therapy, what next?

Let me try answering this by first describing our research plan. We intend to subdivide it into 3 parallel research tracks: (1) development of an optimal dosing regimen using OSKM factors; (2) search for safer factors of epigenetic rollback that do not lead to complete de-differentiation; (3) creation of the best 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 clock of most cells in the body, if not all cells. Thanks to the work of Belmonte's group, we know that this is possible by delivering OSKM factors (or other transcription factors) into the cell. However, this is a tricky endeavor: roll back too little and you get no sizable effect; roll back too much and you might get cancer, as cells would lose their identity and become pluripotent again. After all, their ability to turn cells back into pluripotent state was the main selection criterion for picking the 4 OSKM factors from the original 24 candidates. So, while OSKM factors are effective and represent a "bird in hand", they are far from ideal for our purposes.

We should strive to find better, safer epigenetic rollback factors; we plan to start by revisiting the remaining 20 factors of Yamanaka's original 24, and also try to use the Oct4 factor alone, since there is evidence that it alone is able to roll back epigenetics and is generally the main "guardian of the epigenetic gates." However, narrowing down the factors is only half of the challenge. Delivering them safely and, ideally, cheaply is the other half. The epigenetic aging program is quite robust even in the face of weekly rollbacks, as demonstrated by Belmonte et al., therefore, obtaining meaningful rejuvenation in humans would most likely require monthly or even weekly induction of epigenetic rollback factors (whether OSKM or otherwise). The most cost-effective way of achieving this would be to integrate a special, normally silent polycistronic cassette containing the genes for the rollback factors into virtually each cell of a patient. Such a cassette would be activated by a unique and normally inert custom agent that would need to be developed separately, and would enable this approach to be patentable. Today such cassettes are activated by, for example, tetracycline or doxycycline. With this approach, the marginal cost of a weekly induction of rejuvenating factors would only be the cost of the induction agent (presumably, a small molecule or a peptide) - comparatively cheap.

In summary, we see the most optimal research plan as a step-by-step, iterative improvement of the already proven approach, the induction of OSKM factors with doxycycline; such a cassette with OSKM factors can be delivered to the body using a lentiviral carrier available on the market today. This will proceed in parallel with the development of an ideal therapy: maximally safe and effective factors activated by a unique, inert, patentable agent. Patentability is crucial for being able to interest Big Pharma in in licensing this therapy upon reaching the IND stage. If the project successfully reaches the IND stage, we believe Big Pharma companies will then be sure to license this therapy to begin clinical studies, first for prevention of atherosclerosis, Alzheimer's disease, diabetes or other age-related indications that anti-aging drugs are using today for regulatory purposes, as aging itself is not yet classified as an indication by the WHO. In a nutshell, that is our plan - get the therapy to the IND stage and then let Big Pharma do what it does best: validate it clinically. We estimate that to get to the IND stage it would take 5-6 years if all goes well.