Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults

Abstract

Dietary habits such as caloric restriction or nutrients that mimic these effects may exert beneficial effects on brain aging. The plant-derived polyphenol resveratrol has been shown to increase memory performance in primates; however, interventional studies in older humans are lacking. Here, we tested whether supplementation of resveratrol would enhance memory performance in older adults and addressed potential mechanisms underlying this effect. Twenty-three healthy overweight older individuals that successfully completed 26 weeks of resveratrol intake (200 mg/d) were pairwise matched to 23 participants that received placebo (total n = 46, 18 females, 50-75 years). Before and after the intervention/control period, subjects underwent memory tasks and neuroimaging to assess volume, microstructure, and functional connectivity (FC) of the hippocampus, a key region implicated in memory functions. In addition, anthropometry, glucose and lipid metabolism, inflammation, neurotrophic factors, and vascular parameters were assayed. We observed a significant effect of resveratrol on retention of words over 30 min compared with placebo (p = 0.038). In addition, resveratrol led to significant increases in hippocampal FC, decreases in glycated hemoglobin (HbA1c) and body fat, and increases in leptin compared with placebo (all p < 0.05). Increases in FC between the left posterior hippocampus and the medial prefrontal cortex correlated with increases in retention scores and with decreases in HbA1c (all p < 0.05). This study provides initial evidence that supplementary resveratrol improves memory performance in association with improved glucose metabolism and increased hippocampal FC in older adults. Our findings offer the basis for novel strategies to maintain brain health during aging.

Keywords: Aging; CR-mimetic; HbA1c; microstructure; resting-state fMRI.

Figure 1.

Flowchart of the study. Twenty-three healthy overweight older adults successfully completed 26 weeks of resveratrol intake (200 mg/d) and were pairwise matched to 23 control subjects receiving placebo supplementation. Before and after the intervention/control period, subjects were tested for memory performance and underwent 3T MRI neuroimaging to evaluate resting-state FC, volume, and microstructure of the hippocampus. In addition, fasting blood samples were taken to assess markers of glucose metabolism, lipid profile, inflammatory parameters, and neurotrophic factors.

Figure 2.

Memory retention performance dependent on group. Note the significant increase in performance after 26 weeks of resveratrol (triangles, black, n = 23) compared with placebo (circles, gray, n = 23; p = 0.038). Memory retention was defined as the number of correct words immediately recalled after the fifth learning trial of the auditory verbal learning task subtracted from those correctly recalled after the 30 min delay. Raw scores were standardized into z-scores and multiplied by −1 to create positive relations. Triangles/circles indicate mean retention z-scores dependent on group and time point; error bars indicate SE. *p < 0.05 according to paired t test of differences between baseline and follow-up in memory scores between the resveratrol and placebo group-matched pairs.

Figure 3.

Increases in resting-state FC of the HC_ant and HC_post after 26 weeks of supplementary resveratrol (n = 23) versus placebo (n = 23). FC was measured using individual masks of the left and right anterior (orange) and posterior part (blue) of the hippocampus as seeds. A, Probabilities of included voxels in any of the subjects' HC_ant and HC_post masks coregistered to a study-specific template, with bright orange/blue showing high probability and dark orange/blue showing low probability. Note the significant increases in FC between the left HC_ant and the anterior cingulate cortex (AC) and precuneus (Prec) shown in B. C, Significant increases in FC between the left HC_post and the medial prefrontal cortex (mPFC), left lateral angular cortex (lAng), and precunues (Prec). Selective increases in FC between the right HC_post and the right lateral occitipital cortex (lOcc) are visualized in D. B–D, Colors indicate t-values of significant voxels (cluster-based thresholding, p < 0.05) superimposed on a study-specific template. Images are displayed in neurological convention, coordinates in mm according to MNI space. R, Right; L, left.

Figure 4.

Intervention-induced changes in FC correlate with changes in retention of words over a 30 min delay in subjects of the resveratrol group (n = 23). Memory retention was defined as the number of correct words immediately recalled after the fifth learning trial of the auditory verbal learning task subtracted from those correctly recalled after the 30 min delay. Raw scores were standardized into z-scores and multiplied by −1 to create positive relations. Triangles show median changes in FC within a significant cluster in the left medial prefrontal cortex (mPFC, outlined in red, see inset; for details, see Fig. 3) using the left posterior hippocampus as seed in relation to changes in retention scores. Spearman's correlation, r = 0.4, p = 0.04, line gives regression fit.

Figure 5.

Changes in glycated HbA1c and leptin. A, Note the significant decrease in fasting HbA1c after resveratrol (black bar, n = 21) compared with placebo (gray bar, n = 21; p = 0.014). B, Leptin concentrations significantly increased after resveratrol (black striped bar, n = 23) and decreased after placebo (gray striped bar; n = 23). C, In the resveratrol group, decreases in HbA1c correlated significantly with increases in FC (n = 21; r = 0.4, p = 0.04). Triangles show median changes in FC within a significant cluster in the left medial prefrontal cortex (outlined in red, see inset; for details, see Fig. 3) using the left posterior hippocampus as seed in relation to changes in HbA1c. Line indicates regression fit. *p < 0.05, paired t test.