Urolithins, microbiota-derived metabolites of ellagitannins, phenolic compounds abundant in walnuts, possess anti-inflammatory and antioxidant properties that might mitigate neuronal damage. However, clinical data supporting their effects on cognition are limited. In participants in the Walnuts and Healthy Aging (WAHA) trial, we determined urinary urolithin concentrations and examined their association with cognitive performance. The WAHA study was a parallel-group, 2-center (Barcelona, Spain; Loma Linda, California), randomized controlled trial. Cognitively healthy individuals followed a 2-year walnut-rich diet (15% daily energy) or a control diet excluding walnuts. Baseline and 2-year determinations included urinary urolithins by liquid chromatography-mass spectrometry and a comprehensive neuropsychological battery. The primary outcome was the association between changes in a global cognition composite score and urinary urolithins as the exposure, assessed by multivariable-adjusted regression. Secondary outcomes included associations of urolithins with domain-specific changes in memory, language, perception, and frontal function. A total of 612 participants (66% women, mean age 69 y) were included in analyses. Urolithin A, urolithin C and their glucuronide forms were objective biomarkers of walnut consumption (area under the curve at receiver operator characteristic analysis, 0.83; 95% CI, 0.80-0.86, 0.78; 95% CI, 0.74-0.82, 0.81; 95% CI, 0.77-0.84, and 0.80; 95% CI, 0.76-0.83, respectively). In the WAHA cohort following the walnut diet, changes in urolithin A glucuronide (β = 0.014 [95% CI, 0.003-0.025] per 1-SD) and urolithin C (β = 0.017 [95% CI, 0.001-0.033] per 1-SD) were associated with concurrent changes of the global cognition score. Urinary urolithins, particularly UroA, UroC and their glucuronides, are reliable biomarkers of walnut consumption. Changes in urolithin levels after 2 years of daily walnut consumption disclosed a direct association with cognitive performance in cognitively healthy older individuals. These findings provide clinical evidence linking dietary (poly)phenols and cognitive health.

The protective role of (poly)phenols against metabolic disorders has been extensively studied in adults but not in adolescents. To assess associations of dietary (poly)phenols and their subclasses with cardiometabolic health parameters in adolescents. A cross-sectional study was conducted in 944 individuals aged 11–14 years enrolled in the SI! Program for Secondary Schools trial (NCT03504059). (Poly)phenol intake was assessed using semi-quantitative food frequency questionnaires and the Phenol-Explorer database. The measured cardiometabolic parameters were waist circumference (WC) age-sex Z-score, blood pressure (BP) age-sex Z-score, blood glucose (BG), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-c). Multilevel mixed-effect linear regression models were applied to examine the association between (poly)phenol quintiles and cardiometabolic health parameters. Compared to the lowest quintile, adolescents in the highest quintile of total (poly)phenol intake had lower WC Z-scores, mean arterial pressure Z-scores, and HDL-c after multivariable adjustment. The WC Z-scores and HDL-c were lower in the highest quintile of flavonoid intake compared to the lowest quintile. The highest quintile of phenolic acid intake was associated with a lower WC Z-score and TG levels, and the highest quintile of stilbene intake with lower BG and TG, and with higher HDL-c compared to the lowest quintile. A higher intake of (poly)phenols, especially flavonoids, phenolic acids, and stilbenes, was associated with better cardiometabolic parameters in adolescents.

With increasing life expectancy, neurodegenerative diseases have become one of the leading causes of ill-health in the elderly. Preventive strategies include following healthy diets, such as the Mediterranean diet, which is particularly rich in polyphenols, bioactive compounds with neuroprotective properties. The aim of this study was to assess the association of microbial phenolic metabolites (MPM) with cognition. This cross-sectional analysis was performed with 200 participants of the PREDIMED trial (Barcelona-Clinic recruitment center). A novel method based on liquid chromatography coupled to mass spectrometry was used to identify urinary MPM (protocatechuic acid, enterodiol glucuronide, enterolactone glucuronide, urolithin B glucuronide, and vanillic acid glucuronide), and cognitive function was evaluated with neuropsychological tests. Multivariable-adjusted ordinary least squares regression was used to assess the associations between cognitive function and MPM, and a score was calculated as the weighted sum of MPM. A higher MPM score was associated with better frontal lobe function. Among individual metabolites, vanillic acid glucuronide was correlated with frontal cognitive performance. Participants with higher concentrations of vanillic acid glucuronide and urolithin B glucuronide obtained better scores in the Color Trail Test part 2. A higher score for urinary multi-MPM was associated with better frontal cognitive performance in an older Mediterranean population.