Psychological stress drives aging-like hematopoietic stem cell dysfunction through a brain-gut-bone marrow axis.

Chronic stress influences hematopoietic stem cells (HSCs). However, how psychological stress regulates HSC function remains incompletely understood. Here, we show that psychological stress impairs HSC self-renewal and lymphoid differentiation, inducing aging-like phenotypes. Stress suppresses neuronal activity in the medial prefrontal cortex (mPFC) and periaqueductal gray (PAG), leading to HSC dysfunction, whereas chemogenetic activation of these regions restores HSC function. Psychological stress or chemogenetic inhibition of the mPFC and PAG reduces the abundance of L. reuteri in the gut microbiota and lowers spermidine levels. Mechanistically, spermidine depletion suppresses mitochondrial autophagy, promotes mitochondrial peroxidative stress, and increases ferroptotic stress in HSCs. We further demonstrate that mPFC and PAG activity regulate the intestinal environment through a sympathetic pathway, reducing intestinal mucin levels, L. reuteri abundance, and spermidine levels. These findings identify a brain-gut-bone marrow axis linking psychological stress to aging-like HSC dysfunction through sympathetic regulation of intestinal microbiota and spermidine metabolism.