Abstract: Objective To explore the role of silent information regulator 1 (SIRT1) signaling pathway in mediating the effect of dexmedetomidine (DEX) to alleviate postoperative cognitive dysfunction (POCD) in aged rats. Methods Seventy-two healthy male Sprague-Dawley rats aged 18-20 months (weighing 500-700 g) were randomized equally into normal control group, POCD model group, DEX pretreatment group, and DEX and SIRT1 inhibitor (EX527) pretreatment group. In the latter 2 groups, DEX (25 μg/kg) was injected intraperitoneally in the rats 30 min before the operation, and normal saline was injected instead in the other 2 groups; in EX527 group, EX527 (1 μg/kg) was injected intravenously 5 min before the operation. In all but the control group, the rats were subjected to laparotomy lasting 30 min, and on days 1, 3, and 5 following the operation, 6 rats were randomly selected from each group for Morris water maze test to evaluate their cognitive functions. Immediately after the test, the rats were sacrificed and the hippocampus was collected for determination of the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) using ELISA; Western blotting was used to detect the expression of SIRT1 and nuclear factor- κB (NF-κB) in the hippocampal neurons. Results Compared with the control rats, the rats in POCD group and EX527 group showed significantly prolonged escape latency, decreased frequency of crossing the original platform, increased TNF-α and IL-6 levels, lowered SIRT1 expression in the hippocampal neurons, and increased NF-κB expression (P<0.05), and these parameters were comparable between POCD group and EX527 group (P>0.05). DEX pretreatment significantly alleviated cognitive dysfunction and attenuated the changes in TNF-α, IL-6, SIRT1, and NF-κB expressions induced by the operation (P<0.05), and EX527 pretreatment of the rats obviously blocked the effects of DEX (P<0.05). Conclusion DEX alleviates POCD in aged rats probably via SIRT1 signaling pathway.