期刊
AGING-US
卷 12, 期 1, 页码 650-671出版社
IMPACT JOURNALS LLC
DOI: 10.18632/aging.102647
关键词
spermidine; polyamine metabolism; SIRT1; PGC-1 alpha; mitochondrial biogenesis
资金
- National Natural Science Foundation of China [81170178, 8160344]
- Emergency Management Project of National Natural Science Foundation in China [31751004]
- Postgraduate Research Innovation Fund of Harbin Medical University [YJSCX2014-06HYD]
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-1 alpha) signaling pathway, an important regulator of mitochondrial biogenesis. SPD administration increased SIRT1, PGC-1 alpha, 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-1 alpha knockdown experiments confirmed that SPD activated mitochondrial biogenesis through SIRT1-mediated deacetylation of PGC-1 alpha. These data provide new insight into the antiaging effects of SPD, and suggest potential applicability to protect against deterioration of cardiac function with aging.
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