| Title: |
Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice |
| Authors: |
Bergo, Veronica; Bousounis, Pavlos; To Vu, Giang; Douté, Mélodie; Polyzou, Aikaterini; Lalioti, Maria-Eleni; Grigorash, Bogdan B.; Tsurkan, Lyudmila; Morchel, Nicholas; Deboutte, Ward; Brau, Frédéric; Manke, Thomas; Sagar; Medyouf, Hind; Bulavin, Dmitry V.; Cabezas Wallscheid, Nina; id_orcid:0 000-0003-0870-0530; Derecka, Marta; Trompouki, Eirini |
| Source: |
Nature Communications, 17 (1) |
| Publisher Information: |
Nature |
| Publication Year: |
2026 |
| Collection: |
ETH Zürich Research Collection |
| Description: |
“Inflammaging”, the chronic increase in inflammatory signaling with age, remains poorly understood in hematopoietic aging. Here, we identify the innate immune RNA sensor melanoma differentiation–associated protein 5 (MDA5) as an important factor of hematopoietic stem cell (HSC) aging. Aged Mda5 -/- mice exhibit reduced HSC accumulation and myeloid bias. Importantly, aged Mda5 -/- HSCs retain greater quiescence and superior repopulation capacity in noncompetitive transplants compared to wild-type counterparts. Multiomic analyses— including chromatin accessibility, transcriptomics, and metabolomics—reveal decreased inflammatory signaling, a youthful metabolic profile, and improved proteostasis in Mda5 -/- HSCs, through regulation of HSF1 and phospho-EIF2A, key proteostasis regulators. Activation of HSF1 in aged wild-type HSCs partially restores youthful features, supporting a causal role for proteostasis maintenance. Collectively, our findings demonstrate that attenuating MDA5-dependent inflammation preserves HSC function during aging by maintaining metabolic fitness and proteostasis and provide insight into potential therapeutic strategies for mitigating hematopoietic aging. ; ISSN:2041-1723 |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/application/pdf |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/wos/001689721200002; https://hdl.handle.net/20.500.11850/796151 |
| DOI: |
10.3929/ethz-c-000796151 |
| Availability: |
https://hdl.handle.net/20.500.11850/796151; https://doi.org/10.3929/ethz-c-000796151 |
| Rights: |
info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/ ; Creative Commons Attribution 4.0 International |
| Accession Number: |
edsbas.A5E77481 |
| Database: |
BASE |