Multi-omic rejuvenation of human cells by maturation phase transient reprogramming

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. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of somatic cell reprogramming, which suggests full 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reprogramming (MPTR) method, where reprogramming factors are selectively expressed until this rejuvenation point then withdrawn. Applying MPTR to dermal fibroblasts from middle-aged donors, we found that cells temporarily lose and then reacquire their fibroblast identity, 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 was rejuvenated to a similar extent, including H3K9me3 levels and the DNA methylation ageing clock. The magnitude of rejuvenation instigated by MPTR 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 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.

Automated summary

Ageing is a gradual decline in organismal fitness that is associated with reduced cellular function and altered gene expression. Recent research has shown that the epigenome can be rejuvenated during somatic cell reprogramming, suggesting that full reprogramming may not be necessary to reverse ageing. In this study, the researchers developed a method called maturation phase transient reprogramming (MPTR), which selectively expresses reprogramming factors until a rejuvenation point and then withdraws them. They found that this method rejuvenated multiple cellular attributes, including the transcriptome and epigenome, to a larger extent than previous protocols. Overall, this work demonstrates the possibility of separating rejuvenation from complete pluripotency reprogramming and may facilitate the discovery of anti-ageing genes and therapies.