Gene regulators could restore the aging body's ability to self-repair

As we age, we don't recover from injury or illness like we did when we were young. But new research from UCSF has found gene regulators - proteins that turn genes on and off - that could restore the aging body's ability to self-repair. 

The scientists looked at fibroblasts, which build the scaffolding between cells that give shape and structure to our organs.  

Fibroblasts maintain this scaffolding in the face of normal wear, disease, and injury. But over time, they slow down, and the body suffers.  

The study found telltale signs of decline in the way that old fibroblasts expressed their genes. A computational analysis of these changes led the scientists to a set of gene regulators, known as transcription factors, that might reverse these age-related changes, along with some of the consequences of aging. 

"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, PhD, UCSF professor of Biochemistry and Biophysics and senior author of the paper, which appears Jan. 9 in Proceedings of the National Academy of Sciences. The work was funded by the National Institutes of Health.  

Li's team first compared the way that young and old fibroblasts express genes as they grow in petri dishes and used computational modeling to find out which transcription factors were driving this kind of aging.  

Next, they used CRISPR to prompt these transcription factors to give old fibroblasts a younger gene expression profile. 

Adjusting the levels of any one of 30 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.
 
In collaboration with UCSF's Saul Villeda, PhD, an associate professor of Anatomy, they 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, PhD, who led the project as a graduate student in Li's lab and is the first author of the paper.

Source:

University of California - San Francisco

Journal reference:

Sengstack, J., et al. (2026). Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation. Proceedings of the National Academy of Sciences. doi: 10.1073/pnas.2515183123. https://www.pnas.org/doi/10.1073/pnas.2515183123