Published on: Dec 15, 2025
As people age, immune dysfunction increases, leaving older adults more vulnerable to severe conditions such as sepsis. New research from scientists at the University of Minnesota sheds light on the mechanisms behind this process, revealing how immune cells called macrophages remain persistently inflammatory during aging in preclinical models.
The researchers discovered that aging macrophages produce a protein known as GDF3, which acts in a self-reinforcing loop to sustain their inflammatory state, ultimately worsening the body’s response to sepsis. Led by biochemistry graduate student In Hwa Jang, the study demonstrated that GDF3 signals through the SMAD2/3 pathway, triggering lasting genomic changes that increase the secretion of inflammatory cytokines.
“Macrophages play a central role in driving inflammation, and our work identifies a specific pathway that maintains their inflammatory behavior,” said Christina Camell, PhD, Associate Professor at the University of Minnesota Medical School and College of Biological Sciences. “Targeting this pathway may help prevent excessive inflammation that damages organs and could represent a promising strategy for future therapies.”
The team showed that deleting the GDF3 gene significantly reduced harmful inflammatory responses to bacterial toxins. They also found that drugs inhibiting the GDF3–SMAD2/3 signaling pathway altered inflammatory macrophage behavior in fat tissue and improved survival in older preclinical models facing severe infection. In collaboration with Pamela Lutsey from the School of Public Health, and using data from the Atherosclerosis Risk in Communities (ARIC) Study, the researchers further demonstrated that GDF3 levels correlate with inflammatory signaling in older adults.
While additional studies are needed to fully define the molecular drivers of this pathway, the findings highlight GDF3 as a key regulator of age-related inflammation. Building on this work, Dr. Camell has received a 2025 AFAR Discovery Award to further explore how inflammatory macrophages affect metabolic organs and overall metabolic healthspan.
Source: https://med.umn.edu/news/new-study-identifies-key-protein-driving-inflammation-age
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