Spermine and gene methylation: a mechanism of lifespan extension induced by polyamine-rich diet.

Abstract

The polyamines spermidine and spermine are synthesized in almost all organisms and are also contained in food. Polyamine synthesis decreases with aging, but no significant decrease in polyamine concentrations were found in organs, tissues, and blood of adult animals and humans. We found that healthy dietary patterns were associated with a preference for polyamine-rich foods, and first reported that increased polyamine intake extended the lifespan of mice and decreased the incidence of colon cancer induced by repeated administration of moderate amounts of a carcinogen. Recent investigations have revealed that changes in DNA methylation status play an important role in lifespan and aging-associated pathologies. The methylation of DNA is regulated by DNA methyltransferases in the presence of S-adenosylmethionine. Decarboxylated S-adenosylmethionine, converted from S-adenosylmethionine by S-adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize spermine and spermidine and acts to inhibit DNMT activity. Long-term increased polyamine intake were shown to elevate blood spermine levels in mice and humans. In vitro studies demonstrated that spermine reversed changes induced by the inhibition of ornithine decarboxylase (e.g., increased decarboxylated S-adenosylmethionine, decreased DNA methyltransferase activity, increased aberrant DNA methylation), whose activity decreases with aging. Further, aged mice fed high-polyamine chow demonstrated suppression of aberrant DNA methylation and a consequent increase in protein levels of lymphocyte function-associated antigen 1, which plays a pivotal role on inflammatory process. This review discusses the relation between polyamine metabolism and DNA methylation, as well as the biological mechanism of lifespan extension induced by increased polyamine intake.