Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of -adenosylmethionine (SAM), which serves as a me...

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Bibliographic Details
Published in:International journal of molecular sciences 2018-10, Vol.19 (10), p.3106
Main Author: Soda, Kuniyasu
Format: Article
Language:English
Subjects:
Aging - genetics
Aging - immunology
Aging - metabolism
Animals
Carbon - metabolism
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Dietary Supplements
DNA
DNA Methylation
DNA methyltransferases (DNMT)
DNA Modification Methylases - metabolism
Epigenesis, Genetic
Humans
Immunosenescence - genetics
LFA-1 promoter (ITGAL)
lymphocyte function-associated antigen 1 (LFA-1)
Metabolic Networks and Pathways
methylation
Nutrients - metabolism
one carbon metabolism
polyamine
Polyamines - metabolism
Review
spermidine
spermine
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Summary:Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of -adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, -adenosyl-l-homocysteine (SAH) and decarboxylated -adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.
ISSN:1422-0067
1422-0067
DOI:10.3390/ijms19103106