Erigeron breviscapus alleviates senescence via AMPK-SIRT1 signaling by modulating FOXO3a-mediated antioxidant defense and p53-dependent apoptosis.

Erigeron breviscapus Hand-Mazz. (EBHM) is a well-documented herbal medicine with recognized antioxidant, anti-apoptotic, and anti-inflammatory bioactivities. However, its anti-senescence effects and the underlying mechanisms remain poorly understood. Here, we investigated the anti-senescence potential of EBHM employing Caenorhabditis elegans and SAMP8 mice. In C. elegans, EBHM treatment prolonged the average lifespan of C. elegans to a maximum of 18.68%, while also significantly enhancing stress resistance and motor function. The lifespan-extending effects of EBHM were abolished in mutants of aak-2, sir-2.1, daf-16, and cep-1. EBHM treatment increased p-AMPK/AMPK ratio and elevated levels of SIR-2.1 protein, facilitated the nuclear import of DAF-16::GFP as well as the upregulation of SOD-3::GFP expression, lowered MDA content, and enhanced the enzymatic activities of SOD, GSH-Px and CAT through a DAF-16-dependent mechanism. Furthermore, EBHM downregulated the mRNA levels of the pro-apoptotic genes cep-1and ced-3 (CASP3 homolog), while upregulating the anti-apoptotic gene ced-9 (Bcl-2 homolog) in C. elegans. In SAMP8 mice, EBHM reduced SA‑β‑gal‑positive cells, collagen deposition, and α-SMA expression in the liver and kidney, elevated the p-AMPK/AMPK ratio and SIRT1 expression, decreased levels of acetyl-FOXO3a, p53, acetyl-p53, p16, and p21, lowered MDA levels while enhancing antioxidant enzyme activities, diminished the proportion of apoptotic cells, downregulated Bax and CASP3, and upregulated Bcl-2. Collectively, these findings suggest that EBHM prolongs lifespan and healthspan in C. elegans and ameliorates aging‑associated tissue alterations in SAMP8 mice through activation of the AMPK-SIRT1 pathway, which enhances FOXO3a-dependent antioxidant defenses and modulates p53-mediated apoptosis, thereby alleviating oxidative stress and cellular damage.