Chronic psychological stress impairs hematopoietic stem cell (HSC) self-renewal and lymphoid differentiation by suppressing neuronal activity in the medial prefrontal cortex (mPFC) and periaqueductal gray (PAG). This neural suppression propagates via sympathetic pathways to reduce intestinal mucin, deplete Lactobacillus reuteri in the gut microbiome, and lower systemic spermidine levels. Spermidine depletion then disables mitochondrial autophagy, elevates mitochondrial peroxidative stress, and triggers ferroptotic stress in HSCs — producing a cellular aging phenotype. Crucially, chemogenetic reactivation of mPFC/PAG neurons fully rescued HSC function, establishing causality rather than correlation.
This work is genuinely paradigm-shifting for several reasons. It mechanistically closes a loop that has long been suspected but never mapped end-to-end: mind → autonomic nervous system → gut microbiome → polyamine metabolism → stem cell aging. Spermidine's role in autophagy and longevity is well-established — it extends lifespan in model organisms and associates with reduced all-cause mortality in human cohorts — but its upstream regulation by stress-driven microbiome shifts is new. The ferroptosis angle is particularly striking, placing iron-mediated oxidative cell death at the center of stress-induced HSC aging, a mechanism distinct from classical ROS pathways. Limitations include the mouse-model basis; whether the same mPFC-PAG circuitry governs human HSC aging under chronic stress remains untested. Still, the findings immediately implicate L. reuteri supplementation and dietary spermidine as tractable interventions, and reframe stress management as a direct tool for preserving hematopoietic — and potentially broader stem cell — longevity.
