Impaired iron recycling from erythrocytes is an early hallmark of aging

  1. Patryk Slusarczyk
  2. Pratik Kumar Mandal
  3. Gabriela Zurawska
  4. Marta Niklewicz
  5. Komal Chouhan
  6. Raghunandan Mahadeva
  7. Aneta Jończy
  8. Matylda Macias
  9. Aleksandra Szybinska
  10. Magdalena Cybulska-Lubak
  11. Olga Krawczyk
  12. Sylwia Herman
  13. Michal Mikula
  14. Remigiusz Serwa
  15. Malgorzata Lenartowicz
  16. Wojciech Pokrzywa
  17. Katarzyna Mleczko-Sanecka  Is a corresponding author
  1. International Institute of Molecular and Cell Biology, Poland
  2. Maria Sklodowska-Curie National Research Institute of Oncolog, Poland
  3. Jagiellonian University, Poland
  4. Polish Academy of Sciences, Poland

Abstract

Aging affects iron homeostasis, as evidenced by tissue iron loading and 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 possibility that has been unexplored to date. Here, we found that 10-11-month-old female mice exhibit iron loading in RPMs, largely attributable to a drop in iron exporter ferroportin, which diminishes their erythrophagocytosis capacity and lysosomal activity. Furthermore, we identified a loss of RPMs during aging, underlain by the combination of proteotoxic stress and iron-dependent cell death resembling ferroptosis. 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 reduces damage. Consequently, this diet ameliorates hemolysis of splenic RBCs and reduces the burden of protein aggregates, mildly increasing serum iron availability in aging mice. Taken together, we identified RPM collapse as an early hallmark of aging and demonstrated that dietary iron reduction improves iron turnover efficacy.

Data availability

RNA sequencing data are deposited in the GEO repository (under accession no: GSE199879).Mass spectrometry proteomics data were deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifiers: PXD032900 and PXD038660.All other numerical data used to generate the figures are provided as Source data files.

The following data sets were generated

Article and author information

Author details

  1. Patryk Slusarczyk

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  2. Pratik Kumar Mandal

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  3. Gabriela Zurawska

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  4. Marta Niklewicz

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  5. Komal Chouhan

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  6. Raghunandan Mahadeva

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  7. Aneta Jończy

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  8. Matylda Macias

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  9. Aleksandra Szybinska

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  10. Magdalena Cybulska-Lubak

    Maria Sklodowska-Curie National Research Institute of Oncolog, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  11. Olga Krawczyk

    Maria Sklodowska-Curie National Research Institute of Oncolog, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  12. Sylwia Herman

    Department of Genetics and Evolution, Jagiellonian University, Cracow, Poland
    Competing interests
    The authors declare that no competing interests exist.
  13. Michal Mikula

    Maria Sklodowska-Curie National Research Institute of Oncolog, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  14. Remigiusz Serwa

    International Institute of Molecular Mechanisms and Machines, Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  15. Malgorzata Lenartowicz

    Department of Genetics and Evolution, Jagiellonian University, Cracow, Poland
    Competing interests
    The authors declare that no competing interests exist.
  16. Wojciech Pokrzywa

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5110-4462
  17. Katarzyna Mleczko-Sanecka

    International Institute of Molecular and Cell Biology, Warsaw, Poland
    For correspondence
    kmsanecka@iimcb.gov.pl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9095-9597

Funding

National Science Centre (Sonata Bis grant (UMO-2020/38/E/NZ4/00511).)

  • Patryk Slusarczyk
  • Pratik Kumar Mandal
  • Gabriela Zurawska
  • Marta Niklewicz
  • Komal Chouhan
  • Raghunandan Mahadeva
  • Aneta Jończy
  • Katarzyna Mleczko-Sanecka

Norwegian Financial Mechanisms 2014-2021/Polish National Science Centre (UMO-2019/34/H/NZ3/00691)

  • Patryk Slusarczyk
  • Pratik Kumar Mandal
  • Wojciech Pokrzywa

Foundation for Polish Science (International Research Agendas program MAB/2017/2)

  • Remigiusz Serwa

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures were approved by the local ethical communities for animal care and use in Olsztyn and Warsaw (II LKE) (decisions: WAW2/015/2019; WAW2/149/2019; WAW2/026/2020; WAW2/149/2020).The procedure was approved by the local ethical committee in Warsaw (decision: WAW2/122/2019).

Copyright

© 2023, Slusarczyk et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Patryk Slusarczyk
  2. Pratik Kumar Mandal
  3. Gabriela Zurawska
  4. Marta Niklewicz
  5. Komal Chouhan
  6. Raghunandan Mahadeva
  7. Aneta Jończy
  8. Matylda Macias
  9. Aleksandra Szybinska
  10. Magdalena Cybulska-Lubak
  11. Olga Krawczyk
  12. Sylwia Herman
  13. Michal Mikula
  14. Remigiusz Serwa
  15. Malgorzata Lenartowicz
  16. Wojciech Pokrzywa
  17. Katarzyna Mleczko-Sanecka
(2023)
Impaired iron recycling from erythrocytes is an early hallmark of aging
eLife 12:e79196.
https://doi.org/10.7554/eLife.79196

Share this article

https://doi.org/10.7554/eLife.79196

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