Cell stem cellJul 2, 2026

Stress causes aging-like problems in blood stem cells through a connection between the brain, gut, and bone marrow

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 3, 2026

Abstract

Psychological stress impairs hematopoietic stem cell (HSC) self-renewal and lymphoid differentiation.

Psychological stress induces aging-like characteristics in HSCs.
Reduced neuronal activity in the medial prefrontal cortex and periaqueductal gray is associated with HSC dysfunction.
Chemogenetic activation of the mPFC and PAG may restore HSC function.
Psychological stress and inhibition of mPFC and PAG decrease the abundance of L. reuteri in the gut microbiota and lower spermidine levels.
Spermidine depletion could hinder mitochondrial recycling, elevate mitochondrial stress, and increase ferroptotic stress in HSCs.
The mPFC and PAG may influence the gut environment via a sympathetic pathway, affecting mucin levels and microbiota composition.

Simplified

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.