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<p>“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 <i>Mda5</i><sup>-/-</sup> mice exhibit reduced HSC accumulation and myeloid bias. Importantly, aged <i>Mda5</i><sup>-/-</sup> 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 <i>Mda5</i><sup>-/-</sup> 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.</p>

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Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月12日

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  • 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

摘要

“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.