Objective To study the proteomic changes in the liver of aging female mice, to find the core age- related differential proteins, and to explore the aging mechanism based on proteomics, with the aim of providing molecular targets for the study of the mechanisms of aging. Methods In this study, differential proteins between 12- and 3-month-old female mice were analyzed using relative and absolute quantitative isotopic labeling (iTRAQ), LC-MS and bioinformatics. Results A total of 369 different proteins were identified by comparing the two groups, among which 182 were upregulated and 187 were downregulated. After screening, 13 age-related differential proteins in the core DEP were obtained. Conclusions The exploration and in-depth study of differential proteins will help elucidate the mechanisms of aging and identify potential markers, providing new molecular targets for the prevention of aging and the diagnosis and treatment of aging-related diseases.