Abstract: AIM To explore the role of transcription factor EB (TFEB) in myocardial autophagic decline with aging. METHODS Age-related autophagic and TFEB changes in male C57BL/6 young (4 mo) and aged (22 mo) mice were analyzed. RESULTS Compared with young hearts, the aged heart had a lower level of autophagy (P<0.05). The autophagic markers including Atg5, LC3, Beclin-1 and lysosomal maker LAMP1 decreased in both protein and gene in the aged heart (P<0.05). In addition, cardiomyocyte TFEB, especially in cardiomyocyte nuclei, was significantly reduced in the aged heart (P<0.05), demonstrating that transcriptional activity of cardiomyocyte TFEB declined with aging. Systemic treatment with rapamycin in aged heart partly improved cardiomyocyte nuclear TFEB and autophagy as evidenced by increased autophagosome LC3-II level and increased lysosome LAMP1 level (P<0.05). CONCLUSION We demonstrate that age-related myocardial TFEB decreases significantly affects cardiomyocyte autophagy. TFEB is the key regulatory point of aging-associated myocardial autophagy decline.