FASTING-INDUCED DEPLETION OF GLUTATHIONE IN THE AGING MOUSE

Previous results indicate that aging is associated with a general deficiency of glutathione (GSH). As fasting is also known to lower hepatic GSH levels, we investigated the combined effects of aging and 24 hr of food deprivation on liver, kidney and blood GSH and cyst(e)ine levels in C57BL/6N mice of ages 6 (young), 12 (mature) and 24 (old) months. No age-related differences in baseline hepatic GSH were observed in these mice, consistent with previous findings where the deficiency in liver is not apparent until about 29 months of age. By 6 hr of fasting, an age-related reduction in hepatic GSH was evident, culminating in a 4-fold greater decrease during maturation, and a 5-fold greater decrease during aging (P < 0.001) compared to young animals. Liver weight also declined, decreasing total liver GSH content by 24% in young, 44% in mature, and 56% in old mice. Renal GSH and hepatic cyst(e)ine concentrations were unaffected by fasting. In young and mature mice, depletion of hepatic GSH was accompanied by a concomitant increase in blood GSH and kidney cyst(e)ine levels after 6 hr of fasting, suggesting enhancement of hepatic GSH efflux. However, in old animals, GSH depletion was associated with decreased blood GSH and kidney cyst(e)ine. Altogether, these results suggest that the stress of fasting reveals aging changes in hepatic GSH homeostasis occurring well before the GSH deficiency of aging is observed. These aging changes are likely due to decreased GSH turnover resulting from impaired biosynthesis.