Impaired iron recycling from erythrocytes is an early iron-dependent hallmark of aging
Impaired iron recycling from erythrocytes is an early iron-dependent 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 cell (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 lysosomal activity, and 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 ferroptotic RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation and reactive oxygen species build-up in RPMs, improves their ability to clear and degrade erythrocytes, and limits ferroptosis. Consequently, this diet improves splenic RBCs fitness, limits hemolysis and the formation of iron-rich protein aggregates, and increases serum iron availability in aging mice. Using RPM-like cells, we show that diminished erythrophagocytic and lysosomal activities of RPMs can be attributed to a combination of increased iron levels and reduced expression of heme-catabolizing enzyme heme oxygenase 1 (HO-1). Taken together, we identified RPM dysfunction as an early hallmark of physiological aging and demonstrated that dietary iron reduction improves iron turnover efficacy.
Macias Matylda、Cybulska Magdalena、Krawczyk Olga、Herman Sylwia、Mleczko-Sanecka Katarzyna、Mandal Pratik Kumar、Mikula Michal、Slusarczyk Patryk、Niklewicz Marta、Pokrzywa Wojciech、Serwa Remigiusz、Lenartowicz Malgorzata、Chouhan Komal Kumari、Zurawska Gabriela、Szybinska Aleksandra
International Institute of Molecular and Cell Biology in WarsawMaria Sklodowska-Curie National Research Institute of OncologyMaria Sklodowska-Curie National Research Institute of OncologyDepartment of Genetics and Evolution, Institute of Zoology and Biomedical Research, Jagiellonian UniversityInternational Institute of Molecular and Cell Biology in WarsawInternational Institute of Molecular and Cell Biology in WarsawMaria Sklodowska-Curie National Research Institute of OncologyInternational Institute of Molecular and Cell Biology in WarsawInternational Institute of Molecular and Cell Biology in WarsawInternational Institute of Molecular and Cell Biology in WarsawIMol Polish Academy of Sciences||ReMedy International Research Agenda Unit, IMol Polish Academy of SciencesDepartment of Genetics and Evolution, Institute of Zoology and Biomedical Research, Jagiellonian UniversityInternational Institute of Molecular and Cell Biology in WarsawInternational Institute of Molecular and Cell Biology in WarsawInternational Institute of Molecular and Cell Biology in Warsaw
基础医学生理学生物化学
Macias Matylda,Cybulska Magdalena,Krawczyk Olga,Herman Sylwia,Mleczko-Sanecka Katarzyna,Mandal Pratik Kumar,Mikula Michal,Slusarczyk Patryk,Niklewicz Marta,Pokrzywa Wojciech,Serwa Remigiusz,Lenartowicz Malgorzata,Chouhan Komal Kumari,Zurawska Gabriela,Szybinska Aleksandra.Impaired iron recycling from erythrocytes is an early iron-dependent hallmark of aging[EB/OL].(2025-03-28)[2025-05-17].https://www.biorxiv.org/content/10.1101/2022.01.16.476518.点此复制
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