Altered expression of iron regulatory proteins with aging is associated with transient hepatic iron accumulation after environmental heat stress

Abstract

An increasing body of evidence suggests that dysregulation of iron metabolism contributes to age-related pathologies. We have previously observed increased hepatic iron with aging, and that environmental heat stress stimulates a further increase in iron and oxidative liver injury in old rats. The purpose of this study was to determine a mechanism for the increase in hepatic iron in old rats after heat stress. Young (6 mo) and old (24 mo) Fischer 344 rats were exposed to two heating bouts separated by 24 h. Livers were harvested after the second heat stress, and protein levels of the iron import protein, transferrin receptor-1 (TFR1), and the iron export protein, ferroportin (Fpn) were determined by immunoblot. In the nonheated condition, old rats had lower TFR1 expression, and higher Fpn expression. After heat stress, TFR1 declined in the old rats, and iron chelation studies demonstrated that this decline was dependent on a hyperthermia-induced increase in iron. TFR1 did not change in the young rats after heat stress. Since TFR1 is inversely regulated by iron, our results suggest that the increase in intracellular iron with aging and heat stress lower TFR1 expression. Fpn expression increased in both age groups after heat stress, but this response was delayed in old rats. This delay in the induction of an iron exporter suggests a mechanism for the increase in hepatic iron and oxidative injury after heat stress in aged organisms.

Testosterone propionate activated the Nrf2-ARE pathway in ageing rats and ameliorated the age-related changes in liver

“…Ageing is characterized by a process of physiological degeneration and is accompanied by pathophysiological age-related changes, including impaired functioning and increased vulnerability to death 1–3 . Age-related changes in the liver are commonly associated with structural and physiological changes 4,5 . The mechanisms of hepatic injury caused by ageing are complicated and involve apoptosis, inflammation, hepatic clearance function and toxicity 6–8 .…”

Hepatic Macrophage Abundance and Phenotype in Aging and Liver Iron Accumulation

“…However, since macrophages were not counted, it is unknown whether their results represented a change in marker expression or the number of tissue macrophages. The increases in macrophage markers and iron in their study resemble the aging phenotype, yet the hepatic iron concentrations are far in excess of those observed in old animals (~23,000 vs. ~800 μg/gram dry weight [ 31 , 32 ]).…”

Cellular Senescence and Their Role in Liver Metabolism in Health and Disease: Overview and Future Directions

“…Although a more precise mechanism of organelle damage was not enunciated, iron deposition mediated a decrease in Transferrin-receptor-1 which upregulates the iron storage protein ferritin after heat stress. Nevertheless, the synthesis of the iron exporter protein ferroportin was delayed [26]. Effect that may explain at least in part, organelle damage in the aging cell that occurs after natural oxidants depletion ( Figure 2B).…”

“…GSH deficiency can be alleviated by the oral intake of cysteine and its restoration rates appears to be age and sex dependent. Older animal models are associated with increased cellular stress and an enhanced subcellular injury after heat stress associated with an increased iron intracellular deposition [26]. These cause damages to mitochondria and lysosomes.…”