DATE: October 16, 2026 at 06:00AM
SOURCE: PSYPOST.ORG
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TITLE: Some adults’ brains look older than their age, and gut biology may be part of the picture
Some young and middle-aged adults have brain activity patterns that look “older” than their actual age, and new research suggests these differences are linked to thinking skills, mood, and the gut. Adults with older-looking brain patterns tended to score somewhat lower on tests of working memory and executive function, report more depressive symptoms, and have modestly different gut bacteria and stool chemicals. The findings were published in eBioMedicine.
A central concept in this research is the brain aging index. Researchers train a computer model to estimate a person’s age from brain scans alone, and the index is the gap between that estimate and the person’s actual age. A positive score means the brain looks older than expected, while a negative score means it looks younger. The authors of a 2017 review argued that such estimates could serve as a marker of brain health, pointing to evidence that an older-appearing brain is linked to poorer cognitive and physical aging and a higher risk of death.
Most of this research has focused on older adults who are already at risk for cognitive decline. However, the authors of a 2024 review argued that middle age may mark a turning point, with biological changes during this period shaping a person’s later brain health.
At the same time, evidence has grown linking the digestive system to brain health. A 2025 study comparing people with Alzheimer’s disease, people with mild cognitive impairment, and healthy adults found that gut bacteria and stool chemicals shifted step by step across these groups, and these shifts were tied to brain shrinkage and poorer thinking skills. A study covered by PsyPost in 2024 similarly found that depressed adults tend to have an imbalance of gut bacteria that relates to altered brain connectivity.
This progression of research led Kanhao Zhao, who conducted the study during his postdoctoral training under Arpana Church at the Church Lab at the University of California, Los Angeles, to test whether gut biology relates to early brain aging in young and middle-aged adults. The work was supported by National Institutes of Health grants awarded to Church.
“Most brain-age research has focused on older adults or people who already have neurological disease,” Zhao, who is now a postdoctoral scholar in the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, told PsyPost. “We therefore wanted to ask whether meaningful differences in brain aging could already be detected in young and mid-life adults, and whether these differences were linked not only to cognition and mental health, but also to gut microbial and metabolic features.”
To investigate this, the research team analyzed brain imaging and biological data from healthy adults aged 18 to 65. They divided the data into three separate groups to ensure their results were consistent across different samples: a discovery group of 674 people, a replication group of 444 people, and an independent group of 344 people.
The participants underwent resting-state functional magnetic resonance imaging. This technique measures changes in blood oxygen levels, which rise and fall with brain activity, while a person lies still and rests. By tracking which regions rise and fall together, a pattern known as functional connectivity, scientists can see how different brain regions communicate.
Participants also completed various tests to measure their cognitive and emotional health. These included assessments of intelligence, working memory, executive function, and self-reported questionnaires for depressive symptoms.
In the independent group of participants, the researchers collected stool samples. They analyzed these samples using metagenomics, which sequences the genetic material of the bacteria living in the gut, and metabolomics, which identifies specific metabolites. Metabolites are the small chemical molecules left over from cellular processes, digestion, and bacterial activity.
Across all three groups, the model’s age estimates tracked participants’ actual ages reasonably well, though imperfectly: its predictions were off by about 6 to 9 years on average. People whose brains looked older than expected showed a consistent pattern. A higher index score was associated with stronger connections involving the default mode network, a set of regions most active during inward-focused thought such as daydreaming and recalling memories, and the frontoparietal network, which helps control goal-directed thinking. The strongest links involved the precuneus and posterior cingulate cortex, regions along the brain’s midline that are involved in internal thought and memory retrieval.
At the same time, people with older-appearing brains showed weaker connections in the ventral attention network, a brain system that helps humans orient themselves to sudden changes in their environment. This network imbalance was linked to worse performance on cognitive tests. Individuals with a higher brain aging index scored lower on performance IQ, working memory, and executive function tasks, while also reporting more symptoms of depression.
These associations were modest. Correlations between brain-age scores and individual test results ranged from about 0.12 to 0.38, meaning brain-age scores accounted for at most about 14 percent of the variation in any single measure, and usually much less. Not every measure lined up: verbal IQ showed no reliable link in either group where it was tested, and several test scores were linked in one group but not another. In the first group, the links held after accounting for participants’ actual ages.
