Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice
Year: 2026
Type: article
Abstract: “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.
Source: Nature Communications
Authors: Veronica Bergo, Pavlos Bousounis, Giang To Vu, Mélodie Douté, Aikaterini Polyzou, Maria-Eleni Lalioti, Bogdan B. Grigorash, Lyudmila Tsurkan, Nicholas Morchel, Ward Deboutte, Frédéric Brau, Thomas Manke, Sagar, Hind Medyouf, Dmitry V. Bulavin, Nina Cabezas-Wallscheid, Marta Derecka, Eirini Trompouki
Institutions: Max Planck Society, University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Centre National de la Recherche Scientifique, Inserm, Université Côte d'Azur, Institut de Recherche sur le Cancer et le Vieillissement de Nice, St. Jude Children's Research Hospital, ETH Zurich, HTW Berlin - University of Applied Sciences, University Medical Center Freiburg, RWTH Aachen University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Association pour la Recherche sur le Cancer, Infrastructures en Biologie Santé et Agronomie, European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation ARC pour la Recherche sur le Cancer, Max-Planck-Gesellschaft, Ministère de l'Enseignement Supérieur et de la Recherche, Centre National de la Recherche Scientifique, José Carreras Leukämie-Stiftung, Institut National Du Cancer, Université Côte d’Azur, Canceropôle Provence-Alpes-Côte d’Azur, National Cancer Institute, H2020 Marie Skłodowska-Curie Actions
Awards: G1014860659, G103968205, G143561721, G181390637, G1869544603, GRK 2344: MeInBio BioInMe: Untersuchung räumlicher und zeitlicher Dynamik der Genregulation mit hochauflösenden Hochdurchsatzverfahren, G2525723408, G259924242, G2899880, AGE-RELATED CHANGES IN HEMATOPOIESIS, G3512865558, G3527965702, G3819759563, SFB 1479: Onkogengetriebener Immun Escape (OncoEscape), G3986724495, G4103076731, The role of transposable element-induced inflammation in hematopoietic aging and rejuvenation, G4766096375, EXC 2189: CIBSS Centre for Integrative Biological Signalling Studies, G5094003450, SFB 992: Medizinische Epigenetik (MEDEP) Von grundlegenden Mechanismen zu klinischen Anwendungen, G5224721593, G5277035050, G638129023, G6841115835, AGE-RELATED CHANGES IN HEMATOPOIESIS, G7351631475, SFB 1425: Die heterozelluläre Natur kardialer Läsionen: Identitäten, Interaktionen, Implikationen, Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie, G8534655814, G8574747223, G8800819381, G880779785, Cancer Center Support Grant (CCSG)
OpenAlex ID: W7128724931