A groundbreaking study by an international team of scientists from Ben-Gurion University, Harvard University, and Leipzig University has revealed novel insights into the connection between diet and biological brain aging. Through secondary analysis of the DIRECT PLUS randomized controlled trial, researchers identified two serum proteins – galectin-9 (Gal-9) and decorin (DCN) – that serve as potential biomarkers of accelerated brain aging. More importantly, their levels appear modifiable through dietary interventions, particularly the polyphenol-enriched "green" Mediterranean diet.
Methodology: From Proteomics to Neuroimaging
The study involved 294 participants over 30 years old with abdominal obesity or dyslipidemia. Participants were randomly assigned to three dietary groups for an 18-month period:
• Control group (HDG): Followed basic healthy eating guidelines.
• Traditional Mediterranean diet (MED): Included calorie restriction and daily consumption of 28g walnuts.
• "Green" Mediterranean diet (green-MED): Enriched with polyphenols through daily consumption of 3-4 cups of green tea and 500ml of mankai beverage.
At baseline and after 18 months, researchers performed brain MRI scans to assess "brain age" using a convolutional neural network and calculated Brain Age Gap (BAG) – the difference between predicted brain age and chronological age. Simultaneously, they analyzed levels of 87 serum proteins using the Olink proteomics platform.
Key Biomarkers of Accelerated Brain Aging
The analysis revealed two proteins with the strongest association with brain aging:
Galectin-9 (Gal-9) – a protein involved in modulating neuronal activity and inflammation. Elevated levels induce the release of pro-inflammatory cytokines, including IL-6, and interact with the Tim-3 receptor on microglia, triggering inflammatory reactions. Gal-9 levels were significantly higher in participants with accelerated brain aging.
Decorin (DCN) – an extracellular matrix component influencing cell differentiation and inflammation. Previously, elevated DCN levels in cerebrospinal fluid have been associated with early signs of amyloid-β pathology characteristic of Alzheimer's disease. In this study, higher DCN levels also correlated with accelerated brain aging.
Notably, incorporating these two markers into predictive models significantly improved BAG prediction accuracy compared to using cardiometabolic indicators alone.
• Those with signs of accelerated brain aging exhibited substantially increased DCN levels.
• The "green" Mediterranean diet (green-MED) group demonstrated the most impressive results: these participants showed significant Gal-9 reduction compared to the control group and their own baseline measurements.
• While DCN levels increased across all groups, the rise was minimal in the green-MED group.
Additional analysis established that daily consumption of four cups of green tea and seven servings of walnuts per week was closely associated with decreased Gal-9 levels – the key neuroinflammation marker.
Mechanisms of Polyphenol Action
Polyphenols found in green tea and other foods likely reduce microglial activation – the key factor in neuroinflammation within the central nervous system. They also promote the reduction of amyloid-β accumulation, one of the primary pathological features of Alzheimer's disease.
Practical Implications
These discoveries have several important implications:
1. Diagnostic potential: Gal-9 and DCN could become potential markers for early diagnosis and monitoring of neurodegenerative processes.
2. Therapeutic prospects: The polyphenol-rich "green" Mediterranean diet may serve as a non-pharmacological strategy for slowing brain aging.
3. Personalized nutrition: Specific foods like green tea and walnuts could be recommended to reduce the risk of accelerated brain aging.
Limitations and Future Research
The authors note some study limitations, including the predominance of male participants and specific selection criteria (individuals with lipid metabolism disorders). Additional research in more diverse populations is needed to confirm these findings.
Nevertheless, this research opens new pathways for understanding the connection between nutrition, neuroinflammation, and brain aging. It underscores that dietary interventions can directly influence molecular mechanisms underlying neurodegenerative processes and potentially slow biological brain aging – a discovery with profound implications for healthy longevity.
Publication date: 20.09.2025 Source: Pachter D. et al. Serum Galectin-9 and Decorin in relation to brain aging and the green-Mediterranean diet: A secondary analysis of the DIRECT PLUS randomized trial. Clin Nutr. 2025 Oct;53:99-108. doi: 10.1016/j.clnu.2025.08.021. Epub 2025 Aug 23. PMID: 40897150. https://www.clinicalnutritionjournal.com/article/S0261-5614(25)00235-3/fulltext