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

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.