Summary: A large-scale dietary trial found that a green-Mediterranean (green‑MED) diet can slow brain aging by changing blood proteins associated with neurodegeneration. Using MRI-based brain-age estimates and blood proteomic profiling, researchers followed nearly 300 participants for 18 months and observed that diet influenced the brain age gap and specific circulating proteins linked to Alzheimer’s disease and cognitive decline.
Two proteins—Galectin-9 and Decorin—were identified as markers of accelerated brain aging. Participants on the polyphenol-rich green‑MED diet showed reduced levels of these proteins, suggesting that targeted dietary patterns may modulate biological pathways involved in age-related brain degeneration.
Key facts
- Brain age gap: The difference between MRI-predicted brain age and chronological age reflects brain health; a positive gap suggests accelerated brain aging.
- Protein markers: Elevated Galectin-9 and Decorin associate with an older-than-expected brain age and are linked to neurodegenerative processes.
- Dietary impact: The green‑MED diet, high in polyphenols from sources such as Mankai, green tea, and walnuts, lowered levels of these proteins and slowed brain aging in the trial.
Source: Ben‑Gurion University of the Negev
Researchers from Ben‑Gurion University of the Negev, Harvard University, and the University of Leipzig conducted an 18‑month randomized dietary intervention to test whether diet can alter biological markers of brain aging. The trial combined whole-brain MRI scans with a focused proteomics panel to track changes in brain structure and circulating proteins.
Understanding the brain age gap
Chronological age does not always match biological brain age. Conditions and risk factors such as diabetes, chronic inflammation, hypertension, high cholesterol, and the accumulation of β‑amyloid and tau proteins can accelerate brain atrophy. The brain age gap measures the difference between MRI-derived brain age and a person’s actual age: a positive gap reflects accelerated brain aging, while a negative gap suggests a younger, healthier brain relative to chronological age.
A larger brain age gap has been observed in people with mild cognitive impairment and Alzheimer’s disease, making it a useful, noninvasive marker for tracking the impact of interventions on brain health.
The DIRECT PLUS trial — a major brain MRI dietary study
The DIRECT PLUS trial is among the most extensive MRI-based dietary intervention studies, enrolling 294 participants randomized into three groups and followed over 18 months. Participants received whole-brain MRI scans at baseline and at the end of the study. Advanced machine-learning models calculated each participant’s MRI-predicted brain age to determine individual brain age gaps and track changes over time.
Earlier reports from the trial showed that both a traditional Mediterranean diet and a green‑MED diet reduced age-related brain atrophy by roughly half over 18 months, with improved blood sugar control—particularly lower HbA1c—contributing to this protective effect.
The role of blood proteins (proteomics)
This secondary analysis examined whether changes in circulating proteins differed between participants with divergent brain aging trajectories and whether diet influenced those changes. Researchers measured 87 serum proteins using a cardiovascular-focused proteomics panel and related these profiles to brain age gap changes derived from 3D T1-weighted MRI scans.
Participants whose brains aged faster than expected showed distinct shifts in proteomic profiles over the intervention. In particular, Galectin-9 (Gal‑9) and Decorin (DCN) emerged as key proteins associated with accelerated brain aging. Levels of Gal‑9 fell significantly among those following the green‑MED diet, while increases in Decorin were linked with accelerated brain aging in other participants.
The green‑MED diet tested in the trial emphasized reduced red and processed meat and added high-polyphenol foods—walnuts, green tea, and the aquatic plant Mankai—delivering substantially more daily polyphenols than the other arms. The anti‑inflammatory and antioxidant properties of these foods likely contributed to reductions in pro‑aging protein signals.
Galectin-9 is produced by microglial cells in the brain and can bind the Tim‑3 receptor, promoting pro‑inflammatory cytokine production that may accelerate neurodegeneration. Elevated Gal‑9 has been observed in people with mild cognitive impairment and early Alzheimer’s. Decorin is an extracellular matrix protein; higher levels in cerebrospinal fluid have been associated with early Alzheimer’s changes. Modulating these proteins through diet suggests a feasible pathway to influence brain aging.
Lead investigator Prof. Iris Shai describes this work as progress in nutri‑omics—the integration of nutrition with omics technologies such as proteomics—and an important step toward dietary strategies that could slow neurological disease processes. First author Dafna Pachter notes the potential for blood-based omics signatures to serve as accessible indicators of brain status in future screening or monitoring tools.
Funding and authorship
Funding: The DIRECT PLUS trial received support from the German Research Foundation (DFG), the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnuts Commission. Funders did not influence 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)
About this research news
Author: Ehud Zion Waldoks
Source: Ben‑Gurion University of the Negev
Contact: Ehud Zion Waldoks – Ben‑Gurion University of the Negev
Image: The image is credited to Neuroscience News
Original research (open access): “Serum Galectin‑9 and Decorin in relation to brain aging and the green‑Mediterranean diet: A secondary analysis of the DIRECT PLUS randomized trial” by Iris Shai et al., published in Clinical Nutrition.
Abstract
Title: Serum Galectin‑9 and Decorin in relation to brain aging and the green‑Mediterranean diet: A secondary analysis of the DIRECT PLUS randomized trial
Background and aims
This analysis assessed whether changes in serum proteomic profiles differ among participants with distinct brain aging trajectories and whether those changes are influenced by dietary intervention.
Methods
In the 18‑month DIRECT PLUS trial, 294 participants were randomized to one of three groups: 1) Healthy dietary guidelines (HDG); 2) Mediterranean (MED) diet with an additional 440 mg/day polyphenols from walnuts; or 3) green‑MED diet with reduced red/processed meat and an added 1,240 mg/day polyphenols from walnuts, Mankai, and green tea. Eighty‑seven serum proteins were measured (Olink‑CVDII). MRI-based 3D T1-weighted scans were analyzed with a convolutional neural network to compute brain age and identify protein markers associated with the brain age gap (BAG).
Results
At baseline, lower weight, smaller waist circumference, lower diastolic blood pressure, and lower HbA1c were linked to a younger MRI‑predicted brain age. Higher serum levels of Galectin‑9 and Decorin correlated with an increased BAG. Principal component analysis of the proteomics panel revealed differences over time among participants with accelerated brain aging. Over 18 months, Galectin‑9 decreased significantly among individuals whose brain aging was attenuated, while Decorin rose among those with accelerated brain aging. A significant interaction showed that the green‑MED diet produced beneficial proteomic changes compared with the HDG arm, including a notable reduction in Galectin‑9.
Conclusions
Elevated serum Galectin‑9 and Decorin may signal accelerated brain aging. A green‑MED, high‑polyphenol, low‑red/processed meat diet was associated with reductions in these proteins, suggesting a diet‑based approach to slow biological brain aging.