Age-related IGF-1 decline permits a redox-sensitive transcriptional shift that directs hematopoiesis toward a CCR2<sup>+</sup> myeloid fate.

Aging reshapes hematopoiesis toward myelopoiesis, particularly increased output of classical monocytes, contributing to immunosenescence. However, the underlying mechanisms remain unclear. Here, we identify that aging drives hematopoietic stem cells (HSCs) to progressively commit to a CCR2⁺ monocyte fate along a defined lineage trajectory, which is executed through a redox-sensitive transcriptional cascade. We find that the age-related decline in bone marrow IGF-1 is the upstream niche signal that releases suppression of the oxidative stress/NF-κB/IRF8 axis, allowing this cascade to redirect early progenitors toward a CCR2⁺ myeloid-primed fate. Functional assays confirm that cells following this CCR2⁺ trajectory drive myeloid-biased hematopoiesis and directly contribute to age-associated immunosuppression. Our work delineates a hierarchical pathway from niche decay to lineage redirection, establishing the CCR2⁺ fate trajectory as a key driver of immunosenescence and a potential therapeutic target.