Diet can directly influence brain aging

Beer-Sheva, Israel – September 15, 2025 – A new study led by researchers from Ben-Gurion University of the Negev, Harvard University, and the University of Leipzig has uncovered innovative biological evidence that diet can directly influence brain aging. Published in Clinical Nutrition (https://doi.org/10.1016/j.clnu.2025.08.021), the study examined brain MRI scans alongside detailed blood protein profiles (proteomics) over an 18-month dietary intervention. The research identified specific proteins linked to accelerated brain aging, with blood levels that were altered following dietary intervention.

Understanding Brain Age Gap

Age-related neurodegenerative conditions, such as brain atrophy, do not always align with our chronological age. Factors such as diabetes, inflammation, hypertension, high cholesterol, and the accumulation of β-amyloid and tau proteins can speed up brain aging. The “brain age gap” is defined as the difference between a person’s MRI-predicted brain age and their actual chronological age. A positive gap indicates an older brain age than expected – signifying accelerated brain aging – while a negative gap reflects a younger brain age, suggesting a slowdown in brain aging. A higher brain age gap has been observed in various neurological conditions, including mild cognitive impairment and Alzheimer’s disease.

The DIRECT PLUS Trial – One of the World’s Largest Brain MRI Dietary Studies

The DIRECT PLUS trial is one of the most extensive and longest-running brain MRI intervention studies to date, involving nearly 300 participants divided into three dietary groups. Whole-brain MRI scans were performed before and after the 18-month trial to track changes in brain health. Using advanced brain-age prediction models based on brain MRI data, researchers estimated each participant’s brain age before and after the dietary intervention.

Previous studies, published in The American Journal of Clinical Nutrition, revealed that both the traditional Mediterranean diet and the green-Mediterranean diet slowed age-related brain atrophy by approximately 50% within 18 months (https://doi.org/10.1093/ajcn/nqac001). In addition, improved glycemic control – particularly reductions in HbA1c – also contributed to this protective effect (https://doi.org/10.1016/j.ajcnut.2024.09.013).

The Role of Blood Proteins

The present study investigated whether changes in blood proteomic profiles (a panel of approximately 90 proteins) differed between participants with distinct brain aging trajectories, and whether these differences were influenced by diet. The findings showed that participants whose brain age was older than their chronological age exhibited distinct shifts in their blood protein profiles over the 18 months of the intervention.

Two proteins – Galectin-9 and Decorin – emerged as especially relevant to accelerated brain aging. Their levels significantly decreased among participants following the green-Mediterranean diet, which includes green tea and the aquatic plant Mankai. This suggests a potential beneficial impact on biological processes related to brain aging through blood protein modulation. The study’s lead researcher, Prof. Iris Shai of Ben-Gurion University, an adjunct professor at Harvard University and an honorary professor at Leipzig University, explains: “This research represents an advance in the field of nutri-omics – the integration of nutrition science with omics technologies such as proteomics – and opens new pathways for developing targeted dietary strategies to slow the progression of neurological diseases.”
 

Green-MED Diet Targets Key Proteins Driving Brain Aging

There is evidence that Galectin-9, a protein from the Galectin family, is expressed in microglial cells in the brain and that, upon binding to the Tim-3 receptor, it may induce the production of pro-inflammatory cytokines, which may accelerate neurodegenerative processes in diseases like Alzheimer’s.  Elevated levels of Galectin-9 have been found in individuals with mild cognitive impairment and in the early stages of Alzheimer’s disease. 

Decorin is a structural protein of the extracellular matrix. High levels of Decorin in cerebrospinal fluid have been linked to early changes in Alzheimer’s disease. Dafna Pachter, a Ph.D. student and the first author of the paper, adds: “In this study, we are taking a small step toward a new possibility – a simple, accessible, and affordable blood test that could, in the future, provide an indication of brain status by analyzing omics layers in the blood”.
 

In the current study, the green-MED diet, rich in polyphenols from sources such as Mankai, green tea, and walnuts, significantly reduced Galectin-9 levels and slowed the increase in Decorin. The anti-inflammatory activity of these components may explain the potential neuroprotective effect observed in the study.

Dr. Anat Yaskolka-Meir, postdoctoral research fellow at Harvard T.H. Chan School of Public Health and the co-first author of the paper, explains the importance of studying circulating proteomics in brain health: “Studying the circulating proteins in blood allows us to observe, in a real-life setting, how the brain’s aging processes are influenced by lifestyle and dietary changes. This approach gives us a dynamic window into brain health, helping to reveal biological changes long before symptoms may appear. By mapping these protein signatures, we gain powerful new insight into how interventions, such as diet, may help preserve cognitive function as we age.”

Funding: The DIRECT PLUS trial was supported by the German Research Foundation (DFG), the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnuts Commission. The funding bodies had no role in study design, data collection, analysis, interpretation, or publication.

Authors: Dafna Pachter*, Anat Y Meir*, Alon Kaplan, Gal Tsaban, Hila Zelicha, Ehud Rinott, Gidon Levakov, Ofek Finkelstein, Ilan Shelef, Moti Salti, Frauke Beyer, Veronica Witte, Nora Klöting, Berend Isermann, Uta Ceglarek, Tammy R Raviv, Matthias Blüher, Michael Stumvoll, Dong D. Wang, Frank B Hu, Meir J Stampfer, Galia Avidan, and Iris Shai. (*Equal contribution)