Progress in Separating Rejuvenation from Pluripotency in Cell Reprogramming
Reprogramming of adult cells occurs early in embryonic development, changing the adult germline cell into a pluripotent embryonic stem cell. This also removes epigenetic changes characteristic of age to rejuvenate cell functions, such as mitochondrial activity. A recipe for recreating this reprogramming process in any cell was discovered 20 years ago, and involves increased expression of the four Yamanaka factors. Over time, the interest of the scientific community has expanded from initial efforts to use reprogramming in order to generate patient-matched induced pluripotent stem cells for research and cell therapies. Now, researchers are equally interested in partial reprogramming that can produce epigenetic and functional rejuvenation in tissues without erasing cell type.
Researchers have expected these two aspects of reprogramming, dedifferentiation to pluripotency versus epigenetic rejuvenation, to be regulated separately. That underneath the regulatory layer of the Yamanaka factors, there would be other regulatory layers that distinctly produce dedifferentiation versus epigenetic rejuvenation. So far progress towards concretely identifying these hypothetical lower levels of regulation has been slow. Today's news from the Shift Bioscience team is a claim to an effective way to induce rejuvenation without dedifferentiation, by altering the expression of a single gene. The preprint does not identify the gene, of course, given that this is a corporate rather than an academic research group, but that information will emerge with time. One caution is that the researchers have validated the effects in a few cell types, but it may or may not generalize to all cell types.
A single factor for safer cellular rejuvenation
Ageing is a key driver of the major diseases afflicting the modern world. Slowing or reversing the ageing process would therefore drive significant and broad benefits to human health. Previously, the Yamanaka factors (OCT4, SOX2, KLF4, with or without c-MYC: OSK(M)) have been shown to rejuvenate cells based on accurate predictors of age known as epigenetic clocks. Unfortunately, OSK(M) induces dangerous pluripotency pathways, making it unsuitable for therapeutic use.
To overcome this therapeutic barrier, we screened for novel factors by optimising directly for age reversal rather than for pluripotency. We trained a transcriptomic ageing clock, unhindered by the low throughput of bulk DNA methylation assays, to enable a screen of unprecedented scale and granularity.
Our platform identified what we here designate as SB000, the first single gene intervention to rejuvenate cells from multiple germ layers with efficacy rivalling the Yamanaka factors. Cells rejuvenated by SB000 retain their somatic identity, without evidence of pluripotency or loss of function. These results reveal that decoupling pluripotency from cell rejuvenation does not remove the ability to rejuvenate multiple cell types. This discovery paves the way for cell rejuvenation therapeutics that can be broadly applied across age-driven diseases.
Last week an article on using small molecule drugs to replace the use of the Yamanaka factors in epigentically "resetting" cells was highlighted. However it was pointed out that small molecule drugs frequently have off target effects that limit or prevent usage. I commented that Spiroligomers might be able to over these difficulties, as they have the specificity of antibodies, but can enter cells like small molecule drugs.
Once the identity of this gene is revealed by Shift Bioscience, perhaps a Spiroligomer to mimic its effect could be produced? It seems like a faster path forward than waiting for gene therapy to get to an acceptable level of performance.
Wow this is a big claim. Essentially they landed on what New Limit is after but with a smaller budget and team?
I wonder if they are using it to see what effect intermittent, life long use would have on the lifespan.