GDF3 protein sustains harmful inflammation in aging immune cells

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 were published today in Nature Aging.

In the study, researchers found macrophages produce a protein called GDF3, 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. 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."

Christina Camell, PhD, associate professor, University of Minnesota Medical School and College of Biological Sciences

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. Dr. Camell was recently awarded a 2025 AFAR Discovery Award based on this research, which will further investigate the consequences of these inflammatory macrophages on multiple metabolic organs and metabolic healthspan.

This research was supported by the National Institute of Health [grants F99AG095479, R00AG058800, R01AG069819, R01AG079913], the McKnight Land-Grant Professorship, the Glenn Foundation for Medical Research/AFAR 2025 Discovery Award, the Diana Jacobs Kalman/AFAR Scholarships for Research in the Biology of Aging and the Medical Discovery Team on the Biology of Aging. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health, and Human Services, under Contract nos. (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). SomaLogic Inc. conducted the SomaScan assays in exchange for use of ARIC data. This work was supported in part by NIH/NHLBI grant R01 HL134320.