AIM Data from clinic trials showed Liu-Wei-Di-Huang decoction (LW) enhanced cognitive processing in normal young adults and improved age-related cognitive dysfunction.This study alms to investigate the molecular mechanism of LW improving learning and memory deterioration empolying senescence accelerated mouse prone 8 (SAMP8).METHODS The ability of learning and memory of SAMP8 administrated LW were examed by step up and down test, shuttle-box test, and morris-water maze test.Gene expression was investigated using cDNA microarray and RT-PCR.Bioinformatics techniques were used to analyses biomolecale interaction network.RESULTS The chronic administration of LW to SAMP8 enhanced the memory registration and retention ability in passive avoidance performance, promoted the spatial memory ability in the water maze test and partially improved the leaning behavior in conditioned avoidance performance.There are 39 gene expression in hippocampus and 52 genes expression in cerebral cortex regulated by LW.These genes involved in the biomolecular network with 384 nodes and 383 edges, characteristic path length 4.416 and network heterogeneity 2.112.LW mainly effected on pathways with nodes RPS6KA1, TICAM2, MAST2, NRXN1, NSF, STUB1 and UBE2D2.Furthermore, RPS6KA1, SLC17A7 and FHIT may be direct targets for LW improving age-related with cognitive deterioration.CONCLUSION LW enhanced cognitive processing via regulating the biomolecular network with 384 nodes and 383 edges, and its direct targets may be RPS6KA1, SLC17A7 and FHIT.