Gal-9 and DCN Serum Expression Reflect Accelerated Brain Aging and Are Attenuated by the Green-Mediterranean Diet: The 18-month DIRECT PLUS Proteomics-Brain MRI Trial

Abstract Background We recently reported that a green-Mediterranean (green-MED), high-polyphenol diet is potentially neuroprotective for age-related brain atrophy. Here, we explored the interplay between dietary intervention, proteomics profile, and accelerated brain age. Methods In the 18-month DIRECT PLUS trial, 294 participants (adherence rate=89%) were randomized to one of three arms: 1) Healthy dietary guidelines (HDG); 2) MED diet; or 3) green-MED diet. Both MED diets included 28g/day of walnuts. Additionally, the low red/processed meat green-MED group received daily supplements of polyphenol-rich green-tea and green Mankai aquatic plant. In this secondary analysis, we measured 87 serum proteins (Olink-CVDII) and conducted Magnetic Resonance Imaging (MRI) to obtain brain 3D-T1-weighted for brain age calculation based on brain convolutional neural network to identify protein markers reflecting the brain age gap (BAG: residual deviation of MRI-assessed brain age from chronological age). Results We analyzed eligible brain MRIs (216 at baseline and 18-month) for BAG calculation. At baseline (age=51.3yrs, 90% men), lower weight, waist circumference, diastolic blood pressure, and HbA1c parameters were associated with younger brain age than expected (p<0.05 for all). At baseline, higher levels of two specific proteins: Galectin-9 (Gal-9) and Decorin (DCN), were associated with larger BAG (accelerated brain aging; FDR<0.05). A proteomics principal component analysis (PCA) revealed a significant difference between the 18-month time points among participants who completed the trial with accelerated brain aging (p=0.02). Between baseline and 18 months, Gal-9 significantly decreased (p<0.05) among individuals who completed the intervention with attenuated brain age, and DCN significantly increased (p<0.05) among those who completed the trial with accelerated brain age. A significant interaction was observed between the green-MED diet and proteomics PCA change compared to the HDG (β=-1.7; p-interaction=0.05). Participants in the green-MED diet significantly decreased Gal-9 compared to the HDG diet (p=0.015) and from baseline (p=0.003). DCN levels, however, marginally increased in the HDG diet from baseline (p=0.053). Conclusion Higher serum levels of Gal-9 and DCN may indicate an acceleration of brain aging and might be reduced by the green-MED/high-polyphenol diet rich in Mankai and green-tea and low in red/processed meat. Trial registration number NCT03020186.