Summary: Researchers have demonstrated a definitive brain-gut-bone marrow axis in mice that explains this destructive link. The data reveals that chronic psychological stress suppresses key executive and emotional regions of the brain, disrupting the delicate ecosystem of the gut microbiome.
This intestinal crash causes a severe drop in an essential microbial compound called spermidine, which travels to the bone marrow and accelerates aging-like defects in hematopoietic stem cells, the precious master cells responsible for producing all blood and immune defense networks in the body.
Key Facts
- The Brain Circuit Shutdown: By monitoring four different mouse models of chronic stress, researchers confirmed a marked reduction in neural activity across two critical brain regions: the medial prefrontal cortex (governing executive control and emotional coping) and the periaqueductal gray (processing threat responses).
- The Intestinal Collapse: This specific brain shutdown alters downward autonomic signaling to the digestive tract. Stressed mice experienced a catastrophic loss of Lactobacillus reuteri, a keystone bacterial species that plays a fundamental role in maintaining a well-balanced intestinal microbiome.
- The Spermidine Deficit: With the depletion of Lactobacillus reuteri, the production of a natural, life-extending metabolite called spermidine plummeted. Spermidine is a crucial biological compound responsible for triggering cellular autophagy, the essential housekeeping process that clears out damaged, toxic cellular debris.
- Stem Cell Stagnation: Deprived of spermidine, the body’s blood-forming stem cells in the bone marrow—hematopoietic stem cells (HSCs), began aging prematurely. This degradation led to a steep decline in overall HSC numbers and a severe reduction in lymphocyte (white blood cell) production, effectively inducing premature immune aging.
- Sufficient Neural Suffocation: A major surprise for the research team was that artificially suppressing only these two isolated brain regions (the prefrontal cortex and periaqueductal gray) was fully sufficient to replicate the exact same gut collapse and bone marrow defects seen under total psychological stress.
- The Translational Horizon: While further rigorous validation is required before human clinical implementation, this study provides an explicit conceptual framework to build novel therapies. Future treatments could combine targeted brain stimulation, custom probiotics, or spermidine supplementation to shield the immune systems of chronically stressed or elderly individuals.
Source: Cell Press
Psychological stress is increasingly recognized as a risk factor for certain health conditions including cardiovascular disease and diabetes, especially when paired with an impaired immune response.
In a study in the Cell Press journal Cell Stem Cell publishing on July 2, researchers describe a mechanism in mice that explains this association: psychological stress speeds up aging-like changes in the body’s blood-forming stem cells in the bone marrow—called hematopoietic stem cells—by altering the intestinal microbiota.
“Our research shows how stress-responsive brain regions regulate the balance of the intestinal microbiota, which ultimately affects the function of hematopoietic stem cells,” says senior author Meng Zhao of Sun Yat-sen University in Guangzhou, China.
Previous studies have shown that chronic stress influences immune function and the formation of immune cells in the bone marrow largely through inflammatory pathways and adrenergic receptors, which drive the body’s “fight-or-flight” response. But how these stress signals were transmitted from the brain to the bone marrow was unclear.
In the new study, the researchers used four different mouse models of stress to study interactions among the brain, intestine, and bone marrow. They confirmed that chronic stress reduced activity in two brain regions—the medial prefrontal cortex and the periaqueductal gray. This in turn induced a number of changes in the physiology of the mice, including loss of hematopoietic stem cells and reduced lymphocyte production.
Importantly, the team also observed changes in the signals sent to the intestines. Specifically, the stressed mice had a loss of Lactobacillus reuteri—a species important for maintaining a healthy balance of gut microbes—and lowered levels of spermidine—a naturally occurring compound that plays a crucial role in clearing out damaged cells.
“One surprising finding of our study was that suppression of only two specific brain regions was sufficient to produce many of the hematopoietic defects caused by psychological stress,” says co-corresponding author Linjia Jiang, also of Sun Yat-sen University.
“Alternations in the gut microbiota and in the microbial metabolite spermidine played a crucial role in mediating communication between the brain and the bone marrow,” says Jiang.
Several important questions remain, including how psychological stress alters the neural circuits in different disease settings and whether similar mechanisms operate in humans. This is something the researchers plan to study. They are also looking at whether interventions could be developed to improve bone marrow function in aging or during times of chronic stress.
“Although substantial work is needed before clinical translation, these findings provide a conceptual framework for developing new approaches to mitigate immune aging and stress-associated immune dysfunction,” Zhao says.
“More broadly, our findings raise the possibility that managing psychological stress may not only improve mental well-being but also help preserve immune function and promote healthy aging,” Jiang adds.
Funding:
This research was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Noncommunicable Chronic Diseases-National Science and Technology Major Project, the Sanming Project of Medicine in Shenzhen, and the CAMS Innovation Fund for Medical Sciences (CIFMS).
Key Questions Answered:
A: This study uncovers a surprising biological chain reaction. When you experience chronic stress, it dramatically turns down activity in two executive regions of your brain: the medial prefrontal cortex and the periaqueductal gray. This neural slowdown changes the nervous system signals running down to your digestive tract, causing a massive crash in a healthy gut bacterium called Lactobacillus reuteri. Because this bacterium is responsible for producing an anti-aging compound called spermidine, its loss deprives your bone marrow of the exact molecule it needs to flush out damaged cellular trash, forcing your blood-forming stem cells to age prematurely.
A: Spermidine is a naturally occurring compound generated by healthy gut bacteria that acts as a vital maintenance worker for your cells. It triggers a crucial process called autophagy—which is essentially the cell’s internal trash-disposal and recycling system. When your gut bacteria drop due to stress, your spermidine levels plummet, causing your cellular recycling centers to freeze. Broken proteins and toxic debris quickly pile up inside your hematopoietic stem cells, crippling their ability to divide properly and severely reducing their output of vital white blood cells called lymphocytes.
A: While the research team is currently mapping out therapeutic interventions based on this exact idea, it is important to remember that this study was conducted in highly controlled mouse models. However, co-corresponding author Dr. Linjia Jiang notes that these findings offer an exciting, concrete blueprint for preventative medicine. In the near future, clinicians might utilize targeted therapies, such as specialized probiotics to replenish Lactobacillus reuteri, direct spermidine supplements, or non-invasive brain stimulation, to fortify the gut-bone axis, preserving immune function and promoting healthy aging during seasons of intense chronic stress.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this stress and immune aging research news
Author: Julia Grimmett
Source: Cell Press
Contact: Julia Grimmett – Cell Press
Image: The image is 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, Changzheng Li, Jiayin Zheng, Jingjing Guan, Kaitao Wang, Keyue Yang, Kexin Sun, Linjia Jiang, Meng Zhao, Mengyun Xie, Weiming Liu, Xiaobin Tian, Xiaojing Ye, Yanjun Ling, Yijun Zhao, Ying Wang, Yishan Li. 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 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.
