Gut microbiome linked to accelerated brain aging in young and middle age

Scientists have discovered that signs of accelerated biological aging of the brain can be detected long before old age and that these changes are associated not only with the functioning of neural networks, memory, and mood, but also with the composition of the gut microbiome and the metabolites produced in the gut. The study was published on September 9, 2026, in the journal eBioMedicine.

In their study, the researchers used resting-state functional magnetic resonance imaging (fMRI) to create a model that predicted the brain's "age" based on the interactions between its regions. This indicator was then compared with the individual's actual age. If the brain's functional organization corresponded to an older age, the researchers considered it to have an elevated brain aging index.

The analysis covered three independent groups—674, 444, and 344 participants, or more than 1,400 people. In each group, the model reproducibly identified age-related features of functional brain connectivity. A higher brain aging index was associated with poorer working memory and executive function, as well as more severe depressive symptoms.

The third group proved particularly interesting, as the researchers used not only neuroimaging results but also gut microbiome and fecal metabolite analysis. Individuals with signs of accelerated functional brain aging showed a specific combination of gut bacteria and chemical compounds, including ceramides, 24-hydroxycholesterol, and dicarboxylic acids. However, the study was cross-sectional, so it demonstrates an association but does not prove that microbiome changes are the cause of accelerated brain aging.

The main result	What was discovered?
Brain age can be estimated by functional connections	The model determined age-related characteristics of the brain based on magnetic resonance imaging data.
The result was reproducible.	The relationship between predicted and actual age was confirmed in three groups
An older functional profile	Has been associated with poorer working memory and executive function
Emotional state	A higher aging index was associated with more depressive symptoms.
Gut microbiome	Certain bacteria have been linked to a brain aging index.
Intestinal metabolites	Links have been found for lipids, cholesterol derivatives and other compounds

How scientists determined the "age" of the brain

While standard calendar age only measures the number of years lived, the brain state of two people of the same age can vary significantly. One person may retain the functional organization of neural networks characteristic of a younger age, while another may experience some age-related changes earlier. Therefore, researchers are increasingly using the concept of biological or neuroimaging brain age.

In a new study, scientists analyzed functional magnetic resonance imaging (fMRI) scans performed at rest. This method reveals how synchronously activity changes across different areas of the brain when a person is not performing a specific task. The researchers divided the cortex into 100 regions and calculated the functional connections between them, creating a kind of map of the neural network interactions of each participant.

Based on these maps, a model predicting a person's age was constructed using Bayesian ridge regression. After statistically correcting for age bias, the researchers calculated the difference between the predicted brain age and the participant's actual age. The authors called this difference the brain aging index. A positive value indicated that the organization of functional connections appeared older than would be expected based on the person's chronological age.

Crucially, this isn't a literal definition of "how old the brain is." The model recognizes a set of functional characteristics that statistically change with age. Therefore, the index should be viewed as a research biomarker of individual differences in brain organization, rather than a clinical diagnosis or a precise "biological clock."

Indicator	What does it mean?
Calendar age	Real number of years lived
Functional connections	The degree of coordination of activity between different areas of the brain
Predicted brain age	The age that the model suggests based on the structure of these relationships
Brain Aging Index	Adjusted difference between predicted and calendar age
Positive index	The functional organization appears relatively "older"
Negative index	The functional organization appears relatively "younger"

The result was tested in three independent groups.

The initial model was built using data from 674 participants. The researchers then tested its replicability in another group of 444 participants, and then used an independent third sample of 344 participants. This approach is significantly more robust than a single-group analysis, as it allows them to verify whether the pattern holds when using different data.

In all three groups, the age predicted by functional connections statistically correlated with the individual's actual age. The correlation coefficient was 0.59 in the first group, 0.56 in the second, and 0.50 in the third. This is a moderate correlation: the model clearly recognized the age-related structure of the brain's functional organization, but the individual's age was far from completely determining these features.

It is this remaining variability that is of primary interest. If two 40-year-olds have significantly different functional brain organization, and one more closely resembles the typical profile of an older person, this could potentially indicate differences in the state of the nervous system. Therefore, the researchers focused not so much on the ability to predict chronological age, but on the magnitude of the deviation from the expected age profile.

