Jan 30, 2026
3 min read
CRISPR transcription factors restored gene activity in senescent cells and improved liver health in mice.Explore this new research on aging.
Aging at the level of gene regulation
Transcription factors reprogram senescent fibroblasts to rejuvenate and improve organ health in mice.
As we age, we don't recover from injury or illness as well as we did when we were younger.But new UCSF research has discovered gene regulators—proteins that turn genes on and off—that can restore the aging body's ability to repair itself.
Scientists looked at fibroblasts, which form the scaffolding between cells that gives shape and structure to our organs.
Fibroblasts maintain this scaffold despite normal wear and tear, disease, and injury.But over time it slows down and the body suffers.
The study found signs of a decline in the way old fibroblasts expressed their genes.Computer analysis of these changes led scientists to a set of gene regulators, known as transcription factors, that may reverse age-related changes that accompany some of the consequences of aging.
"By modifying gene expression by identifying transcription factors, old fibroblasts behave like younger ones and improve the health of old mice," said Hao Li, PhD, UCSF professor of Biochemistry and Biophysics and senior author of the paper, which appeared on January 9.The work was sponsored by the National Institutes of Health.
Lee's team first compared how young and old fibroblasts expressed genes when grown in Petri dishes, and used computer modeling to determine which transcription factors caused this type of aging.
Then, they used CRISPR to direct these transcription factors to give the old fibroblasts the youthful gene expression profile.
Adjusting the levels of any of the 30 transcription factors triggered the expression of "young" genes in old fibroblasts.Changes in the levels of four of these factors improved the metabolism of old fibroblasts and their ability to proliferate.
In collaboration with UCSF's Dr.Saul Villeda, associate professor of anatomy, they showed that the high level of EZH2 factor rejuvenated the liver of 20-month-old mice, the same as about 65 years of human.It reverses liver fibrosis;reduce the amount of fat that accumulates in the liver;and improve glucose tolerance.
"Our work opens up exciting new opportunities to understand and ultimately prevent age-related diseases," said Janine Sengstick, PhD, who led the project as a graduate student in Lee's lab and is first author of the paper.
Reference: Sengstack J, Zheng J, Aghayev T, et al.Systematic identification of single transcription factor disruptions that promote cellular and tissue regeneration.Proc Natl Acad Sci USA.2026;123 (2): e2515183123.doi: 10.1073/pnas.2515183123
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