High intestinal iron absorption induced by decreased hepcidin leads to imbalance of iron metabolism in aging mice.

Iron homeostasis which is primarily regulated through intestinal iron absorption, is usually disrupted in the elderly. But changes of intestinal iron absorption with aging have not been elucidated. This study aims to investigate the role of intestinal iron absorption in driving age-related disruption of iron homeostasis. Male C57BL/6 J mice aged 2, 12, 18, and 24 months were utilized in this study to analyze age-related changes in systemic iron status, detect the alterations in intestinal iron absorption via Ussing Chamber, and clarify its regulatory mechanisms during aging via western blot and RT-qPCR. Results showed that iron deposition occurred in the liver, heart, brain, spleen, and kidney with age. Furthermore, intestinal iron absorption elevated in aged mice, particularly in the duodenum, which was accompanied by upregulated DMT1 and FPN. As FPN is the only known iron exporter in enterocytes, the upregulation of FPN was considered as the key factor of higher iron absorption during aging. Then factors influencing FPN expression were determined. It was found that serum hepcidin and hepatic Hamp mRNA levels significantly decreased. And a reduction of over 40% in p-SMAD1/5/8 which is a transcriptional regulator of hepcidin was observed. Overall, these findings suggested that the downregulation of p-SMAD is a key factor limiting the transcription of hepcidin during aging, then increased the expression of intestinal FPN, further resulting in increased iron absorption and iron homeostasis imbalance. This study demonstrated that dysregulation of the hepcidin production during aging is a key driver of iron homeostasis disruption in the elderly, representing a target for precision intervention.