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Impaired iron recycling from erythrocytes is an early hallmark of aging

Patryk Slusarczyk, Pratik Kumar Mandal, Gabriela Zurawska, Marta Niklewicz, Komal Kumari Chouhan, Matylda Macias, Aleksandra Szybinska, Magdalena Cybulska, Olga Krawczyk, Sylwia Herman, Michal Mikula, Remigiusz Serwa, Malgorzata Lenartowicz, View ORCID ProfileWojciech Pokrzywa, View ORCID ProfileKatarzyna Mleczko-Sanecka
doi: https://doi.org/10.1101/2022.01.16.476518
Patryk Slusarczyk
1International Institute of Molecular and Cell Biology in Warsaw, Poland
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Pratik Kumar Mandal
1International Institute of Molecular and Cell Biology in Warsaw, Poland
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Gabriela Zurawska
1International Institute of Molecular and Cell Biology in Warsaw, Poland
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Marta Niklewicz
1International Institute of Molecular and Cell Biology in Warsaw, Poland
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Komal Kumari Chouhan
1International Institute of Molecular and Cell Biology in Warsaw, Poland
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Matylda Macias
1International Institute of Molecular and Cell Biology in Warsaw, Poland
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Aleksandra Szybinska
1International Institute of Molecular and Cell Biology in Warsaw, Poland
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Magdalena Cybulska
2Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
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Olga Krawczyk
2Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
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Sylwia Herman
3Department of Genetics and Evolution, Institute of Zoology and Biomedical Research, Jagiellonian University, Cracow, Poland
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Michal Mikula
2Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
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Remigiusz Serwa
4IMol Polish Academy of Sciences, Warsaw, Poland
5ReMedy International Research Agenda Unit, IMol Polish Academy of Sciences, Warsaw, Poland
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Malgorzata Lenartowicz
3Department of Genetics and Evolution, Institute of Zoology and Biomedical Research, Jagiellonian University, Cracow, Poland
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Wojciech Pokrzywa
1International Institute of Molecular and Cell Biology in Warsaw, Poland
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  • ORCID record for Wojciech Pokrzywa
Katarzyna Mleczko-Sanecka
1International Institute of Molecular and Cell Biology in Warsaw, Poland
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  • ORCID record for Katarzyna Mleczko-Sanecka
  • For correspondence: kmsanecka@iimcb.gov.pl
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Abstract

Aging affects iron homeostasis, as evidenced by tissue iron loading and toxicity and common anemia in the elderly. Iron needs in mammals are met primarily by iron-recycling from senescent red blood cells (RBCs), a task chiefly accomplished by splenic red pulp macrophages (RPMs) via erythrophagocytosis. Given that RPMs continuously process iron, their cellular functions might be susceptible to age-dependent decline, a condition that has been largely unexplored to date. Here, we found that 10-11-months-old female mice exhibit iron loading, diminished lysosomal activity, and decreased erythrophagocytosis rate in RPMs. These impairments lead to the retention of senescent hemolytic RBCs in the spleen, and the formation of undegradable iron- and heme-rich extracellular protein aggregates, likely derived from ferroptotic RPMs. We further found that feeding mice an iron-reduced diet alleviates iron accumulation in RPMs, enhances their ability to clear erythrocytes, and limits ferroptosis. Consequently, this diet ameliorates hemolysis of splenic RBCs and the formation of iron-rich aggregates, increasing serum iron availability in aging mice. Using RPM-like cells, we show that the diminished iron-recycling capacity of RPMs is underlain by iron accumulation and reduced expression of heme-catabolizing enzyme heme oxygenase 1 (HO-1). Taken together, we identified RPM collapse as an early hallmark of aging and demonstrated that dietary iron reduction improves iron turnover efficacy.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • This is a significantly revised version of our manuscript updated with the data generated over last 2 months.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 08, 2022.
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Impaired iron recycling from erythrocytes is an early hallmark of aging
Patryk Slusarczyk, Pratik Kumar Mandal, Gabriela Zurawska, Marta Niklewicz, Komal Kumari Chouhan, Matylda Macias, Aleksandra Szybinska, Magdalena Cybulska, Olga Krawczyk, Sylwia Herman, Michal Mikula, Remigiusz Serwa, Malgorzata Lenartowicz, Wojciech Pokrzywa, Katarzyna Mleczko-Sanecka
bioRxiv 2022.01.16.476518; doi: https://doi.org/10.1101/2022.01.16.476518
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Impaired iron recycling from erythrocytes is an early hallmark of aging
Patryk Slusarczyk, Pratik Kumar Mandal, Gabriela Zurawska, Marta Niklewicz, Komal Kumari Chouhan, Matylda Macias, Aleksandra Szybinska, Magdalena Cybulska, Olga Krawczyk, Sylwia Herman, Michal Mikula, Remigiusz Serwa, Malgorzata Lenartowicz, Wojciech Pokrzywa, Katarzyna Mleczko-Sanecka
bioRxiv 2022.01.16.476518; doi: https://doi.org/10.1101/2022.01.16.476518

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