Researchers at the University of California, San Francisco (UCSF) have identified gene regulators that could help restore the body's ability to repair itself as it ages. The study focused on fibroblasts, which are cells responsible for maintaining the structural framework of organs. As people age, these cells become less effective, leading to slower recovery from injury and illness.
The research team observed changes in gene expression in older fibroblasts and used computational analysis to identify transcription factors—proteins that control which genes are active—that might reverse age-related decline. According to Hao Li, PhD, professor of Biochemistry and Biophysics at UCSF and senior author of the study published on January 9 in Proceedings of the National Academy of Sciences, "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." The project received funding from the National Institutes of Health.
To determine which transcription factors influenced aging in fibroblasts, Li's team compared gene expression between young and old cells grown in laboratory conditions. They then used CRISPR technology to adjust these factors in older cells. Adjusting any one of 30 different transcription factors resulted in older fibroblasts expressing genes more typical of younger cells. Modifying four specific factors led to improvements in metabolism and cell multiplication.
In collaboration with Saul Villeda, PhD, associate professor of Anatomy at UCSF, researchers increased levels of a factor called EZH2 in mice equivalent in age to about 65 human years. This intervention reversed liver fibrosis, reduced fat accumulation by half in the liver, and improved glucose tolerance.
Janine Sengstack, PhD—who led the project as a graduate student in Li's lab and is first author on the paper—said: "Our work opens up exciting new opportunities to understand and ultimately reverse aging-related diseases."
Other contributors to this research include Jiashun Zheng, PhD; Turan Aghayev, MD, PhD; Gregor Bieri, PhD; Michael Mobaraki, PhD; Jue Lin, PhD; and Changhui Deng, PhD.
