Impaired iron recycling from erythrocytes is an early hallmark of aging

Abstract

Aging affects iron homeostasis and erythropoiesis, as evidenced by tissue iron loading in rodents and common anemia in the elderly. Since red pulp macrophages (RPMs) continuously process iron, their cellular functions might be susceptible to age-dependent decline, affecting organismal iron metabolism and red blood cells (RBCs) parameters. However, little is known about the effects of aging on the functioning of RPMs. To study aging RPMs, we employed 10-11-months-old female mice that show serum iron deficiency and iron overload primarily in spleens compared to young controls. We observed that this is associated with iron loading, oxidative stress, diminished mitochondrial and lysosomal activities, and most relevantly, decreased erythrophagocytosis rate in RPMs. We uncovered that these impairments of RPMs lead to the retention of senescent RBCs in the spleen, their excessive local hemolysis, and the formation of iron- and heme-rich large extracellular protein aggregates, likely derived from damaged RBCs and RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation and reactive oxygen species build-up in RPMs, restores mitochondrial and lysosomal functions, and improves their ability to clear erythrocytes. Consequently, this diet improves splenic RBCs fitness, limits hemolysis and formation of iron-rich aggregates, normalizes splenic iron levels, and tends to increase serum iron availability in aging mice. Mechanistically, using readouts from aged RPMs and in vitro cultures of RPM-like cells, we show that diminished erythrophagocytic activity of RPMs can be attributed to a combination of increased iron levels, reduced expression of heme-catabolizing enzyme heme oxygenase 1 (HO-1), and endoplasmic reticulum stress. Taken together, we identified RPM dysfunction as an early hallmark of physiological aging and demonstrated that dietary iron reduction improves iron turnover efficacy.