Research Paper Volume 13, Issue 12 pp 16381—16403

Cardiac senescence is alleviated by the natural flavone acacetin via enhancing mitophagy

Yi-Xiang Hong1, , Wei-Yin Wu1, , Fei Song1, , Chan Wu1, , Gui-Rong Li1,2, , Yan Wang1, ,

  • 1 Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, China
  • 2 Nanjing Amazigh Pharma Ltd., Nanjing, Jiangsu, China

Received: October 14, 2020       Accepted: June 1, 2021       Published: June 27, 2021
How to Cite

Copyright: © 2021 Hong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Cardiac senescence is associated with cardiomyopathy which is a degenerative disease in the aging process of the elderly. The present study investigates using multiple experimental approaches whether the natural flavone acacetin could attenuate myocardial senescence in C57/BL6 mice and H9C2 rat cardiac cells induced by D-galactose. We found that the impaired heart function in D-galactose-induced accelerated aging mice was improved by oral acacetin treatment in a dose-dependent manner. Acacetin significantly countered the increased serum advanced glycation end products, the myocardial telomere length shortening, the increased cellular senescence marker proteins p21 and p53, and the reduced mitophagy signaling proteins PINK1/Parkin and Sirt6 expression in aging mice. In H9C2 rat cardiac cells, acacetin alleviated cell senescence induced by D-galactose in a concentration-dependent manner. Acacetin decreased p21 and p53 expression, up-regulated PINK1/Parkin, LC3II/LC3I ratio, pLKB1, pAMPK and Sirt6, and reversed the depolarized mitochondrial membrane potential in aging cardiac cells. Mitophagy inhibition with 3-methyladenine or silencing Sirt6 abolished the protective effects of acacetin against cardiac senescence. Further analysis revealed that acacetin effect on Sirt6 was mediated by Sirt1 activation and increase of NAD+/NADH ratio. These results demonstrate that acacetin significantly inhibits in vivo and in vitro cardiac senescence induced by D-galactose via Sirt1-mediated activation of Sirt6/AMPK signaling pathway, thereby enhancing mitophagy and preserving mitochondrial function, which suggests that acacetin may be a drug candidate for treating cardiovascular disorders related to aging.


AGEs: advanced glycation end products; BW: body weight; DMEM: Dulbecco’s modified Eagle’s medium; D-gal: D-galactose; EF: ejection fraction, FS: fractional shortening; FDG: Fluorescein di-β-D-galactopyranoside; HE: hematoxylin and eosin; HW: heart weight; H3K9ac: acetylated histone H3 lysine 9; LVAWd: diastolic left ventricular anterior wall thickness; LVPWd: diastolic left ventricular posterior wall thickness; LVESD: left ventricular end-systolic inner diameter; NAD+: oxidized nicotinamide adenine dinucleotide; NADH: nicotinamide adenine dinucleotide hydride (reduced form of nicotinamide adenine dinucleotide); 3-MA: 3-methyladenine; NAMPT: nicotinamide phosphoribosyltransferase; PBS: phosphate buffered saline; PINK1: PTEN-induced kinase 1; SA-β-gal: senescence-associated β-galactosidase; siRNA: small interfering RNA.