An unusual feature of the study was its focus on young and middle-aged individuals. Most studies of the biological age of the brain focus on older adults or patients with established neurological diseases. The authors of the new study wanted to understand whether measurable differences emerge much earlier—when pronounced signs of age-related cognitive decline may not yet be present.

Group	Number of participants	The relationship between predicted and calendar age
Main group	674	r = 0.59
Playback group	444	r = 0.56
Independent group	344	r = 0.50
General approach	More than 1400 participants	The result was reproduced in three data sets.

Higher brain aging index was associated with worse memory and executive functions

The authors found that a high brain aging index has functional significance. People whose brain networks, according to the model, appeared relatively "older" performed, on average, worse on several cognitive tests. The association with working memory and executive functions was particularly robust.

Working memory allows you to temporarily retain information while simultaneously using it to complete a task. It's essential, for example, when memorizing several numbers, performing mental calculations, or following multi-step instructions. Executive functions include the ability to plan actions, switch between tasks, inhibit inappropriate responses, and maintain focused attention.

Age-related changes in functional organization particularly affected connections involving the posterior cingulate cortex, precuneus, and medial frontal areas. These areas are part of large neural systems involved in memory, internally directed thinking, behavioral control, and information integration. Therefore, the link between their functional organization and cognitive test results has a biologically plausible explanation.

However, even a statistically significant association does not necessarily mean that someone with a high index will develop cognitive impairment. The study examined interindividual differences primarily in young and middle-aged individuals, and did not diagnose dementia. It is also unknown whether people with a high brain aging index actually experience accelerated cognitive decline; long-term follow-up is needed to determine this.

Linked to high brain aging index	Result
Working memory	On average worse
Executive functions	On average worse
Functional organization of the brain	Changes in the connections of the posterior cingulate cortex, precuneus, and medial frontal areas
Clinical diagnosis	The index itself is not a diagnosis.
Prognosis of dementia	This study did not establish

Accelerated functional brain age has also been linked to symptoms of depression.

The authors found another reproducible pattern: a higher brain aging index was associated with more severe depressive symptoms. This does not mean the researchers have discovered a new test for depression. Rather, the result demonstrates that some functional characteristics of the brain that change with age are also associated with emotional state.

This intersection seems logical, as neural networks are not divided into isolated systems specifically for memory or specifically for mood. The medial frontal areas, posterior cingulate cortex, and precuneus are involved in self-referential thinking, processing emotionally significant information, and the interaction between internal thoughts and the external environment. Changes in their coordinated functioning can therefore impact several psychological functions simultaneously.

Furthermore, depressive symptoms and cognitive performance may be interrelated. Decreased attention and working memory often accompany depressive states, and chronic emotional disturbances can alter sleep, physical activity, and other factors associated with brain health. The cross-sectional design of the current study does not allow us to determine which of these phenomena appears first.

Therefore, the most cautious interpretation is that the functional aging index of the brain reflects a comprehensive characteristic of the state of large neural networks. An "older" profile was found to be simultaneously associated with both cognitive and emotional traits, potentially making this indicator interesting for future studies of early risk factors.

Observation	Possible meaning
More severe symptoms of depression	Associated with a higher brain aging index
Changes in the medial frontal areas	May affect emotional and cognitive regulation
Changes in the posterior cingulate cortex and precuneus	Associated with the operation of large neural networks
Direction of causality	Not defined
Diagnostic use	Not yet established

Gut microbiome linked to functional brain aging

The most unusual part of the study concerned the gut-brain axis. In an independent group of 344 participants, the researchers combined neuroimaging measurements with metagenomic analysis of stool samples. This allowed them to identify not only individual bacteria but also sets of microbial signatures associated with the brain aging index.

Among the microbial characteristics associated with the index were representatives of groups related to Clostridium and Collinsella. The context of the entire microbial community is important: the detection of a particular bacterial genus does not necessarily mean that it is "good" or "bad" for the brain. Different representatives of the same genus can have different metabolic properties, and the microbiome's actions are determined by the interactions of multiple organisms.

To go beyond the bacterial catalog, the researchers simultaneously studied the fecal metabolome—the set of small chemical compounds formed as a result of human metabolism, diet, and microbial activity. This approach allows us to gain insight into the functional aspects of the microbiome: two relatively similar bacterial ecosystems can produce different amounts of biologically active compounds.

