Impaired iron recycling from erythrocytes is an early hallmark of aging
- International Institute of Molecular and Cell Biology, Poland
- Maria Sklodowska-Curie National Research Institute of Oncolog, Poland
- Jagiellonian University, Poland
- 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.
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Impaired iron recycling from erythrocytes is an early hallmark of agingNCBI Gene Expression Omnibus, GSE199879.
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Impaired iron recycling from erythrocytes is an early hallmark of agingProteomeXchange Consortium, PXD032900.
Article and author information
Author details
Katarzyna Mleczko-Sanecka
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.
Reviewing Editor
- Yelena Ginzburg, Icahn School of Medicine at Mount Sinai, United States
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).
Version history
- Preprint posted: January 19, 2022 (view preprint)
- Received: April 3, 2022
- Accepted: January 30, 2023
- Accepted Manuscript published: January 31, 2023 (version 1)
- Version of Record published: February 15, 2023 (version 2)
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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Impaired iron recycling from erythrocytes is an early hallmark of aging
eLife 12:e79196.
https://doi.org/10.7554/eLife.79196
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