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.
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.
so Mr. Knoepfler and other contributors. What is your opinion now that one year has passed since publishing this paper. Any followup studies, perhaps with wild type mice? I have the feeling that this was a dead end research.
Upon reading this paper, my first question is:
Why would one do any of this?
First, Hutchison-Gilford progeria isn’t really, truly premature aging. As the authors seem to base all of their aging markers off this intial mouse model, their findings should be examined extremely critically. Also, relying on transcript levels intstead of protein (even presence/absence would have been ok) is maybe not a decision the authors should have made for aging markers.
Second, none of the experiments appear to have been done in mice considered by the field to actually be “old” (12mo is not considered “old” by the aging field).
Third, the whole paper is done in trangenic mice or cell lines, meaning that every cell can express the factors. If the mouse needs every cell to be inducible for the fairly modest beneficial effects, then it’s not translatable, full stop. Some sort of viral treatment experiment would have been the only thing that would have made this paper interesting. As it stands, none of their data is really compelling from an aging standpoint.
It seems like nearly every time there’s a paper from the Belmonte lab, I’m astounded by how poorly it’s done and by how much hype there is. Almost without fail, everything from the rationale to the experiments have major logical flaws. I would really like to know how his lab’s papers get into such “good” journals.
Also, it wouldn’t surprise me that the “aging” reversal in the human cells could be more easier gotten rid of simply by culturing the cells under physiological (5% or less) rather than atmospheric oxygen levels.
I would place good money on the mechanism being simply histone remodeling.
In vivo reprogramming was previously shown. Telomerase in iPSC induction was previously shown. This advance seems more marginal but important.
@Paul,
Fascinating science! Reminds me of all the hype surrounding David Sinclair, resveratrol and sirtuins. Is there any type of biological link between the two?
Interesting but we all have different notions of what aging is. DNA damage and cytosolic aggregates accumulate with age and getting rid may increase healthy functionality – but that’s not the whole aging story.
I would like to know what happens in the brain when 4F is applied. Is memory and learning still intact?
Given the size of the iPSC bandwagon, I believe this will get a lot of press. It will be interesting if the result here will be replicated. I believe the age of the cells that were engineered could also play a role in future successes and/or failures.