The Nrf2-SLPI axis in aging and its role in the pathophysiology of pulmonary Mycobacterium avium complex disease.

Old mice were more susceptible to MAC infection than young mice, with increased bacterial load in the lungs.

• Young and old mice were intranasally infected with Mycobacterium avium and lung bacterial burden was compared.
• Old mice showed increased bacterial load compared to young mice following MAC infection.
• Old mice also showed decreased expression of secretory leukocyte protease inhibitor (SLPI) in the lungs compared to young mice.

SLPI demonstrated direct antimicrobial activity against M. avium.

• SLPI was identified through RNA-seq analysis of lung tissues as an age-related differentially expressed gene.
• Direct antimicrobial activity of SLPI against M. avium was experimentally demonstrated.
• SLPI expression was lower in old mice compared to young mice following MAC infection.

SLPI expression in the lungs was regulated by Nrf2, a transcription factor with reduced activity in infected old mice.

• Nrf2 activity was reduced in MAC-infected old mice compared to young mice.
• Nrf2-deficient mice showed decreased SLPI expression and increased bacterial load following MAC infection.
• RNA-seq and pathway analysis were used to identify Nrf2 as an upstream regulator of SLPI.

Treatment with sulforaphane, an Nrf2 activator, restored SLPI expression and reduced bacterial burden in old mice.

• Sulforaphane was administered to old mice infected with M. avium.
• Sulforaphane treatment restored SLPI expression in the lungs of old infected mice.
• Sulforaphane treatment reduced bacterial burden in old MAC-infected mice.

Cluster analysis of 100 untreated pulmonary MAC patients identified three clusters based on age and SLPI expression with differing disease severity.

• Whole blood cells from 100 untreated patients with pulmonary MAC disease were analyzed for SLPI mRNA expression.
• Three clusters were identified: cluster C1 (younger age and high SLPI), and cluster C3 (older age and lower SLPI), among others.
• Compared to C1, C3 had larger pulmonary lesions on computed tomography.
• Pathway analysis indicated reduced Nrf2 activation in C3 compared to C1, consistent with findings in the mouse experiments.

Pathway analysis in human patient clusters showed reduced Nrf2 activation in the older, lower-SLPI cluster, consistent with mouse experimental findings.

• Pathway analysis was performed on gene expression data from the three patient clusters.
• Nrf2 pathway activation was reduced in cluster C3 (older age, lower SLPI) compared to cluster C1 (younger age, high SLPI).
• These findings were consistent with observations in old versus young MAC-infected mice.
• The convergence of human and mouse data supported the role of the Nrf2-SLPI axis in age-related susceptibility to MAC disease.