The Human Aging Clock to be Boosted by 30%
From Next Big Future
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.
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.