Study Identifies Transcription Factor Pertubations That Drive Cellular Rejuvenation

Among the novel approaches to counter aging is cellular rejuvenation through transcriptional reprogramming. In a new study, a team from UCSF developed a platform that they used to identify more than a dozen single transcription factor pertubations that drive cellular and tissue rejuvenation.

The team’s high-throughput platform, the Transcriptional Rejuvenation Discovery Platform (TRDP), uses a fibroblast-based model of human cell aging and Perturb-seq screening. With TRDP, the team not only identified more than a dozen candidate TF perturbations, it validated four of them (E2F3, EZH2, STAT3, ZFX) through cellular/molecular phenotyping. 

Once identified, the team used CRISPR to prompt these transcription factors to give old fibroblasts a younger gene expression profile.   Adjusting the levels of any one of identified transcription factors triggered “young” gene expression in old fibroblasts. Changes to the levels of four of these factors improved metabolism in the old fibroblasts as well as their ability to multiply.   

“By altering gene expression using the transcription factors we identified, old fibroblasts behaved as if they were younger, and improved the health of old mice,” said Hao Li, senior author of the study published in Proceedings of the National Academy of Sciences.

In collaboration with UCSF’s Saul Villeda, the team also demonstrated that higher levels of the factor EZH2 rejuvenated the livers of mice that were 20-months-old, which is equivalent to about 65 human years. It reversed liver fibrosis; cut the amount of fat that accumulated in the liver in half; and improved glucose tolerance.  

"Our work opens up exciting new opportunities to understand and ultimately reverse aging-related diseases," said Janine Sengstack, first author of the paper.