A new  Cell  paper from Juan Carlos Izpisua Berlmonte’ s team has made headlines about anti-aging across the globe because it suggests that the particular four core induced pluripotent stem cell (IPSC) aspects use by Shinya Yamanaka to make IPSC can invert aging. I’ ve pasted the graphical abstract in the paper below and done a quick journal club design overview based on a quick skim of the paper.

Graphical abstract from Ocampo, et al Cell 2016

A few of the media headlines are rather dramatic  on this story. For example, in a story on it over at STAT the four Yamanaka factors (referred to as 4F: OCT4, SOX2, KLF4, and MYC) are referred to in the name   on the new paper as “ fountain-of-youth” molecules.

Yeah, I’ d say that’ s way over the top. But in contrast from my preliminary look at the paper, I don’ t think the writers engaged in hype in the discussion of their results so thankyou.

There are a number of  reasons to be interested in this papers. It is novel and touches on some exciting regions of science, but I have some sizable questions about it as well even just after a quick skim-read of it. A video from the Salk about the studies is below.

The papers used not only both surrogate molecular markers of getting older such as DNA damage examined by staining, but also research of both literal tissue aging and lifespan within mice as outcome measures (which is a lot of function and impressive). They found that pulses of the 4F condition  seems to counteract aging, which is particularly evident within mutant mice that prematurely aging. These Progeria rodents that received intermittent pulses of 4F exhibited considerably reduced speed of aging. More generally 4F rodents also were able to recover from various kinds of injury better.

Just the right ‘ Goldilocks’ amount of 4F is needed as the group found that persistent 4F outright kills the rodents due to tumors. Since the 4F contains a powerful oncogene known as MYC (one of my lab’ s favorite proteins), another caveat longer term would be that even mice just given intermittent 4F might be more prone to tumors. Nevertheless , the team did not report  tumors in the intermittent 4F mice so far, which is encouraging.

It’ h hard to imagine any human therapy that involves giving individuals more MYC or inducing MYC somehow given exactly how dangerous an oncogene it is (other than maybe in certain of the most extreme health cases such as studies I’ ve seen trying to tackle imminently fatal glioblastoma for instance making use of MYC-immortalized cells as delivery devices).

A fascinating question is whether other reprogramming combinations including those lacking  MYC would also have anti-aging properties. As the authors take note, others have conducted in vivo reprogramming studies previously and reported tumors:

“ Discovery studies led by the Serrano and Yamada groups have demostrated that cellular reprogramming to pluripotency, although associated with growth development (e. g., teratoma formation), can be achieved in  vivo in mice by the forced expression of the Yamanaka elements ( Abad et  al., 2013 , Ohnishi et  al., 2014 ). ”

Then one should consider the particular broader,   major issue with mouse studies that they occasionally (more often than we’ d all like)  aren’t replicable in humans, which comes into play here as well. The particular authors do examine human cells and find some information consistent with their overall findings in mice, but the human being data is quite limited. We cannot be sure yet issue effect in mice is for sure reproducibly going to be the situation in human cells let alone in humans, should several future application be applied to fight aging in humans based on this in future decades.

Because 4 factors are very powerful molecules that impact the particular epigenome, I would also worry from a translational anti-aging viewpoint about applications in humans potentially having transgenerational results on development unless germ cells could be protected through whatever method was used. It would be of interest to study whether or not the transient 4F (but otherwise WT) mice can give delivery to normal mice and so on.

More broadly, getting some genomic and epigenomics data in this paper (which largely relies on quantification of staining images) such as ChIP-Seq and RNA-Seq would have given it a boost. Such  data could have potentially addressed the fact that as it is we come away from the particular paper not knowing what the mechanism is by which the 4F pulses block aging in mice.

Probably that will come in the next paper.

Defining that will molecular mechanism could be the blockbuster future advance from this type of in vivo reprogramming research by the various teams doing work in this area. Using chemicals instead of the four factors with this kind of reprogramming is a very promising and exciting idea too.

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