The microbiota-gut-brain axis has attracted significant attention with respect to studying the mechanisms of brain aging; however, the specific connection between gut microbiota and aging remains unclear. The abnormal expression and mutation of proteins belonging to the P4-ATPase family, including , results in a variety of neurological diseases. The results of our analysis demonstrate that there was a shift in the abundance of certain gut microbiota in -knockout (KO) mice. Specifically, there was an increase in pro-inflammatory bacteria that accelerate aging and a decrease in probiotics that delay aging. Consequently, an enhanced oxidative stress response was observed, which was characterized by a reduction in the superoxide dismutase (SOD) activity and an increase in malondialdehyde (MDA) and reactive oxygen species (ROS) levels. In addition, our data demonstrate that there was a decrease in the number of cells in the dentate gyrus (DG) region of the hippocampus, and aggravation of aging-related pathological features such as senescence β-galactosidase (SA-β-Gal), p-HistoneH2AX (Ser139), and p16. Moreover, KO mice show typical aging-associated behavior, such as memory impairment and slow pain perception. Taken together, we demonstrate a possible mechanism of aging induced by gut microbiota in -KO mice, which provides a novel perspective for the treatment of aging through the microbiota-gut-brain axis.