Older adults are much more likely to become seriously ill from flu or COVID because aging lung cells can drive excessive immune responses, according to a new study led by researchers at UC San Francisco.
The findings enhance the understanding of the inflammation that accompanies aging, explaining how an otherwise minor cough can sometimes send an elderly person to the hospital.
To understand what goes wrong in old lungs, the scientists engineered the lung's structural cells, fibroblasts, to turn on an age-related distress signal in young mice. The signal led the lungs to form clusters of inflamed cells, including some marked by the GZMK gene, which was first seen in severe COVID-19. A future therapy might target these cells to counter the damaging spiral of inflammaging.
"We were surprised to see lung fibroblasts working hand-in-hand with immune cells to drive inflammaging," said Tien Peng , MD, a professor of Medicine and a member of the Cardiovascular Research Institute and Bakar Aging Research Institute at UCSF. "It suggests new ways to intervene before patients progress to severe inflammation that can require intubation."
Peng is senior author of the paper, which appeared in Immunity on March 27. Nancy Allen MD, PhD, a clinical fellow in the Pulmonary and Critical Care Division in the UCSF Department of Medicine, is the first author.
Fibroblasts maintain the airtight tubes and chambers of the lungs but can trigger inflammation in lung diseases like COPD. Peng's team wanted to see whether a signal coming from fibroblasts could disrupt otherwise healthy lungs.
The signal is part of a pathway called NF-kB that is often seen in the diseases of aging. The fibroblasts prompted the lung's macrophages to rally an immune response. Then, immune cells, including some marked by GZMK, rushed into the lungs from the bloodstream.
Although the GZMK cells were impotent against disease, they were still capable of damaging the lungs.
Once they had these immune clusters, the lungs of the young mice experienced severe symptoms from an infection — as if they were old. When the scientists used a genetic trick to eliminate the GZMK cells in these mice, their lungs were able to withstand the infection.
This suggests the aging lung tissue itself is driving inflammation.
The team examined lung tissue from older patients hospitalized with COVID-related ARDS (acute respiratory distress syndrome) and found it had clusters of cells that looked like what they had seen in mice. The sicker the patient, the more inflamed clusters they had. Lung tissue from healthy donors had none.
"We saw during COVID that our most vulnerable patients no longer had the infection but still had persistent and devastating lung inflammation," Peng said. "This circuit of dysfunction between lung and immune cells makes for a promising new therapeutic target."
Authors: Other UCSF authors are Christian Ringler; Sang Ho Woo, PhD; Sophie Phipps; Jin Young Lee, PhD; Nabora Reyes, PhD; Ritusree Biswas, PhD; Lucile Neyton, PhD; Andrew Willmore; Sofia Caryotakis; Jessica Roginsky, PhD; Lu Guo; Melia Magnen, PhD; Chaz Langelier, MD, PhD; COMET Consortium; Mark Looney, MD; Averil Ma, MD; Vincent Auyeung, MD, PhD; Carolyn Calfee, MD; and Ari B. Molofsky, MD, PhD; as well as Pedro Ruivo of UC Davis.
Funding: This work was supported by the National Institutes of Health (P30DK063720, R01HL160895, F32HL156452, K08HL169723) and the Bakar Aging Research Institute.
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