GDF3 Protein Drives Inflammatory Macrophages in Aging

As people age, their immune system becomes dysfunctional, leaving older adults more vulnerable to conditions such as sepsis. New work from University of Minnesota scientists shows how macrophages can remain locked in a persistently inflammatory state in aging preclinical models. The study, led by In Hwa Jang and published in Nature Aging, focuses on how these cells reinforce their own inflammatory behavior and thereby worsen the body’s response to severe infection.

The researchers discovered that macrophages produce a protein known as GDF3, which acts back on the same cells to sustain their inflammatory activity. GDF3 signals through SMAD2/3, triggering lasting changes in the genome that boost the production of inflammatory cytokines secreted by macrophages. According to senior author Christina Camell, “Macrophages are critical to the development of inflammation; in our study, we identified a pathway which is used to maintain their inflammatory status.” She added that the findings suggest this pathway could be blocked to prevent amplified inflammation that harms organ function and might serve as a promising target for future therapies aimed at reducing damaging inflammation.

To test this idea, the team removed the GDF3 gene in preclinical models and found that this reduced harmful inflammatory responses to bacterial toxins. They also showed that pharmacologically blocking the GDF3–SMAD2/3 signaling pathway changed how inflammatory macrophages in fat tissue behave. In older preclinical models exposed to severe infection, this intervention improved survival, indicating a functional benefit of disrupting the pathway that sustains macrophage-driven inflammation.

The study also connected these experimental findings to human data. Working with School of Public Health researcher Pamela Lutsey and using information from the Atherosclerosis Risk in Communities Study (ARIC), the investigators found that GDF3 protein levels correlate with inflammatory signaling in older adults. This association suggests that similar mechanisms may operate in human aging, although more work is needed to define the details.

Additional research will focus on identifying the molecular factors involved in the GDF3–SMAD2/3 pathway and clarifying how it regulates specific inflammatory signals. Dr. Camell recently received funding to support further studies examining how these inflammatory macrophages affect multiple metabolic organs and overall metabolic healthspan.