Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice
- 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
2026-02-12
“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.