Reversal of Chronic Stress‐Induced Inflammaging by Bazi Bushen Formula Through AMPK‐Sirtuins Axis Activation and Myeloid Reset

ABSTRACT Chronic stress potentially accelerates aging and increases age‐related disease risk. However, the underlying mechanisms and organ specificity remain unclear. Utilizing a 12‐month unpredictable chronic mild stress (UCMS) mouse model, we revealed chronic stress significantly exacerbates systemic inflammation, causing widespread tissue damage and lifespan shortening. Integrated single‐cell RNA sequencing analysis of multiple tissues suggests a common feature of lymphocyte reduction and myeloid cell expansion. The lungs and kidneys exhibited pronounced stress responses, including epigenetic dysregulation and mitochondrial dysfunction. Both β‐nicotinamide mononucleotide (NMN) and compound medicine Bazi Bushen (BZBS) effectively alleviate the UCMS‐induced aging phenotypes. BZBS restores immune system homeostasis and reduces stress/inflammation levels in various tissues. Bioactive compounds from BZBS constituents —Schisandra chinensis (Turcz.) Baill. and Cnidium monnieri (L.) Cusson— improved mitochondrial function via AMPK‐SIRT‐PGC‐1α signaling activation. The present study underscores the importance of early intervention in chronic stress to prevent or delay age‐related diseases, with significant implications for public health strategies aimed at healthy aging.