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Research Paper|Volume 12, Issue 1|pp 650—671

Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function

Junying Wang1,2, Shaoqi Li1, Ju Wang1, Feixiang Wu1,3, Yuhan Chen1, Hao Zhang1,4, Yubo Guo5, Yan Lin6, Lingxu Li1, Xue Yu1, Ting Liu1, Yajun Zhao1,7
  • 1Department of Pathophysiology, Harbin Medical University, Harbin, China
  • 2Department of Medical Technology, Beijing Health Vocational College, Beijing, China
  • 3Affiliated Hospital of Hebei University, Baoding, China
  • 4Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
  • 5The Second Affiliated Hospital of Harbin Medical University, Harbin, China
  • 6Department of Pathophysiology, Qiqihar Medical University, Qiqihar, Heilongjiang, China
  • 7Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Harbin, China
Received: August 11, 2019Accepted: December 23, 2019Published: January 6, 2020
https://doi.org/10.18632/aging.102647

Copyright: © 2020 Wang 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.

Abstract

Polyamines have been shown to delay cellular and organismal aging and to provide cardiovascular protection in humans. Because age-related cardiovascular dysfunction is often accompanied by impaired mitochondrial biogenesis and function, we explored the ability of spermidine (SPD), a major mammalian polyamine, to attenuate cardiac aging through activation of mitochondrial biogenesis. Cardiac polyamine levels were reduced in aged (24-month-old) rats. Six-week SPD supplementation restored cardiac polyamine content, preserved myocardial ultrastructure, and inhibited mitochondrial dysfunction. Immunoblotting showed that ornithine decarboxylase (ODC) and SPD/spermine N1-acetyltransferase (SSAT) were downregulated and upregulated, respectively, in the myocardium of older rats. These changes were paralleled by age-dependent downregulation of components of the sirtuin-1/peroxisome proliferator-activated receptor gamma coactivator alpha (SIRT1/PGC-1α) signaling pathway, an important regulator of mitochondrial biogenesis. SPD administration increased SIRT1, PGC-1α, nuclear respiratory factors 1 and 2 (NRF1, NRF2), and mitochondrial transcription factor A (TFAM) expression; decreased ROS production; and improved OXPHOS performance in senescent (H2O2-treated) cardiomyocytes. Inhibition of polyamine biosynthesis or SIRT1 activity abolished these effects. PGC-1α knockdown experiments confirmed that SPD activated mitochondrial biogenesis through SIRT1-mediated deacetylation of PGC-1α. These data provide new insight into the antiaging effects of SPD, and suggest potential applicability to protect against deterioration of cardiac function with aging.