An interesting step forward in glass… making skin cells younger in cultures.
It leaves open the question of how to do this in a living animal. It might be trivial, or lethal. So more work on that front for sure.
Multi-omic rejuvenation of human cells by maturation phase transient reprogramming
Diljeet Gill, Aled Parry, Fátima Santos, Hanneke Okkenhaug, Christopher D Todd, Irene Hernando-Herraez, Thomas M Stubbs, Inês Milagre Is a corresponding author , Wolf Reik Is a corresponding author
Babraham Institute, United Kingdom; Chronomics Limited, United Kingdom; Instituto Gulbenkian de Ciência, Portugal; Altos Labs, United Kingdom
Research Article Apr 8, 2022
Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming, somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first ‘maturation phase transient reprogramming’ (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells temporarily lose and then reacquire their fibroblast identity during MPTR, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that more extensive reprogramming does not necessarily result in greater rejuvenation but instead that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.
Basically they reset the biological clock by about 30 years, but do not revert the cell to a precursor foetal type that doesn’t know what function it is to do in the mature body yet.
Methylation is the process that marks certain genes to be turned on or off. Their description implies some aging defects are caused by methylation errors or artifacts that can be reset to a more neutral starting point.
This article explains it all more and with a bit of a downer:
Exposing these cells to the OSKM factors was performed with a doxycycline-activated lentiviral package. While this method cannot be safely and effectively used inside a human being, it did allow the time of exposure to be carefully controlled, and such careful control is necessary; 10 days of exposure did not epigenetically rejuvenate cells as well as 13 days of exposure, but the researchers showed that too much exposure (15 and 17 days) led to cellular stresses that aged the epigenome once again. This study had only a few donors, and results after 13 days varied greatly by person.
This does leave open the possibility of rejuvenating cells in culture, then injecting them into a person. Cells injected have been shown to preferentially take residence in tissues of their type (though who knows how perfectly…).
However, it is feasible that such an approach could be used for the development of cell cultures that can be re-introduced back into an older person. This experiment used fibroblasts, which form collagen, so it is reasonable to imagine a world in which such reprogrammed cells are developed as a therapy against wrinkles and other effects of the aging extracellular matrix. This approach may one day be used to create viable, rejuvenated populations of muscle (incluluding cardiac muscle) and brain cells, and such freshly reprogrammed near-somatic cells may ultimately be the best option in many clinical applications.
Still, it is an interesting step toward repair of the damage of aging.