The scientists then used multivariate statistical analysis to search for consistent combinations of microbes, metabolites, and neuroimaging features. As a result, they identified a cluster of biological signals associated with a higher brain aging index. This is not a single "aging microbe" or a single metabolite, but a complex signature of the gut ecosystem.

This is precisely what makes the result interesting from the perspective of the biology of the gut-brain axis. The microbiome can influence the body through metabolic, immune, hormonal, and neural mechanisms, so the simultaneous detection of bacterial and metabolic associations provides a more comprehensive picture than comparing bacterial composition alone. However, for now, the data remain associative and do not indicate the direction of interaction.

Analysis component	What was discovered?
Gut metagenome	Microbial signatures associated with brain age index
Clostridium -associated symptoms	Were included in the identified signature
Collinsella -related symptoms	Also linked to the index
Metabolome	Brain-related chemical compounds discovered
Result type	Comprehensive microbial-metabolic signature
Causality	Not proven

Among the associated metabolites were ceramides and a cholesterol derivative.

One of the most prominent groups of compounds associated with the brain aging index were ceramides. These lipid molecules are structural components of cell membranes and also participate in intracellular signaling. Changes in ceramide metabolism are associated with inflammation, insulin resistance, vascular disorders, and certain processes in the nervous system, so their presence in the detected signature is of particular interest.

Another related compound was 24-hydroxycholesterol. This cholesterol derivative is closely linked to cholesterol metabolism in the central nervous system. The brain contains large amounts of cholesterol but is virtually unable to remove it directly across the blood-brain barrier. Conversion of cholesterol to the more soluble 24-hydroxycholesterol is one of the main pathways for its removal from the brain.

The authors also found associations with certain dicarboxylic acids—compounds involved in energy and lipid metabolism. Pathway analysis revealed that the set of metabolites identified may be linked to mitochondrial function, vascular mechanisms, immune regulation, and signaling between nerve cells. These results should be considered mechanistic hypotheses rather than proof of a specific biochemical pathway.

Interestingly, for some substances, the direction of the association was reversed. Specifically, higher concentrations of estetrol were associated with a lower brain aging index. However, this statistical association does not lead to the conclusion that estetrol protects the brain or that its use can slow aging. Such claims would require entirely different experimental and clinical studies.

Metabolite or group	Why is this interesting?
Ceramides	Associated with membranes, inflammation and metabolic regulation
24-hydroxycholesterol	Associated with cholesterol metabolism in the brain
Dicarboxylic acids	Participate in energy and lipid metabolism
Estetrol	Showed an inverse association with the index
Aggregate signature	Indicates multiple potential biological pathways simultaneously

What mechanisms may link the gut and brain aging?

An analysis of functional pathways revealed that the identified microbial-metabolic signatures are linked to neuroimmune regulation processes. The intestine contains a large population of immune cells, and microbial metabolites can influence cytokine production, immune cell activity, and the state of barrier tissues. Theoretically, long-term changes in the peripheral inflammatory environment may also impact nervous system function.

The second possible pathway involves blood vessels. The brain is exceptionally sensitive to the state of the vascular system, as neural activity requires a continuous supply of oxygen and energy substrates. Metabolic and inflammatory signals of intestinal origin have the potential to alter vascular endothelial function, although the new study did not directly prove such a causal pathway.

The third potential mechanism involves mitochondria—cellular structures that account for a significant portion of energy metabolism. The brain is one of the most energy-demanding organs, so changes in mitochondrial processes can have a particularly strong impact on neurons. Pathway enrichment analysis indeed identified mitochondrial processes among the systems associated with the detected intestinal signature.

Finally, the analysis pointed to processes associated with synaptic function, that is, the transmission of signals between nerve cells. Taken together, the authors created a model in which the intestinal ecosystem is potentially linked to the functional state of the brain through several parallel systems—metabolic, immune, vascular, and neural. However, all these mechanisms require experimental verification.

Proposed route	How is it potentially connected to the brain?
Immune	Microbiome metabolites may influence inflammatory regulation
Vascular	The condition of the blood vessels determines the blood supply and metabolic support of the brain.
Mitochondrial	Affects the energy supply of neurons
Synaptic	Determines the efficiency of nerve cell communication
Metabolic	Connects intestinal metabolism with systemic physiology

Does the study mean the microbiome makes the brain age faster?

