Ageing is the gradual decline in fitness and health that occurs over time leading to tissue dysfunction and disease. As we age, our cells undergo a variety of changes that cause them to become less functional. In particular, changes occur in our epigenome, which is the set of chemical modifications to DNA that help our cells to decide which genes to use and which to ignore. Recent work has demonstrated that the epigenome is rejuvenated during a process called iPSC reprogramming, where adult cells are converted into stem cells similar to those found in the developing embryo. Notably, epigenetic rejuvenation occurs at the intermediate stage of the reprogramming process, suggesting that complete reprogramming (which causes the original cell type and functions to be lost) is not needed to reverse features of ageing. This is exciting as it can be difficult to convert stem cells back into useful adult cell types.

We have developed a novel method called “maturation phase transient reprogramming”, where the factors required for reprogramming are expressed until this rejuvenation point and then withdrawn. Applying our method to fibroblasts (a cell type found in the skin) from middle-aged donors, we found the cells temporarily lost and then regained their original fibroblast cell type, demonstrating that we can avoid the caveats of complete reprogramming. Excitingly, our method still substantially rejuvenated multiple attributes including the transcriptome (which genes the cells are using) and the epigenome, which were both rejuvenated by around 30 years. After our method was applied, the fibroblasts also behaved like younger cells – they produced youthful levels of collagen proteins (which are important for the structure of healthy skin) and moved (migrated) more quickly.

Overall, maturation phase transient reprogramming appears very promising and in the future this technology could be used to improve cell therapies by functionally rejuvenating cells before they are given to patients. In addition, by further studying the mechanisms that underlie transient reprogramming, we may be able to separate those responsible for rejuvenation from those responsible for making stem cells. This may enable us to develop methods or treatments that promote rejuvenation without reprogramming at all.