MDA5 drives hematopoietic aging by modulating inflammaging and proteostasis
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. We took a multiomic approach spanning chromatin accessibility, bulk and single-cell transcriptomics, 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.