Age‐dependence of Methylation, Transsulfuration and Glutathione Synthesis Pathways in Human Frontal Cortex

Neuronal synthesis of the antioxidant glutathione (GSH) depends upon availability of cysteine, provided either by cellular uptake or by transsulfuration of homocysteine generated by the methionine cycle of methylation (Fig. 1). To evaluate age‐dependent changes in the relative contribution of these two cysteine sources, we measured redox and methylation metabolite levels in postmortem human frontal cortex from subjects across the lifespan. Levels of the transsulfuration intermediate cystathionine were significantly decreased in 60–80 yr‐old subjects, indicating that the balance between these two cysteine sources shifts to transsulfuration in older age. This shift was accompanied by decreased methionine and S‐adenosylmethionine, and an increase in homocysteine, indicating lower activity of the folate and B12‐dependent enzyme methionine synthase (MS), consistent with earlier finding of decrease MS expression with age. Cystathionine levels in 10 yr‐old autistic subjects were decreased, similar to those of 60 yr‐old subjects. In vitro studies with human neuronal cells showed that the pro‐inflammatory cytokine TNF‐alpha increased transsulfuration and inhibited MS activity in association with decreased cysteine uptake. Transsulfuration pathway enzymes cystathionine beta synthase (CBS) and cystathionine gamma lyase (CGL) both produce hydrogen sulfide, which inhibits oxidative respiration and increases glycolysis. This action decreases production of reactive oxygen species (ROS), limiting the demand for antioxidant. Together these observations illustrate how an age‐dependent increase in transsulfuration links antioxidant synthesis to methylation status in human brain. TNF‐alpha, whose levels increase with age, may be a regulator of transsulfuration, with important implications for epigenetic regulation during early brain development. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .