Research Paper Volume 12, Issue 1 pp 650—671
Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function
- 1 Department of Pathophysiology, Harbin Medical University, Harbin, China
- 2 Department of Medical Technology, Beijing Health Vocational College, Beijing, China
- 3 Affiliated Hospital of Hebei University, Baoding, China
- 4 Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China
- 5 The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- 6 Department of Pathophysiology, Qiqihar Medical University, Qiqihar, Heilongjiang, China
- 7 Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Harbin, China
Received: August 11, 2019 Accepted: December 23, 2019 Published: January 6, 2020
https://doi.org/10.18632/aging.102647How to Cite
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.