Glycemic Control Contributes to the Neuroprotective Effects of Mediterranean and Green-Mediterranean Diets on Brain Age; The DIRECT PLUS Brain-MRI Randomized Controlled Trial

Dafna Pachter; Alon Kaplan; Gal Tsaban; Hila Zelicha; Anat Yaskolka Meir; Ehud Rinott; Gidon Levakov; Moti Salti; Yoram Yovell; Sebastian Huhn; Frauke Beyer; Veronica Witte; Peter Kovacs; Martin von Bergen; Uta Ceglarek; Matthias Blüher; Michael Stumvoll; Frank B Hu; Meir J Stampfer; Alon Friedman; Ilan Shelef; Galia Avidan; Iris Shai

doi:10.1016/j.ajcnut.2024.09.013

Glycemic Control Contributes to the Neuroprotective Effects of Mediterranean and Green-Mediterranean Diets on Brain Age; The DIRECT PLUS Brain-MRI Randomized Controlled Trial

Am J Clin Nutr. 2024 Sep 14:S0002-9165(24)00745-7. doi: 10.1016/j.ajcnut.2024.09.013. Online ahead of print.

Authors

Dafna Pachter¹, Alon Kaplan¹, Gal Tsaban², Hila Zelicha¹, Anat Yaskolka Meir¹, Ehud Rinott¹, Gidon Levakov³, Moti Salti⁴, Yoram Yovell⁵, Sebastian Huhn⁶, Frauke Beyer⁷, Veronica Witte⁷, Peter Kovacs⁸, Martin von Bergen⁹, Uta Ceglarek¹⁰, Matthias Blüher¹¹, Michael Stumvoll¹⁰, Frank B Hu¹², Meir J Stampfer¹², Alon Friedman¹³, Ilan Shelef², Galia Avidan³, Iris Shai¹⁴

Affiliations

¹ Faculty of Health Sciences, The Health & Nutrition Innovative International Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
² Faculty of Health Sciences, The Health & Nutrition Innovative International Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Soroka University Medical Center, Beer-Sheva, Israel.
³ Department of Cognitive and Brain Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
⁴ Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
⁵ Department of Medical Neurobiology, The Hebrew University-Hadassah School of Medicine, Jerusalem, Israel.
⁶ Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.
⁷ Department of Neurology, Max-Planck-Institute for Human Cognitive and Brain Sciences, and Cognitive Neurology, University of Leipzig Medical Center, Leipzig, Germany.
⁸ Medical Department III - Endocrinology, Nephrology, Rheumatology.
⁹ Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.
¹⁰ Department of Medicine, University of Leipzig, Germany.
¹¹ Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
¹² Department of Nutrition, Harvard THChan School of Public Health, Boston, MA, USA; Department of Medicine, Harvard Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹³ Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Department of Medical Neuroscience, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
¹⁴ Faculty of Health Sciences, The Health & Nutrition Innovative International Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany; Department of Nutrition, Harvard THChan School of Public Health, Boston, MA, USA. Electronic address: irish@bgu.ac.il.

PMID: 39284453
DOI: 10.1016/j.ajcnut.2024.09.013

Abstract

Background: We recently reported that Mediterranean (MED) and green-MED diets significantly attenuated age-related brain atrophy by ∼50% within 18 months.

Objective: To explore the contribution of specific diet-induced parameters to brain volume deviation from chronological age.

Methods: A post-hoc analysis of the 18-month DIRECT-PLUS trial, where participants were randomly assigned to: (1)-healthy-dietary-guidelines (HDG); (2)-MED diet; or (3)-green-MED diet, high in polyphenols and low in red meat. Both MED groups consumed 28g walnuts/day (+440mg/day polyphenols). The green-MED group further consumed green-tea (3-4 cups/day) and Mankai green shake (Wolffia-globosa aquatic plant) (+800mg/day polyphenols). We collected blood samples through the intervention and followed brain structure volumes by magnetic-resonance-imaging (MRI). We used hippocampal-occupancy (HOC) score (hippocampal and inferior-lateral-ventricle volumes ratio) as a neurodegeneration marker and brain age proxy. We applied multivariate-linear-regression models.

Results: Of 284 participants (88% male; age=51.1years; BMI=31.2kg/m²; HbA1c=5.48%; APOE-ε4 genotype=15.7%), 224 completed the trial with eligible whole-brain MRIs. Individuals with higher HOC-deviations (i.e., younger brain age) presented lower body weight (r=-0.204;95%CI[-0.298,-0.101]), waist-circumference (r=-0.207;95%CI[-0.310,-0.103]), diastolic (r=-0.186;95%CI[-0.304,-0.072]), and systolic blood pressure (r=-0.189;95%CI[-0.308,-0.061]), insulin (r=-0.099;95%CI[-0.194,-0.004]) and HbA1c (r=-0.164;95%CI[-0.337,-0.006]) levels. After 18 months, greater changes in HOC-deviations (i.e., brain-age decline attenuation) were independently associated with improved HbA1c (β=-0.254;95%CI[-0.392,-0.117]), HOMA-IR (β=-0.200;95%CI[-0.346,-0.055]) fasting glucose (β=-0.155;95%[CI -0.293,-0.016]), and s-CRP (β=-0.153;95%[CI -0.296,-0.010]). Improvement in diabetes status was associated with greater HOC-deviation changes compared to either no change in diabetes status (0.010;95%CI]0.002,0.019[) or with an unfavorable change (0.012;95%CI]0.002,0.023]). A decline in HbA1c is further associated with greater deviation changes in the Thalamus, Caudate nucleus, and Cerebellum (p<0.05). Greater consumption of Mankai and green-tea (green-MED diet components) were associated with greater HOC-deviation changes beyond weight loss.

Conclusions: Glycemic control contributes to the neuroprotective effects of the MED and green-MED diets on brain age. Polyphenols-rich diet components as Mankai and green-tea may contribute to a more youthful brain age.

Trial-registration-clinical-trials-identifier: NCT03020186 URL OF REGISTRATION: https://clinicaltrials.gov/study/NCT03020186.

Keywords: aging; brain age; dietary intervention; glycemic control; green-Mediterranean; hippocampal occupancy score; polyphenols.

Associated data

ClinicalTrials.gov/NCT03020186