Researchers at the University of Minnesota have identified a mechanism by which certain immune cells, called macrophages, maintain an inflammatory state as people age. The study, published in Nature Aging, found that these cells produce a protein known as GDF3. This protein sends signals back to the macrophages themselves, reinforcing their inflammatory behavior and worsening responses to sepsis.
"Macrophages are critical to the development of inflammation; in our study, we identified a pathway which is used to maintain their inflammatory status," said Christina Camell, PhD, associate professor at the University of Minnesota Medical School and College of Biological Sciences. "Our findings suggest that this pathway could be blocked to prevent the amplified inflammation that can be damaging to organ function and may be a promising target for future treatments that reduce harmful inflammation."
The research led by graduate student In Hwa Jang showed that GDF3 signals through SMAD2/3 proteins. This signaling induces permanent changes in the genome of macrophages and increases production of inflammatory cytokines.
Further experiments demonstrated that removing the GDF3 gene reduced harmful inflammation caused by bacterial toxins. The team also tested drugs designed to block the GDF3–SMAD2/3 pathway and found they altered how fat-tissue macrophages respond during infection in older models and improved survival rates after severe infections.
Collaboration with Pamela Lutsey from the School of Public Health involved analyzing data from the Atherosclerosis Risk in Communities Study (ARIC). Results indicated that higher levels of GDF3 protein are associated with increased inflammatory signaling in older adults.
Dr. Camell recently received a 2025 AFAR Discovery Award for this research, which will further examine how these inflammatory macrophages affect metabolic organs and healthspan during aging.
Funding for this work came from several sources including grants from the National Institutes of Health, support from foundations such as AFAR and Glenn Foundation for Medical Research, and contributions from SomaLogic Inc., which performed assays using ARIC data.
