Objective：To explore the role and regulation mechanism of leptin in senescence of mouse cardiomyocytes（MCM）. Methods：The mRNA expression levels of senescence related indicators p16，p21，and senescence-associated secretory phenotype （SASP）in leptin stimulated MCM were examined by qPCR；the protein expressions of p16，p21，γ-H2AX，PI3K，AKT，p-PI3K，and p-AKT were detected by Western blot；the senescence of MCM was detected by β-galactosidase staining. PI3K inhibitor（LY294002） was pretreated for 2 h and then stimulated with leptin，the mRNA and protein levels of p16 and p21 were detected by qPCR and Western blot；the mRNA levels of SASP were examined by qPCR；MCM senescence was detected by β-galactosidase staining. Results： In MCM stimulated by leptin，the mRNA and protein levels of p16 and p21，as well as the protein level of γ-H2AX increased，the mRNA levels of SASP[（interleukin，IL）-1β，tumor necrosis factor（TNF）-α、IL-6，monocyte chemoattractant protein（MCP）-1]were up -regulated，the phosphorylation levels of proteins in PI3K/AKT signaling pathway increased；and β-galactosidase staining showed the senescence of MCM. When pretreated with PI3K inhibitor for 2 h，the mRNA and protein levels of p16 and p21，as well as the protein level of γ-H2AX were down-regulated，and the expressions of SASP mRNA were down-regulated，the senescence of MCM was alleviated. Conclusion：Leptin regulates the progression of MCM senescence by activating PI3K/AKT signaling pathway and promoting SASP（IL-1β，TNF-α，IL-6 and MCP-1）secretion.