ICO will fund resetting epigenetic aging clock to prolong human lives by over 30%

Youthereum Genetics believes aging is ultimately controlled by the hypothalamus, just like all other aspects of ontogenesis.

The information for this article is from an interview at Fightaging.

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.

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.

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.

Aubrey de Grey, who is one of their 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.

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.

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.

Key hypothesis

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.

They want to get the investigational new drug stage in 5-6 years and then license to Big Pharma.

8 thoughts on “ICO will fund resetting epigenetic aging clock to prolong human lives by over 30%”

  1. If they succeed in selling the drug to Big Pharma, you’ll never hear from it again. Big Pharma makes its money selling expensive drugs to sick patients. And there’s few sicker populations than old people. If everyone could be made youthful again, and relatively cheaply, the big profits would dry up for Big Pharma. They have no interest in that. It’s why they’re not in the vitamin business, or the nutricutical business. The big money is made from cancer, heat disease etc., and these are primarily diseases of the old. They are not going to dry up that market and make billions of dollars worth of drugs obsolete overnight.

    Reply
    • “Big Pharma. They have no interest in that. It’s why they’re not in the vitamin business, or the nutricutical business.”
      Does anyone have some data on whether that is true? Getting millions of people to take your vitamin pills every day is a nice cash cow. (Whether the vitamins do any good or not.) I would be a bit surprised if Big Pharma is not in those businesses.

      Reply
      • Interesting question. Let’s see
        Google: Pfizer vitamins …… well, it seems that big pharm Pfizer is a major manufacturer of vitamins.
        Google: Pfizer neutricutical …. yep. that too.
        Google: Bayer vitamins … Johnson and Johnson vitamins… Novartis….

        So far it seems that all the big pharma companies have major vitamin businesses. I can’t be bothered looking at any more.

        Not that I’m surprised. Anyone who starts with the idea that a company will ignore a HUGE new market just because it might, over many decades, result in a smaller market for the industry as a whole has no idea of what “competition” means. Or the word “quarterly earnings”. Or “stock options”.

        Reply
      • So what happens when I start a company and start selling this to people? Does “Big Pharma” have some way they plan to stop me? Sounds like the business opportunity of the millennium, I wonder how hard it would be for me to get funding?

        Reply
  2. Michael Rae of the SENS Research foundation expressed doubts about the use of Yamanaka factors to “reset aging” in the comments under this fightaging.org blog post:

    https://www.fightaging.org/archives/2017/02/sens-after-de-grey/

    “@Steve Hill: “Epigenetic changes we know thanks to SALK and Blasco this year are important and when you reset epigenetic changes we see increased lifespan and cells restored to younger function. Almost certainly a pathway worth pursuing.”

    I take it you’re referring to this paper [http://www.cell.com/fulltext/S0092-8674%2816%2931664-6] (in FightAging! here[https://www.fightaging.org/archives/2016/12/temporarily-applying-pluripotency-reprogramming-factors-to-adult-mice/]). There was no increased lifespan in this report: there was partial normalization of the miserably-short lives of mutant progeroid mice. Since these mice suffer a variety of phenotypes caused by severe premature stem cell depletion, it makes sense (though I wouldn’t suggest that it was obvious) that intermittently partially restoring pluripotency in a subset of their cells would help to ameliorate their severe phenotype – and even there, doing so chronically actually shortened it. It makes even more sense that a one-time short-term application of the same factors normal life enhanced regenerative response to injury in aged mice. But none of that meaningfully suggests that the cyclic lifelong protocol used in the mutant mice would be a net benefit in actual aging.

    And remember, in any case, that there are no such semi-pluripotent cells in somatic tissues in a mature adult body, so nothing about this experiment is informative about age-related epigenetic changes or their reversal, as your comment seems to imply.

    Finally, note Blasco wasn’t on that paper – is there a second paper by her to which you refer?”

    Reply
    • Michael Rae/fightag. make negative comments on everybody except sens … When they will produce a research similar to Belmonte or other similar labs that do real studies (not white papers like deGrey), then we can discuss about something. There is a big difference between real research done in lab by groups like Belmonte, Church, Maria Blasco, etc. and amateurs like fightag. that are paid by sens to blog 24/7 against everybody else. So yeah, would be nice to stop posting whatever comments they do on that fa blog, that is NOT science.

      Reply

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