The Nrf2-SLPI Axis in Aging and Its Role in the Pathophysiology of Pulmonary Mycobacterium avium Complex Disease

Sosuke Matsumura¹Masashi Matsuyama^1,2*Masayuki Nakajima¹Chio Sakai¹Kodai Ueda¹Mizu Nonaka³KENGO NISHINO¹Zhenting Wei¹Yuki Yabuuchi¹Kenya Kuramoto¹Kai Yazaki¹Kazufumi Yohida¹Takumi Kiwamoto¹Yuko Morishima¹Yukio Ishii^1,3Masafumi Muratani⁴Nobuyuki Hizawa¹

• ¹Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
• ²Tsukuba Daigaku Igaku Iryokei, Tsukuba, Japan
• ³National Hospital Organization Ibarakihigashi National Hospital, Nakagun, Japan
• ⁴Department of Genome Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan

Aging is associated with a poor prognosis in pulmonary Mycobacterium avium complex (MAC) disease. This study aimed to elucidate the impact of aging on pulmonary MAC disease and its underlying mechanisms. Young and old mice were intranasally infected with Mycobacterium avium. RNA-seq analysis was performed on lung tissues to identify age-related gene expression changes. Whole blood cells from 100 untreated patients with pulmonary MAC disease were analyzed for SLPI mRNA expression and its association with age and disease severity. Old mice were more susceptible to MAC infection than young mice, with increased bacterial load and decreased expression of secretory leukocyte protease inhibitor (SLPI) in the lungs. SLPI showed direct antimicrobial activity against M. avium and was regulated by Nrf2, a transcription factor with reduced activity in infected old mice. Nrf2-deficient mice showed decreased SLPI expression and increased bacterial load. Treatment with sulforaphane restored SLPI expression and reduced bacterial burden in old mice. In humans, cluster analysis identified three clusters based on age and SLPI expression. Compared to cluster 1 (C1) (younger age and high SLPI), cluster C3 (older age and lower SLPI) had larger pulmonary lesions on computed tomography. Pathway analysis indicated reduced Nrf2 activation in C3 than in C1, consistent with the findings in the mouse experiments. The study suggests that age-related reductions in Nrf2 activity and SLPI expression contribute to poor outcomes in pulmonary MAC disease. Targeting the Nrf2-SLPI axis may represent a novel therapeutic approach for elderly patients.