With advancing age, the human immune system frequently loses its equilibrium, becoming increasingly susceptible to malfunctions. This alteration heightens the risk for elderly individuals to develop life-threatening ailments like sepsis. Recent investigations conducted by experts at the University of Minnesota have illuminated the underlying mechanisms, revealing that specific immune cells known as macrophages become trapped in a persistent inflammatory mode as the body ages, based on observations from preclinical models. These compelling findings appeared in the latest issue of Nature Aging.
The scientific team pinpointed that macrophages in aging organisms generate a particular protein called GDF3. This protein feeds back signals directly to the very cells responsible for its production, thereby perpetuating and intensifying inflammatory processes, which in turn aggravate the body’s reaction to sepsis. Spearheaded by biochemistry doctoral candidate In Hwa Jang, the research demonstrated that GDF3 operates via a signaling cascade that engages SMAD2/3 proteins, triggering enduring modifications within the cellular genome. Consequently, these alterations prompt macrophages to secrete elevated quantities of pro-inflammatory cytokines, exacerbating the inflammatory cascade.
A Promising Avenue for Therapeutic Interventions
“Macrophages play a pivotal role in initiating and sustaining inflammation; in this investigation, we uncovered a specific signaling pathway that locks them into this inflammatory state,” explained Christina Camell, PhD, an associate professor affiliated with both the University of Minnesota Medical School and the College of Biological Sciences. “These discoveries indicate that interrupting this pathway holds potential to mitigate excessive inflammation, which can impair vital organ functions and positions it as a viable candidate for developing novel therapies aimed at curbing detrimental inflammatory responses.”
Additional laboratory tests revealed that eliminating the GDF3 gene significantly diminished destructive inflammatory reactions triggered by bacterial toxins. Moreover, the researchers observed that pharmacological agents capable of inhibiting the GDF3-SMAD2/3 signaling mechanism altered the behavior of inflammatory macrophages residing in adipose tissue and markedly enhanced survival rates in aged preclinical models subjected to acute infectious challenges. Complementing these efforts, a partnership with Pamela Lutsey from the School of Public Health involved scrutinizing data from the Atherosclerosis Risk in Communities Study (ARIC), which established a correlation between GDF3 concentrations and heightened inflammatory signaling in human populations over the age of 65.
Future Directions and Expanding Investigations
Ongoing studies are essential to delineate the exact molecular elements comprising this pathway and to elucidate its precise regulation of distinct inflammatory mediators. Leveraging these initial breakthroughs, Dr. Camell has secured the 2025 AFAR Discovery Award, providing resources to delve deeper into the impacts of these inflammatory macrophages on various metabolic organs and their broader implications for extending healthy metabolic lifespan in aging individuals.
Research Funding and Acknowledgments
The project received financial backing from the National Institutes of Health through multiple grants, including F99AG095479, R00AG058800, R01AG069819, and R01AG079913. Additional support came from 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 was funded, in whole or in part, by federal resources from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under contracts such as 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. SomaLogic Inc. performed the SomaScan assays in return for access to ARIC data. Portions of this work were further bolstered by NIH/NHLBI grant R01 HL134320.
