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Oligosaccharides are one of the major bioactive components in Codonopsis pilosula. The present study was to investigate the protective effect of C. pilosula oligosaccharides (CPO) on d-galactose (D-Gal)-induced aging and to illuminate the underlying mechanisms. The results indicated that CPO effectively increased the growth rate as indicated by body weight, attenuated the decline of thymus and liver indexes, and mitigated the pathological liver injury compared with model group rats. CPO could elevate the activities of anti-oxidative enzymes, including CAT, GSH-Px, and SOD, and reduce MDA level in serum, improve SOD and GSH-Px activities in liver, down-regulate the phosphorylation of MAPK cascade signal transduction components – ERK, JNK, and p38, and inhibit the activation of downstream NF-κB signaling. In addition, CPO treatment noticeably prevented the overexpression of inflammatory factors such as TNF-α, IL-6, and IL-1β in serum, inhibited the expression of apoptosis-related proteins caspase-3, caspase-9, and the ratio of Bax/Bcl-2 in liver caused by the inflammatory cascade, reduced cell apoptosis, and improved liver damage. The above studies suggested that CPO could effectively mitigate the D-Gal-induced aging, and the underlying mechanism might be closely related to ROS-induced oxidative stress, inflammation, and apoptosis. [ABSTRACT FROM AUTHOR]