Objective To explore the role and mechanism of silent information regulator 1 (SIRT1) in postoperative cognitive dysfunction (POCD) of aged mice following sevoflurane (SEV) anesthesia. Methods (1) Fifteen-month-old male C57BL/6 mice were randomly divided into control group (n=8) and SEV group (n=24), and SIRT1 expression in hippocampus of mice was assessed using Western blotting on the 1st, 3rd and 7th day after 2% SEV exposure. (2) Fifteen-month-old male C57BL/6 mice were randomly divided into AAV-GFP, AAV-SIRT1, SEV+AAV-GFP and SEV+AAV-SIRT1 groups (n=20). AAV-SIRT1 and control AAV-GFP vectors were transfected into the brain of mice respectively. Five days after the transfection, the corresponding groups of mice were exposed to 2% SEV for 5 h. Morris water maze test was used to evaluate the spatial memory of mice before and after SEV exposure, TUNEL staining was applied to assess hippocampal neurons apoptosis, and Western blotting was utilized to measure the expression levels of SIRT1, xCT and glutathione peroxidase 4 (GPX4). (3) Hippocampal neurons of mice were divided into control, AAV-SIRT1, Fer-1, SEV, SEV+AAV-SIRT1 and SEV+ferrostatin-1 (Fer-1) groups. Neurons in SEV, SEV+AAV-SIRT1 and SEV+Fer-1 groups were exposed to 5% SEV for 4 h. SEV+AAV-SIRT1 and SEV+Fer-1 groups were transfected with AAV-SIRT1 or treated with Fer-1 respectively prior to SEV exposure. Neuronal death was evaluated via propidium iodide (PI) staining. Malondialdehyde (MDA) level and iron content were determined using ELISA, reactive oxygen species (ROS) level was determined using fluorescence probes. Results (1) Western blotting revealed a significant reduction in SIRT1 protein expression levels in the hippocampus tissue of SEV group mice compared to control group (P<0.05). (2) Morris water maze test results showed that, compared with AAV-GFP group, the escape latency of mice in SEV+AAV-GFP and SEV+AAV-SIRT1 groups significantly prolonged (P<0.05), and the frequency of crossing the platform significantly decreased (P<0.05). Compared with SEV+AAV-GFP group, the escape latency of mice in SEV+AAV-SIRT1 group shortened (P<0.05), and the frequency of crossing the platform on the 7th day increased (P<0.05). TUNEL staining, Western blotting and immunohistochemistry indicated that the apoptosis of hippocampal neurons, Bax and cleaved-caspase-3 protein expression levels significantly increased in SEV+AAV-GFP and SEV+AAV-SIRT1 groups compared with those in AAV-GFP group, while the expression of Bcl-2, GPX4, and xCT protein expression levels significantly decreased (P<0.05 or P<0.01 or P<0.001). Compared with SEV+AAV-GFP group, SEV+AAV-SIRT1 group showed that apoptosis of hippocampal neurons, Bax and cleaved-caspase-3 protein expression levels significantly decreased (P<0.05), while Bcl-2, GPX4, and xCT protein expression levels significantly increased (P<0.05). (3) In vitro, PI staining and ELISA demonstrated significantly increased PI positive rate, MDA level and iron content in hippocampus neurons of SEV group compared to control group (P<0.01). Compared with SEV group, the positive rate of PI staining, MDA level, iron content and ROS level in hippocampus neurons of SEV+AAV-SIRT1 and SEV+Fer-1 groups significantly decreased (P<0.05). Conclusions SEV anesthesia leads to a decrease in SIRT1 expression in hippocampus and neurons of aged mice, and the upregulation of SIRT1 could alleviate SEV-induced neuronal death and ferroptosis.