Promoting multi-omic rejuvenation in human and mouse somatic cells by transient reprogramming

Ageing can be defined as the gradual decline in fitness that occurs in most organisms. The ageing process is characterised by a variety of hallmarks at the cellular and molecular levels including alterations in the epigenome. Notably in the case of the epigenome, these alterations can be measured and quantified by epigenetic clocks. These are models that can predict age based on the DNA methylation levels at particular CpG sites and, interestingly, also appear to capture biological age (where relatively fit individuals are predicted to be younger than their chronological age and vice versa). iPSC reprogramming is the process of converting somatic cells, such as fibroblasts, into induced pluripotent stem cells (iPSCs). Amazingly, this process reverses age associated alterations in the epigenome and resets epigenetic clocks to 0 years old. Complete iPSC reprogramming has the major caveat of losing original cell identity and therefore function. This can be difficult to reacquire as differentiation protocols do not exist for all cell types or existing protocols may be inefficient or generate immature cell types rather than mature adult cells. To avoid this problem, we have developed a new method called maturation phase transient reprogramming, where human cells are reprogrammed up to the maturation phase and then the reprogramming factors are withdrawn. This method enabled cells to reacquire their original cell identity and substantially reversed age-associated changes in the transcriptome, proteome and epigenome, with features such as the transcriptome and epigenome appearing to become 30 years younger. In addition, transiently reprogrammed fibroblasts produced more collagen protein suggesting these cells are functionally younger. Finally, we have also carried out transient reprogramming in vivo, where this approach also promotes rejuvenation in the epigenome. Overall, transient reprogramming appears to capable of eliciting cellular and molecular rejuvenation, which may enable us to better understand the ageing process and develop novel anti-ageing therapies in the future.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Gill, Diljeet

Advisor dc:contributor.advisor

• Reik, Wolf

• Epigenetics
• Ageing
• DNA methylation
• Stem cells
• Reprogramming
• Transcriptome
• Epigenome
• Rejuvenation

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a225aebb-125d-4837-aee2-ed88e2d36e38/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.71150

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/323693