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

## TL;DR

This study shows that the immune sensor MDA5 contributes to aging in blood stem cells, and its absence helps preserve their function by reducing inflammation and improving protein balance.

## Contribution

The study identifies MDA5 as a novel regulator of hematopoietic aging through its effects on proteostasis and inflammation.

## Key findings

- Aged Mda5-/- mice show reduced HSC accumulation and myeloid bias.
- Mda5-/- HSCs maintain quiescence and better repopulation ability compared to wild-type HSCs.
- Reduced inflammation and improved proteostasis in Mda5-/- HSCs are linked to HSF1 and phospho-EIF2A regulation.

## 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.

Exposure to inflammation drives hematopoietic stem cells (HSC) aging, limiting their self-renewal capacity and differentiation. Here, the authors explore the mechanistic link between inflammation and HSC aging. Using mouse models, they identify the innate immune RNA sensor MDA5 as a key mediator of HSC aging and show that MDA5 loss ameliorates the aging phenotype by improving proteostasis in aged HSCs.