Iron accumulation with age alters metabolic pattern and circadian clock gene expression through the reduction of AMP-modulated histone methylation.

Iron accumulates with age in mammals, and its possible implications in altering metabolic responses are not fully understood. Here, we report that both high-iron diet and advanced age in mice consistently altered gene expression of many pathways, including those governing the oxidative stress response and the circadian clock. We used a metabolomic approach to reveal similarities between metabolic profiles and the daily oscillation of clock genes in old and iron-overloaded mouse livers. In addition, we show that phlebotomy decreased iron accumulation in old mice, partially restoring the metabolic patterns and amplitudes of the oscillatory expression of clock genes Per1 and Per2. We further identified that the transcriptional regulation of iron occurred through a reduction in AMP-modulated methylation of histone H3K9 in the Per1 and H3K4 in the Per2 promoters, respectively. Taken together, our results indicate that iron accumulation with age can affect metabolic patterns and the circadian clock.