MDA5 and hematopoietic aging

Aging is characterized by increased inflammatory signaling known as inflammaging, but whether and how these signals drive aging remains understudied. Here, we report a role for the innate immune RNA sensor, melanoma differentiation-associated protein 5 (MDA5), in hematopoietic aging. Hallmarks of aging, including hematopoietic stem cell (HSC) accumulation and the aging-related myeloid bias, were alleviated in aged Mda5 -/- mice. More importantly, Mda5 -/- HSCs from aged mice maintained higher quiescence and were significantly more competent at repopulating irradiated recipients than their aged wild-type counterparts in non ompetitive transplants. We took a multiomic approach spanning chromatin accessibility (ATACseq in young 5-6 months old, middle-aged 12-13 monthls old and aged 19-20 months old), bulk (RNA seq in young 3 months old, middle-aged 11-12 monthls old and aged 21-22 months old) and single-cell transcriptomics (young 2-4 mothn old and aged (22-24 mothn old), but also metabolomics analyses that showed that Mda5 -/- HSCs from aged mice, not only displayed decreased inflammatory signaling, but also metabolic features of younger HSCs, better proteostasis and higher amounts of HSF1, the master regulator of proteostasis. Mechanistically, inhibition of HSF1 abrogated the beneficial effects of MDA5 deficiency. In contrast, treatment of aged wild-type cells with an HSF1 activator ameliorated some of their phenotypes. Overall, our results show that attenuating MDA5 can delay the effects of aging in the HSC compartment by fine-tuning inflammation and retaining active proteostasis.