July 13, 2020

The Niche

Knoepfler lab stem cell blog

Quick journal club on IPSC anti-aging paper: cool, but outstanding questions

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

ipsc-anti-aging-paper
Graphical abstract from Ocampo, et al Cell 2016

Some of the media headlines are rather dramatic on this story. For instance, 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 title on the new paper as “fountain-of-youth” molecules.

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

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

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

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

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

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

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

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

Because these 4 factors are very powerful molecules that impact the epigenome, I would also worry from a translational anti-aging perspective about applications in humans potentially having transgenerational effects on development unless germ cells could be protected from whatever method was used. It would be of interest to study whether the transient 4F (but otherwise WT) mice can give birth to normal mice and so on.

More broadly, having 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 would have potentially addressed the fact that as it is we come away from the paper not knowing what the mechanism is by which the 4F pulses block aging in mice.

Maybe that will come in the next paper.

Defining that molecular mechanism could be the blockbuster future advance from this line of in vivo reprogramming research by the various teams working in this area. Using chemicals instead of the four factors for this kind of reprogramming is a very promising and exciting idea as well.

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