No. This is one of the most important limitations of the study. The study was cross-sectional: neuroimaging, cognitive measures, and biological characteristics were compared between individuals, but the researchers did not follow a single individual for decades, from youth to old age. Therefore, it is impossible to establish whether microbiome changes occurred before brain changes.

At least several scenarios are possible. An altered intestinal ecosystem may indeed impact the nervous system; changes in the brain, through neural and hormonal regulation, may influence the gut; or both systems may be simultaneously altered by third-party factors. These factors include diet, physical activity, sleep, stress, medications, metabolism, and various diseases.

The Brain Aging Index also cannot be interpreted as a predictor of Alzheimer's disease. The authors examined functional connectivity, cognitive performance, and mood primarily well before the age at which neurodegenerative diseases typically manifest. Long-term prospective studies will be needed to determine whether a high index at age 30-50 is associated with an increased risk of dementia several decades later.

For the same reason, it is premature to attempt to "rejuvenate the brain" with probiotics, dietary supplements, or altering specific bacteria based on this work. The study identifies potentially modifiable biological pathways but did not test therapeutic interventions. It is unknown whether targeted microbiome modification will alter the brain aging index and whether such modification will lead to improved cognitive function.

Finally, the functional brain age model remains a research tool. The correlation between predicted age and chronological age was moderate, and individual values depend on the imaging and processing methods, sample composition, and the model used. Standardization and validation in much larger populations will be necessary before clinical application is feasible.

What the study shows	What it doesn't show
Microbiome linked to functional brain age	That the microbiome is the cause of accelerated aging
A higher index is associated with worse cognitive performance.	That a person will definitely develop dementia
Related metabolites were found	That taking or suppressing these substances will change brain age
The results were repeated in several groups.	That the indicator can already be used as a clinical test
Potentially modifiable biological pathways identified	Probiotics and diet have already been proven to "rejuvenate" the brain.

Why are the research results important?

The main value of this work lies in its attempt to study brain aging not after significant age-related diseases have already appeared, but much earlier. If individual aging trajectories truly begin to diverge in young and middle age, identifying their biological causes could open a much longer window for prevention.

The second key feature is the combination of multiple levels of data. The authors went beyond brain imaging or gut bacteria analysis, linking functional neuroimaging, cognitive and emotional measures, metagenomics, and metabolomics. This approach helps identify not a single factor, but a holistic biological system potentially involved in individual differences in aging.

The next logical step would be longitudinal studies. The same participants should be re-examined after several years to determine whether the baseline index predicts subsequent changes in memory, mood, and brain structure or function. At the same time, it will be possible to determine whether changes in the gut microbiome precede or occur after accelerated functional aging.

If the causal role of certain intestinal mechanisms is ever confirmed, it will have practical implications, as the microbiome and metabolic profile are potentially more modifiable than many other risk factors. Diet, physical activity, medications, and other interventions can restructure the intestinal ecosystem. However, the current study should be viewed primarily as a roadmap for future experiments, rather than as a guide to altering the microbiome to prevent brain aging.

The next research question	Why is it needed?
Re-examination after several years	Check the real rate of brain aging
Prospective observation	Determine which comes first - changes in the intestines or the brain
Interventional studies	To test whether microbiome manipulation alters brain health
Studies of different ages and populations	To test the universality of the biomarker
Study of individual metabolic pathways	To elucidate specific biological mechanisms
Long-term observation	Determine the association with future cognitive decline and disease

Research source

Kanhao Zhao, Gabriel A. Vignolle, Jennifer S. Labus, Emeran A. Mayer, Allison Vaughan, Marika Dy, Priten Vora, Ming W. Hung, Keith Vossel, Chris Gill, Daniele Del Rio, Catherine Stanton, R. Paul Ross, John F. Cryan, Rima Kaddurah-Daouk, Yu Zhang, Arpana Church. Brain-gut crosstalk associated with brain aging in young and mid-life adults: a multicohort cross-sectional study. eBioMedicine. Published online September 9, 2026; article 106468. DOI: 10.1016/j.ebiom.2026.106468.