University of Minnesota researchers report that older mice’s macrophages can become locked in an inflammatory state through an autocrine signaling loop involving the protein GDF3 and the transcription factors SMAD2/3. In experiments, genetic deletion of Gdf3 or drugs that interfered with the pathway reduced inflammatory responses and improved survival in older endotoxemia models, while human cohort data linked higher GDF3 levels with markers of inflammation.
As people age, the immune system can become more prone to dysregulation, and older adults face higher risks from severe infections, including sepsis. Researchers at the University of Minnesota say they have identified a mechanism that may help explain how age-associated inflammation is sustained, focusing on macrophages—immune cells that can drive inflammatory responses. (sciencedaily.com)
The work, led by biochemistry graduate student In Hwa Jang, centers on growth differentiation factor 3 (GDF3), a cytokine in the TGFβ family. In preclinical experiments, the team found that inflammatory adipose-tissue macrophages in older mice show increased GDF3 and that the protein can act back on those macrophages through an autocrine signaling loop. According to the study and the university’s summary, the downstream signaling involves activation of SMAD2/3 and is associated with durable shifts in gene regulation and chromatin accessibility that favor higher inflammatory cytokine output. (nature.com)
“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, an associate professor at the University of Minnesota Medical School and College of Biological Sciences. She added that blocking the pathway could, in principle, help prevent amplified inflammation that can damage organ function and could represent a future therapeutic strategy. (sciencedaily.com)
In mouse experiments, lifelong systemic or myeloid-specific deletion of Gdf3 reduced harmful inflammatory responses in endotoxemia, including reductions in inflammatory macrophage populations and inflammatory cytokines, and the researchers reported protection against endotoxemia-associated hypothermia. The study also described pharmacological approaches that interfered with the GDF3–SMAD2/3 axis and improved outcomes in older mice, including reduced mortality in an endotoxemia lethality model with SMAD3 inhibition. (nature.com)
To assess relevance in humans, the researchers analyzed human adipose-tissue samples and data from the Atherosclerosis Risk in Communities (ARIC) cohort. In the ARIC analysis described in the paper, higher serum GDF3 levels were associated with higher C-reactive protein (CRP), a marker of systemic inflammation, including in late-life follow-up. (nature.com)
The research was published in Nature Aging and was highlighted in a January 24, 2026 University of Minnesota release. The paper itself is listed in Nature Aging as a 2025 publication in volume 6, issue 1. (sciencedaily.com)
Separately, the American Federation for Aging Research (AFAR) announced that Camell received a 2025 Glenn Foundation Discovery Award to study macrophage inflammation, cellular identity, and healthspan during aging. (afar.org)
The authors said additional research is needed to clarify the precise molecular components of the pathway and how it controls specific inflammatory signals, while the current findings point to the GDF3–SMAD2/3 axis as a potential target for reducing harmful, age-amplified inflammatory responses without broadly suppressing immunity. (sciencedaily.com)
