The recent paper of Vittori Sebastiano’s group from Stanford reported the progress in the development of a cell-based rejuvenation therapy through partial cellular reprogramming. The therapy applies a patented rejuvenation cocktail OSKMLN that consists of transcription factors (TFs) Oct4, Sox2, Klf4, c-Myc, Lin28, and Nanog. The scientists administered a mix of mRNAs coding these factors for four days to old human fibroblasts and endothelial cells as well as mouse muscle stem cells. In such a relatively short period of time, these TFs changed epigenetics and transcriptional profile of the cells that lead to their functional rejuvenation. It was substantiated by measurements of various aging biomarkers, gene expression and later by in vivo mouse studies.
The name of the startup speaks for itself: the therapy encompasses diverse aspects of aging turning back aging of many cellular systems: the number of senescent cells, reactive oxygen species, and dysfunctional mitochondria decreased whereas work of systems of clearance from cellular debris improved: the number of proteasomes degrading defective proteins and autophagosome also helping get rid of damaged organelles increased. Histone modifications and DNA methylation after the treatment resemble the same marks in young cells. Researchers think that rejuvenation stems from these epigenetic changes which drive consequent gene expression changes. That is why the therapy was called ERA: epigenetic reprogramming of aging.
The effect is also preserved in vivo. For this purpose, researchers partially reprogrammed mouse muscle stem cells and injected them into muscles of pre-elderly mice and observed muscle recovery after injury. However, these cells had been reprogrammed for two days only, not four because stem cells are closer to the iPSC state. Mice after the injection recovered better than without it and almost as good as young mice.
The main reservation in the field of partial reprogramming has been the possibility of tumorigenesis due to a high proliferation rate and expression of oncogenes, primarily c-Myc. Therefore, the use of mRNA for reprogramming is safer than a delivery of the factors by viruses. Vittorio’s group verified that partially reprogrammed cells did not express any endogenous reprogramming factors, and in the mouse experiments they injected cells into 20-24-month-old mice and followed them up for 6 months after the injection. No tumorigenesis has been observed which substantiates the claims about the safety of the therapy.
What about estimating efficacy? For this purpose, probably the best quantitative aging biomarker was used — epigenetic age determined by DNA methylation, namely the multi-tissue Horvath clock. The largest rejuvenation effect was achieved for human endothelial cells: a decrease in epigenetic age by around 5 years with an error of a year and a half. In human fibroblasts, the age declined by 1.84 years with a standard deviation of 1.46.
Now, researchers are actively testing different transfection technologies for systemic delivery of the therapy. Jay Sarkar, the first author who has just graduated from his PhD and his supervisor Vittorio Sebastiano are launching a startup Turn Biotechnologies to reverse aging and have already raised more than half a million dollars. And the startup is trying to raise more money to approach human trials. They plan to start with delivery into eyes and muscles.
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