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)

Alon Kaplan, Hila Zelicha, Anat Yaskolka Meir, Ehud Rinott, Gal Tsaban, Gidon Levakov, Ofer Prager, Moti Salti, Yoram Yovell, Jonathan Ofer, Sebastian Huhn, Frauke Beyer, Veronica Witte, Arno Villringer, Nachshon Meiran, Tamar B. Emesh, Peter Kovacs, Martin Von Bergen, Uta Ceglarek, Matthias BlüherMichael Stumvoll, Frank B. Hu, Meir J. Stampfer, Alon Friedman, Ilan Shelef, Galia Avidan, Iris Shai

Research output: Contribution to journalArticlepeer-review


Background: The effect of diet on age-related brain atrophy is largely unproven. Objectives: We aimed to explore the effect of a Mediterranean diet (MED) higher in polyphenols and lower in red/processed meat (Green-MED diet) on age-related brain atrophy. Methods: This 18-mo clinical trial longitudinally measured brain structure volumes by MRI using hippocampal occupancy score (HOC) and lateral ventricle volume (LVV) expansion score as neurodegeneration markers. Abdominally obese/dyslipidemic participants were randomly assigned to follow 1) healthy dietary guidelines (HDG), 2) MED, or 3) Green-MED diet. All subjects received free gym memberships and physical activity guidance. Both MED groups consumed 28 g walnuts/d (+440 mg/d polyphenols). The Green-MED group consumed green tea (3-4 cups/d) and Mankai (Wolffia-globosa strain, 100 g frozen cubes/d) green shake (+800 mg/d polyphenols). Results: Among 284 participants (88% men; mean age: 51 y; BMI: 31.2 kg/m2; APOE-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 with younger participants, atrophy was accelerated among those ≥50 y old (HOC change: -1.0% ± 1.4% compared with -0.06% ± 1.1%; 95% CI: 0.6%, 1.3%; P < 0.001; LVV change: 3.2% ± 4.5% compared with 1.3% ± 4.1%; 95% CI: -3.1%, -0.8%; P = 0.001). In subjects ≥ 50 y old, HOC decline and LVV expansion were attenuated in both MED groups, with the best outcomes among Green-MED diet participants, as compared with HDG (HOC: -0.8% ± 1.6% compared with -1.3% ± 1.4%; 95% CI: -1.5%, -0.02%; P = 0.042; LVV: 2.3% ± 4.7% compared with 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 parameter most strongly associated with brain atrophy attenuation (P < 0.05). Greater Mankai, green tea, and walnut intake and less red and processed meat were significantly and independently associated with reduced HOC decline (P < 0.05). Elevated urinary concentrations of the 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. This trial was registered at as NCT03020186.

Original languageEnglish
Pages (from-to)1270-1281
Number of pages12
JournalAmerican Journal of Clinical Nutrition
Issue number5
StatePublished - 1 May 2022
Externally publishedYes

Bibliographical note

Funding Information:
Supported by German Research Foundation (DFG) project number 209933838 (SFB 1052; B11) (to I Shai); Israel Ministry of Health grant 87472511 (to I Shai); Israel Ministry of Science and Technology grant 3-13604 (to I Shai); and the CaliforniaWalnut Commission (to I Shai)

Publisher Copyright:
© 2022 The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.


  • age-related atrophy
  • aging
  • dietary intervention
  • Green Mediterranean diet
  • hippocampal occupancy score
  • neurodegeneration
  • polyphenols
  • Diet, Mediterranean
  • Juglans
  • Humans
  • Middle Aged
  • Male
  • Polyphenols/pharmacology
  • Atrophy
  • Brain/diagnostic imaging
  • Tea
  • Exercise
  • Female

ASJC Scopus subject areas

  • Nutrition and Dietetics
  • Medicine (miscellaneous)


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