“The effects should be viewed as meaningful population-level associations rather than as a diagnostic test for an individual person,” Zhao noted. “An important strength of the study is that the brain-age pattern was examined across multiple independent cohorts, but the associations with cognition, mood, and gut biology were generally modest. At this stage, the brain aging index is better understood as a research marker of individual variability in brain health than as something that could tell a person how quickly their brain is aging in a clinical setting.”
The gut findings were similarly small. In the 182 participants with complete data, a combined profile of gut bacteria and stool chemicals accounted for only about 2 percent of the differences in brain-age scores, though this was more than would be expected by chance. The bacteria most strongly tied to older-looking brains in this profile included species of Clostridium and Collinsella, and the stool chemicals included ceramides and 24-hydroxycholesterol, fat-related molecules involved in inflammation, cellular stress, and cholesterol processing.
Some of these bacteria have been tied to inflammation in other research, but the authors note that in these healthy adults they appeared alongside bacteria typically associated with a healthy gut. People with younger-looking brains, by contrast, had higher levels of stool chemicals related to neurotransmitter function and amino acid processing. One of the molecules most strongly tied to a younger-looking brain was estetrol, a form of estrogen, which the authors suggest could hint at a protective role for reproductive hormone pathways.
“What I found particularly interesting was that the signal was not confined to the brain,” Zhao said. “We observed coordinated associations involving functional brain networks, cognition and mood, and gut-derived biological features, including microbial and metabolic signatures related to lipid metabolism, immune and vascular processes, synaptic function, and mitochondrial pathways. This convergence across very different biological levels suggests that understanding brain aging may ultimately require looking beyond the brain alone.”
Notably, the cognitive and mood measures were tied to the brain network patterns rather than directly to any specific gut bacteria or stool chemicals.
“One important message is that people of the same chronological age can show meaningful differences in how their brain networks resemble patterns associated with aging,” Zhao explained. “We also found that these brain-age differences were linked to patterns in gut microbes and metabolites, suggesting that brain aging may be related to broader biological processes across the brain-gut system rather than occurring in isolation.”
As with all research, there are a few things to keep in mind. “The most important caveat is that this was a cross-sectional observational study, so our findings do not establish causality,” Zhao emphasized. “We cannot conclude that particular gut microbes or metabolites cause the brain to age faster, nor that changing the microbiome would necessarily make the brain ‘younger.'”
Because everything was measured at a single point in time, it is also possible that brain changes influence the gut, or that other factors, such as diet, shape both. Zhao also noted that the brain-age measure is a “statistical index derived from functional connectivity, rather than a literal measurement of the biological age of a person’s brain.”
Additionally, the gut microbiome analysis was conducted on 182 participants, mostly women, and the cohorts drew on datasets from the U.S. and Japan. The researchers note that larger, more balanced studies will be necessary to verify the exact bacterial and metabolic signatures identified in this group. The genetic sequencing used in the study also identifies broad bacterial species but cannot pinpoint specific bacterial strains, which might have differing effects on human health.
“The next step is to move from cross-sectional associations toward longitudinal and prospective studies,” Zhao said. “We would like to determine whether these brain-body signatures can predict future cognitive trajectories and whether they change in response to modifiable factors or interventions. More broadly, we are interested in expanding beyond the brain-gut axis toward a more integrated view of brain-body aging. Emerging research suggests that brain function is also closely related to cardiovascular physiology and other organ systems.”
“In future studies, we hope to combine brain imaging with cardiac imaging, physiological signals such as ECG and PPG, and molecular measurements to better understand how aging processes across different organ systems interact,” he added. “Ultimately, our goal is to identify multimodal biomarkers that explain why individuals age differently and may eventually help guide personalized strategies for maintaining brain health.”
An ECG records the heart’s electrical activity, while PPG uses light sensors, like those in many smartwatches, to track pulse and blood flow.
Studying these processes over time could help scientists develop interventions to maintain brain health during middle age. “I think an important broader message is that brain aging is unlikely to be a process that begins suddenly in old age,” Zhao concluded. “Individual differences in brain network organization and their relationships with cognition and peripheral biology can already be observed much earlier in adulthood. Understanding these earlier differences may eventually help us shift the focus from treating late-stage decline toward identifying trajectories of brain health before substantial impairment develops.”
The study, “Brain-gut crosstalk associated with brain ageing in young and mid-life adults: a multicohort cross-sectional study,” was authored by 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, and Arpana Church.
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