Cycloneolitsol prolongs the lifespan of Caenorhabditis elegans by SEK-1/PMK-1/SKN-1 pathway and exerts anti-inflammatory effects by NF-κB pathway.

Aging is a major risk factor for the onset and progression of many neurodegenerative diseases. Inflammation is the body's natural defense mechanism against harmful stimuli. A growing body of research has highlighted the intricate relationship between aging and inflammation, with chronic low-grade inflammation, often referred to as "inflammaging," being a hallmark of the aging process. Cycloneolitsol (CL) is a C-32 cycloartane-type triterpene from Taxodium ascendens which has been reported to possess the anticancer, neuroprotection and antibacterial activities. Its specific role and the underlying molecular mechanisms in modulating the aging process remain unclear. Our study aimed to explore the possible anti-aging effect and mechanisms of CL. Network pharmacology predicted core targets and several potential pathways, which are associated with the anti-aging effect of CL. RAW264.7 macrophages and Caenorhabditis elegans were selected for evaluating its anti-aging and anti-inflammation activity. The results showed that CL exerted obvious anti-inflammatory effects against LPS-induced M1-type polarization of RAW264.7 cells via NF-κB signaling pathway. In C. elegans, CL improved Biological Characteristics and prolonged the lifespan without reproductive toxicity. Furthermore, experiments on different mutant C. elegans strains and the nuclear translocation of SKN-1 confirmed that CL activates autophagy and enhances the antioxidant stress response ability through the SEK-1/PMK-1/SKN-1 signaling pathway. This study provides novel insights into the biological activities of CL, highlighting its potential as a natural product for treating inflammation-related diseases and delay aging.