Some skepticism as Shift Bioscience reports secret purported rejuvenation gene SB000 in preprint

What if there was a rejuvenation gene that made adult cells younger without turning them into potentially destructive embryonic, fetal, or tumor cells?

It could be transformative for how we think about cellular aging and have many impacts on health.

A new preprint posted on June 6th reports on a possible rejuvenation gene. The gene reportedly rejuvenates somatic cells without reprogramming them so far as to become pluripotent stem cells.

What is this potentially amazing gene? The team behind the preprint calls it SB000. In other words, it’s still a secret.

What are we to make of SB000? At this point I remain skeptical of this overall claim and especially of its potential significance for human health.

Let’s discuss the preprint and some important context. Spoiler, this is a long way from a Yamanaka-level discovery at this point.

First impressions of Preprint from Shift Bioscience

Brendan Swain led the team that posted the preprint “A single factor for safer cellular rejuvenation.”

The “SB” part of the gene placeholder name likely comes from the biotech involved, Shift Bioscience, where Swain is CSO.

Right off the bat, keeping the gene a secret, even at the preprint stage, is a problem.

The preprint also makes extraordinary claims about SB000 functions that will require iron-clad evidence, which is just not there yet in this preprint.

I asked Jeanne Loring, a scholar in the stem cell field and expert in reprogramming, for her overall thoughts on the preprint: “In spite of the huge amount of hype and few facts about rejuvenation and longevity, investors’ eyes still light up when they hear about a new thing. Is this also hype? Twenty years ago, Shinya Yamanaka’s reprogramming results had to be reproduced by another lab before they were trusted; I’m going to wait until another lab reproduces this result.”

I first learned of this preprint via a tweet from leading aging researcher Steve Horvath of Altos Labs. Horvath and others have developed aging clocks or epigenetic clocks that are useful tools.

The challenges with in vivo reprogramming & the idea of a rejuvenation gene

One of the challenges with much of the in vivo reprogramming work out there and the anti-aging aspirations based on it is that introduction of Yamanaka factor cocktails tends to yield iPS cells rather than younger somatic cells. We don’t want iPS cells inside of our bodies as they will lead to teratoma.

Note, to be clear, differentiated cells produced from iPS cells in a lab are going to be much safer for transplantation and may have great beneficial properties.  I’m thinking, for example, of clinical trials of cells like iPS cell-produced dopaminergic neurons for Parkinson’s or RPE cells for macular degeneration. Such trials already show solid safety.

Getting back to the longevity field and in vivo reprogramming, researchers like David Sinclair have been hoping to find ways to do partial in vivo reprogramming. They want to get younger somatic cells (cardiomyocytes, neurons, etc.) rather than iPS cells from the process. I’ve been skeptical that such a sweet spot outcome is reproducibly possible with Yamanaka-like factors without getting some iPS cells too or primitive proliferative (and probably highly destructive) committed fetal cells.

Other researchers like Charles Brenner have viewed Sinclair’s work skeptically. 

Candidate anti-aging gene SB000 versus Yamanaka factors

Now comes this new Shift Bioscience preprint claiming a holy grail result: younger cells in vitro without full reprogramming thanks to the candidate rejuvenation gene SB000.

The team first used a transcriptomic clock to try to discover rejuvenation genes. It’s a clever idea. They found a group of candidates and tested SB000 further, sometimes comparing it to outcomes with the Yamanaka reprogramming factors.

The preprint reports that the initial “data support that SB000 drives substantial rejuvenation in the transcriptomes of fibroblasts from both dermal and lung lineages.” The study also argues that SB000 is safer than Yamanaka factor reprogramming.

They go on to show a lot of omics data related to SB000.

The biggest claim here is of about a decade of cellular de-aging with this secret gene based on the Horvath and other epigenetic aging clocks. All while retaining differentiated identities.

SB000 preprint limitations

There are numerous limitations to this preprint:

• They only did this stab at cellular rejuvenation with SB000 in a few cell types, mainly fibroblasts.
• The work was all in vitro and so may not be recapitulated in vivo. A key question — does anything (positive or negative) happen in mice when SB000 is overexpressed transiently or persistently?
• The study has mostly omics data and relies to a large extent on epigenetic clocks, but it is relatively too limited on functional data like how do cells actually behave after getting SB000. From Jeanne Loring on this, “They are reinventing a way of measuring fibroblast aging. I’d like to see some evidence that they function as younger cells.”
• What happens in cells that normally express SB000 if you knock it down or out?
• The story specifically needs data assessing the tumorigenicity, if any, of SB000-overexpressing cells including especially in vivo.
• I would have liked to have seen cell cycle and proliferation data.
• This is a non-peer-reviewed preprint from one group.
• Again, the gene’s identity is a secret. We could speculate that it is an epigenetic regulatory gene, a non-pluripotency-driving transcription factor, cell cycle, or a metabolic gene, etc., but without that context, we are limited in interpreting the data in this preprint.

Is this really a one-hit rejuvenation gene?

Presumably manuscript peer reviewers will discuss such limitations too. They likely say they must know the gene’s identity (if it is again left out in the submitted manuscript) so when this ultimately becomes a published paper, we’ll have more information.

In the meantime, I have many more questions.

Why didn’t someone stumble on this before? Is it just the advent of epigenetic aging clocks, including work by Swain, Horvath, and others, that has made identification of SB000 as an anti-aging gene possible? It’s plausible but would be surprising.

Why would excess of this gene be safe and not transform cells? I guess the idea is that SB000 would not be an oncogene because while it makes cells “younger”, it leaves them in a differentiated state. Still, I would think SB000 would be found elevated or mutated in many cancers. Maybe it is.

How will this fare in peer review and with replication attempts?

Overall, at this point while the preprint is intriguing, there are reasons to be skeptical based on past work and our understanding of core concepts in this field.

Those plus the limitations outlined above, make me very cautious here.

I’m not saying there’s anything wrong with this preprint on my first glance through. However, I need to do a deeper read when I have more time. I also cannot help but think about past claims in this arena like STAP cells.

My very first reaction in seeing this was that it sounds too good to be true, but time will tell.

A long, difficult road toward human applications

A final thought leans even more cautious.

Even if SB000 can make cells inside the murine body younger (and let’s say even in the human body) without turning them into iPS cells or other risky intermediate cell types, making cells and tissues younger is not always going to be a good thing in vivo. It will come with risks including potential disruption of normal tissue function in the body and probably increased cancer risk. Say you have a precancerous cell with a few mutations and it gets a shot of SB000. I doubt that’ll be a good thing.

Jeanne also noted some obstacles to possible human applications and was concerned about the potential for oncogenicity here, “The problem with applying a transgene-driven anti-aging strategy is still that you need to deliver the gene(s) to some part of the body that would be relevant to aging. Easy in mice. Other than making transgenic humans, I don’t see a way to do that. And, another matter is that they haven’t shown that their transgene doesn’t make the cells cancerous.”

So, despite all of the above, will this end up as a Nature (or similar level) paper in just a few weeks? I wouldn’t be surprised.  Maybe reviewers will also be cautious, but we haven’t always seen that with this kind of early finding.