Lack of MDA5 delays hematopoietic aging by modulating inflammaging and proteostasis in mice.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41680183.
- Also identified by DOI 10.1038/s41467-026-69424-x and PMC identifier 12905429.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>-/-</sup> mice exhibit reduced HSC accumulation and myeloid bias. Importantly, aged Mda5<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 Mda5<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.
Medical subject headings
- Proteostasis
- Hematopoietic Stem Cells
- Inflammation
- Aging
- Hematopoiesis
- Cellular Senescence