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As the aging population increases, the focus on elderly patients with acute respiratory distress syndrome (ARDS) is also increasing. In this article, we found progranulin (PGRN) differential expression in ARDS patients and healthy controls, even in young and old ARDS patients. Its expression strongly correlates with several cytokines in both young and elderly ARDS patients. PGRN has comparable therapeutic effects in young and elderly mice with lipopolysaccharide-induced acute lung injury, manifesting as lung injury, apoptosis, inflammation, and regulatory T cells (Tregs) differentiation. Considering that Tregs differentiation relies on metabolic reprogramming, we discovered that Tregs differentiation was mediated by mitochondrial function, especially in the aged population. Furthermore, we demonstrated that PGRN alleviated the mitochondrial damage during Tregs differentiation through the AMPK/PGC-1α pathway in T cells. Collectively, PGRN may regulate mitochondria function to promote Tregs differentiation through the AMPK/PGC-1α pathway to improve ARDS. [Display omitted] • Differential expression of PGRN and mitochondrial respiratory in ARDS patients and healthy controls. • PGRN has an equivalent therapeutic effect on Tregs differentiation in young and old ALI mice induced by LPS intratracheal instillation. • PGRN has a better promotion effect on metabolic reprogramming during the differentiation of old Tregs than that of young. • PGRN promotes mitochondrial function through the AMPK/PGC-1α pathway in T cells. [ABSTRACT FROM AUTHOR]