Summary: New mouse research reveals a clear brain–gut–bone marrow axis that links chronic psychological stress to premature aging of blood-forming stem cells. The study shows that long-term stress suppresses activity in specific brain regions, destabilizes the gut microbiome—especially depleting Lactobacillus reuteri—and sharply reduces levels of the microbial metabolite spermidine. Without spermidine, hematopoietic stem cells (HSCs) in the bone marrow show aging-like defects and reduced production of immune cells.
Key Facts
- Brain circuit shutdown: Four different mouse models of chronic stress consistently showed reduced neural activity in the medial prefrontal cortex (mPFC), which governs executive control and emotional regulation, and the periaqueductal gray (PAG), which processes threat responses.
- Gut ecosystem collapse: This brain suppression alters autonomic signals to the gut, triggering a dramatic loss of the keystone bacterium Lactobacillus reuteri and destabilizing the intestinal microbiome.
- Spermidine deficiency: Loss of L. reuteri leads to a steep decline in spermidine, a microbial metabolite that promotes autophagy—the cellular clearing process essential for removing damaged components.
- HSC aging-like dysfunction: Spermidine depletion impairs mitochondrial autophagy in HSCs, increases oxidative and ferroptotic stress, and causes premature HSC decline and diminished lymphocyte (white blood cell) production, contributing to immune aging.
- Brain-specific sufficiency: Artificially inhibiting just the mPFC and PAG reproduced the same gut and bone marrow defects seen with whole-animal psychological stress, indicating these brain regions are sufficient to drive the observed changes.
- Therapeutic implications: Although human translation requires more research, the findings suggest potential interventions—targeted brain stimulation, microbiome-based therapies, or spermidine supplementation—to protect bone marrow function in chronically stressed or aging individuals.
Source: Cell Press
Overview: Psychological stress is increasingly linked to higher risk for conditions such as cardiovascular disease and diabetes, especially when immune function is compromised. This study, published in the journal Cell Stem Cell, describes a biologically plausible mechanism in mice: chronic psychological stress reduces neural activity in key brain regions, alters gut microbiota composition and metabolite production, and thereby accelerates aging-like dysfunction in hematopoietic stem cells.
Senior author Meng Zhao (Sun Yat-sen University) explains that stress-sensitive brain regions actively regulate the intestinal microbiota balance, and those microbial shifts ultimately affect bone marrow stem cell function. Earlier work had connected chronic stress and immune changes mainly through inflammatory pathways and adrenergic signaling, but the direct route linking brain activity to bone marrow had remained unclear until now.
In their experiments, researchers used four robust models of chronic stress to trace interactions among the brain, gut, and bone marrow. All models showed consistent suppression of the mPFC and PAG, accompanied by physiological consequences including reduced HSC self-renewal and impaired lymphoid differentiation. Parallel analyses revealed a marked decrease in intestinal L. reuteri and lower systemic spermidine levels, identifying a microbial-metabolite pathway that mediates the brain-to-bone marrow signal.
Co-corresponding author Linjia Jiang emphasizes that the study’s surprising finding was how selectively manipulating these two brain regions reproduced the gut collapse and HSC defects, highlighting a focused neural control point for stress-related immune aging. Mechanistically, spermidine depletion compromised mitochondrial quality control in HSCs, increasing peroxidative and ferroptotic stress that compromises stem cell survival and function.
Several important questions remain. It is not yet known whether the same mechanisms operate in humans or across different disease contexts. The research team plans follow-up studies to determine how stress alters neural circuits under varying conditions and to test potential interventions aimed at restoring gut microbiota, replenishing spermidine, or modulating brain activity to preserve HSC function.
Key Questions Answered
- How can psychological stress accelerate stem cell aging? Chronic stress suppresses activity in the mPFC and PAG. This suppressed neural signaling changes autonomic output to the gut, causing loss of protective microbes like L. reuteri, which in turn lowers spermidine production. Without spermidine, HSCs lose effective autophagy and accumulate cellular damage, leading to premature aging-like dysfunction.
- Why is spermidine important? Spermidine is a microbiome-derived metabolite that stimulates autophagy, the cell’s housekeeping process. Adequate spermidine levels help maintain mitochondrial health and prevent toxic buildup of damaged proteins and lipids. Its depletion impairs HSC maintenance and reduces immune cell output.
- Could probiotics or supplements help? The mouse data support the idea that targeted probiotics to restore L. reuteri, spermidine supplementation, or neuromodulation could be promising strategies. However, clinical translation will require rigorous testing in humans.
Editorial Notes
- Article edited for clarity by a Neuroscience News editor.
- Original journal paper reviewed in full by editorial staff.
- Additional context and synthesis provided by reporting team.
About this research
Author: Julia Grimmett
Source: Cell Press
Image: Image credit credited to Neuroscience News
Original research (open access): “Psychological stress drives aging-like hematopoietic stem cell dysfunction through a brain–gut–bone marrow axis” by Binghuo Wu et al., Cell Stem Cell. DOI: 10.1016/j.stem.2026.05.012
Abstract
Psychological stress drives aging-like hematopoietic stem cell dysfunction through a brain–gut–bone marrow axis
Chronic stress impairs hematopoietic stem cell (HSC) self-renewal and lymphoid differentiation, producing aging-like phenotypes. Stress suppresses neuronal activity in the medial prefrontal cortex (mPFC) and periaqueductal gray (PAG), which leads to HSC dysfunction. Chemogenetic activation of these regions restores HSC function. Psychological stress or targeted inhibition of the mPFC and PAG reduces intestinal L. reuteri abundance and lowers spermidine levels. Mechanistically, spermidine depletion suppresses mitochondrial autophagy, promotes mitochondrial peroxidative stress, and increases ferroptotic stress in HSCs. The mPFC and PAG regulate the intestinal environment through sympathetic pathways, reducing mucin levels, L. reuteri abundance, and spermidine production. These findings define a brain–gut–bone marrow axis linking psychological stress to aging-like HSC dysfunction via sympathetic control of the microbiota and spermidine metabolism.