Aging immune cells sabotage themselves with a hidden protein loop, turning minor infections into deadly sepsis storms in the elderly.
Story Snapshot
- University of Minnesota researchers uncover GDF3 protein loop in aging macrophages fueling chronic inflammation.
- Deleting GDF3 or blocking SMAD2/3 pathway slashes inflammation and boosts sepsis survival in mice.
- Human ARIC study data ties higher GDF3 levels to inflammatory signals in older adults.
- Published January 24, 2026, in Nature Aging; positions GDF3 as targeted therapy without broad immune suppression.
Macrophages Trap Themselves in Inflammatory Cycle
Aging macrophages produce GDF3 protein. This protein binds back to the same cells, activating the SMAD2/3 signaling pathway. The pathway locks these immune cells into a pro-inflammatory state. Preclinical mouse models show this self-reinforcing loop amplifies sepsis damage. Sepsis mortality rises sharply in the elderly due to this unchecked response. Researchers validated the mechanism through gene knockouts and pathway inhibitors.
Key Researchers Drive Breakthrough Discovery
In Hwa Jang, a University of Minnesota biochemistry graduate student, led the study. Christina Camell, PhD, served as senior author and associate professor in the Medical School and College of Biological Sciences. Pamela Lutsey from the School of Public Health analyzed ARIC cohort data. AFAR funded Camell’s related work with a 2025 Discovery Award. Their collaboration merged biochemistry, epidemiology, and aging research.
Preclinical and Human Evidence Align
Mouse models mimicked human aging. GDF3 deletion reduced inflammation markers and improved sepsis survival rates. Pharmacological SMAD2/3 blockers yielded similar results. ARIC study of older adults correlated elevated GDF3 with active inflammatory pathways. These findings distinguish this macrophage-specific autocrine loop from broader inflammaging patterns like IL-6 buildup or STING effects.
Publication Marks Pivotal Moment
The team published findings January 24, 2026, in Nature Aging. Press releases followed from ScienceDaily and Mirage News. Camell stated the pathway offers a blockable target to prevent organ damage from excess inflammation. Her AFAR award supports metabolic studies building on this work. The peer-reviewed paper elevates potential for pharmaceutical partnerships.
A hidden immune loop may drive dangerous inflammation with age https://t.co/viZ6GOwDWw
— inmunoes (@inmunoes) January 24, 2026
Implications Challenge Inflammaging Consensus
Short-term, GDF3 inhibitors could enter sepsis trials for seniors. Long-term, resetting macrophage function might extend healthspan amid rising elderly populations. Economic savings arise from lower sepsis treatment costs. Social benefits include better quality of life. Conservative values favor targeted therapies over blanket interventions, aligning with common-sense precision medicine. Experts note inflammaging varies by population, urging caution.
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Expert Views Highlight Nuances
Camell advocates GDF3 blockade for organ protection. Senescence researchers tie infections to NF-κB inflammation, backing senolytics. Tufts’ Sharma warns of STING’s brain-protective role against broad anti-inflammatories. Mount Sinai’s Merad links aged myeloid cells to cancer via IL-1, suggesting NAD+ boosts. ARIC data provides correlative human rigor, though causal trials remain pending.
Sources:
University of Minnesota researchers identify hidden immune loop fueling age-related inflammation
Hidden Immune Loop Fuels Age-Related Inflammation
International Experts Connect Infections and Aging Through Cellular Senescence
Immune Molecule Long Tied to Inflammation May Benefit Aging Brain
What’s the Research Supporting Inflammaging or Skin Aging Caused by Long-Term Inflammation?
How Does the Immune System Age? Chronic Inflammation as a Hidden Driver of Cancer
Aging-Related Inflammation Not Universal Across Human Populations
