by Alex Smith,University of Minnesota Medical School

Gdf3 promotes SMAD-regulated genes via altered chromatin accessibility in ATMs. Credit:Nature Aging(2025). DOI: 10.1038/s43587-025-01034-6

As people age, their bodies develop a dysfunctional immune system, which can leave older adults more susceptible to conditions like sepsis. New research from University of Minnesota researchers reveals how certain immune cells, known as macrophages, stay locked in an inflammatory state during aging in preclinical models.

The findings arepublishedinNature Aging.

In the study, researchers found macrophages produce a protein calledGDF3, which signals back to the same cells and reinforces their inflammatory behavior—ultimately worsening the body's response to sepsis. The study, performed by biochemistry graduate student In Hwa Jang, showed that GDF3 signals through SMAD2/3, inducing permanent changes in the genome. This increases inflammatory cytokines that the macrophages secrete.

"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, Ph.D., an associate professor with the University of Minnesota Medical School and College of Biological Sciences. "Our findings suggest that this pathway could be blocked to prevent theamplified inflammationthat can be damaging to organ function and may be a promising target for future treatments that reduce harmful inflammation."

The researchers showed that removing the GDF3 gene reduced harmful inflammatory responses to bacterial toxins. They also demonstrated that drugs blocking the GDF3–SMAD2/3 signaling pathway can alter how inflammatory, fat-tissue macrophages behave and improve survival in older preclinical models exposed to severe infection.

Finally, in collaboration with Pamela Lutsey (School of Public Health) and using data from the Atherosclerosis Risk in Communities Study (ARIC), the investigators revealed that GDF3 protein correlates with inflammatory signaling in older humans.

Additional research is needed to pinpoint the molecular factors involved in this pathway and understand how it regulates specific inflammatory signals.

More information In Hwa Jang et al, GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging, Nature Aging (2025). DOI: 10.1038/s43587-025-01034-6 Journal information: Nature Aging