Hematopoietic stem cells (HSCs) aging correlates with an increasing risk of myelo-proliferative disease and immunosenescence. In this study, we show that aging-related inflammation promotes HSC aging through TNFα→ERK→ETS1→IL27Ra pathway. TNFα, a well-known biomarker of inflammation, increases during aging and induces the expression of IL27Ra on HSCs via ERK-ETS1 signaling. Deletion of IL27Ra rescues the functional decline and myeloid-bias of HSCs and also reverses the inhibitory effect of TNFα on HSCs. Aged IL27Ra-/- mice had a reduced proportion of myeloid-biased HSCs and did not display the biased myeloid differentiation that occurs in aged WT mice. IL27Ra+ HSCs exhibit impaired reconstitution capacity and myeloid-bias compared to IL27Ra- HSCs, and serve as a myeloid-recovery pool upon inflammatory insult. Inflammation-related genes were enriched in IL27Ra+ HSCs and this enrichment increases with aging. Our study demonstrates that age-induced IL27Ra signaling impairs HSCs and raises the possibility that interfering with IL27Ra signaling can counter the physiologically deleterious effect of aging on hematopoietic capacity.

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