The effect of a high-polyphenol Mediterranean diet (Green-MED) combined with physical activity on age-related brain atrophy: the Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT PLUS)

Abstract

Background The effect of diet on age-related brain atrophy is largely unproven. Objective To explore the effect of a Mediterranean diet higher in polyphenols and lower in red/processed meat (Green-MED diet) on age-related brain atrophy. Methods This 18-month clinical trial longitudinally measured brain structure volumes by magnetic-resonance-imaging using hippocampal-occupancy (HOC) and lateral-ventricle-volume (LVV) expansion scores as neurodegeneration markers. Abdominally obese/dyslipidemic participants were randomly assigned to (1)-healthy dietary guidelines (HDG), (2)-Mediterranean (MED) diet, or (3)-Green-MED diet (MED diet higher in polyphenols and lower in red/processed meat). All subjects received free gym memberships and physical activity guidance. Both MED groups consumed 28g/day walnuts (+440 mg/d polyphenols). The Green-MED group consumed green-tea (3-4 cups/day) and Mankai (Wolffia-globosa strain, 100g frozen-cubes/day) green shake (+800mg/day polyphenols). Results Among 284 participants (age = 51years; 88% men; BMI = 31.2kg/m2; apolipoprotein E-ε4 genotype = 15.7%), 224 (79%) completed the trial with eligible whole-brain MRIs. The pallidum (-4.2%), third ventricle (+3.9%), and LVV (+2.2%) disclosed the largest volume changes. Compared to younger participants, atrophy was accelerated among those ≥ 50 years [HOC change = -1.0±1.4% vs. -0.06±1.1%; 95% confidence-interval (CI):0.6, 1.3; p<0.001; LVV change = 3.2±4.5% vs. 1.3±4.1%; 95%CI:-3.1, -0.8;p = 0.001]. In subjects ≥50years, HOC decline and LVV expansion were attenuated in both MED groups, with the best outcomes among Green-MED diet participants, as compared to HDG (HOC: -0.8±1.6% vs. -1.3±1.4%;95%CI: -1.5, -0.02;p = 0.042, LVV: 2.3±4.7% vs. 4.3±4.5;95%CI;0.3, 5.2;p = 0.021). Similar patterns were observed among younger subjects. Improved insulin sensitivity over the trial was the strongest parameter associated with brain atrophy attenuation (p<0.05). Greater Mankai, green-tea and walnuts intake and less red and processed meat were significantly and independently associated with reduced HOC decline (p<0.05). Elevated urinary levels of the Mankai-derived polyphenols: urolithin-A (r = 0.24;p = 0.013) and tyrosol (r = 0.26;p = 0.007) were significantly associated with lower HOC decline. Conclusions A Green-MED, high-polyphenol diet, rich in Mankai, green tea and walnuts and low in red/processed meat is potentially neuroprotective for age-related brain atrophy.

Dietary and Nutrient Patterns and Brain MRI Biomarkers in Dementia-Free Adults

“…The Mediterranean diet is among the most extensively studied dietary pattern in relation to brain MRI biomarkers. Other dietary patterns that include high consumption of fruits, vegetables, olive oil and low consumption of meat, i.e., components characterizing the MD pattern, have also been associated with larger brain volumes, mean thicker cortical thickness and reduced hippocampal occupancy score [ 28 , 41 , 45 ]. Collectively, these findings suggest that the high intake of specific nutrients, such as unsaturated fatty acids (PUFAs, MUFAs), fibers, vitamin E, vitamin D and flavonoids, may be implicated in the relationships.…”

“…Participants’ ages were ≥50 years, with the majority of them being female. Only three studies had more male volunteers than female [ 28 , 29 , 30 ].…”

“…The majority of investigations indicated that higher adherence to the MD is positively connected with brain atrophy. Specifically, two studies (one cross-sectional and one clinical trial) found that higher MD adherence was related to larger volumes in anatomical regions such as the hippocampus and the dentate gyrus [ 28 , 38 ]. In addition, higher adherence to the MD was associated with larger brain volumes (total brain volume, grey matter volume and white matter volume) in two other studies (one cross-sectional and one observational longitudinal) [ 33 , 39 ].…”

“…Regarding individual MD components, higher fish and walnuts intake and lower meat consumption were associated with larger brain volumes, mean higher cortical thickness and reduced hippocampal occupancy score decline [ 28 , 33 ]. However, there are other studies that do not replicate these associations [ 39 ].…”

JNK1 and JNK3: divergent functions in hippocampal metabolic-cognitive function

“…Later, we used a TaqMan® Array to uncover changes in the transcriptome caused by the absence of JNK1 and JNK3, as well as the individual and synergistic effects of a chronic feeding with a high-fat diet (HFD). Feeding of a HFD was chosen as a model of metabolic stress and potential contributor to the appearance of sporadic forms of neurodegeneration based on preclinical, clinical and epidemiological reported data (Henneberg and Hoyer 1995 ; Hoyer et al 1996 ; Felice and Lourenco 2015 ; Grillo et al 2015 ; Ott et al 1999 ; Willmann et al 2020 ; Kaplan et al 2022 ; Akinola 2016 ; Milstein and Ferris 2021 ; Malan et al 2021 ). In the end, the results allowed us to describe further the pathways affected by loss of function of JNK1 and JNK3 and thus, we were able to gather more evidence on their suitability as targets for pharmacological approaches.…”