Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.
Veronica Bergo, Pavlos Bousounis, Giang To Vu, Mélodie Douté et al.
Kernaussage
The absence of MDA5 delays hematopoietic aging by reducing inflammation and improving proteostasis, leading to enhanced functional capacity in aged hematopoietic stem cells.
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.
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Quelle: PubMed Central / National Library of Medicine (NLM). Apollion steht in keiner Verbindung mit NLM und wird von NLM nicht empfohlen. Evidenzgrade bewerten die methodische Studienqualität — nicht die inhaltliche Richtigkeit.
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