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Background Emerging evidence highlights that diet dynamically shapes the gut microbiome, which in turn influences cognitive function through bidirectional gut-brain communication, offering a promising target for mitigating cognitive decline and neurodegenerative disorders. While the Mediterranean diet (MedDiet) is a well-established dietary pattern with demonstrated neuroprotective benefits, the interplay between MedDiet adherence, gut microbiota, and longitudinal cognitive trajectories remains poorly understood. We aimed to identify a gut microbial signature of the MedDiet adherence and prospectively examine the associations of MedDiet adherence and MedDiet gut microbial signature (MedDiet-GMS) with cognitive changes over time in older adults at high risk of cognitive decline. Methods This study included 746 participants (mean age 65 ± 5 years, 48% women) with overweight/obesity and metabolic syndrome. Adherence to the MedDiet was assessed using a validated 14-item Mediterranean Diet Adherence Screener (MEDAS). Baseline gut microbiota composition was profiled via 16S rRNA sequencing. Cognitive function was evaluated at baseline, 2, 4, and 6 years using a comprehensive neuropsychological battery. Elastic net regressions were applied to derive a MedDiet-GMS, and linear mixed models were used to assess associations of both MEDAS and MedDiet-GMS with trajectories of cognitive function, adjusting for potential confounders. Results Higher adherence to the MedDiet was associated with greater gut microbial diversity ( p  < 0.05) and distinct microbial composition (PERMANOVA, p  = 0.001). The MedDiet-GMS comprised 20 taxa, including short-chain fatty acid-producers (e.g., Barnesiella , Butyricicoccus ) positively weighted and pro-inflammatory taxa (e.g., Eggerthella ) negatively weighted. Both higher MEDAS scores ( p  = 0.007) and MedDiet-GMS ( p  = 0.036) were independently associated with slower global cognitive decline. The MedDiet-GMS was additionally linked to preserved executive function ( p  = 0.049), while MEDAS was associated with attenuated general cognitive decline ( p  = 0.028). Eggerthella , inversely associated with MedDiet adherence, was linked to greater executive function decline (FDR < 0.05). Conclusions Greater adherence to the MedDiet was associated with a favorable gut microbiota profile and slower cognitive decline over 6-year of follow-up. A microbiome-derived signature of MedDiet adherence was prospectively associated with favorable cognitive trajectories in older adults at risk of cognitive decline. External validation and experimental research are warranted to translate these findings into targeted microbiome-based dietary interventions for healthy cognitive aging.

Impulsivity is an important determinant of human behaviour, affecting self-control, reasonable thinking and food choices. Recent evidence suggests a role for gut microbiota in human behaviour, but the relationship between gut microbiota and impulsive behaviours remains largely unexplored. To address this knowledge gap, the present study aims to explore the associations between faecal microbiota composition with trait and behavioural impulsivity, in a subcohort of the PREDIMED-Plus trial, including older adults presenting overweight/obesity. Fecal samples ( n  = 231) were profiled for their microbiota composition using 16 S rRNA amplicon sequencing and impulsivity was determined through four different assessments. Adherence to different dietary patterns was estimated through questionnaires. Beta diversity analyses showed a significant association with the Conner’s Performance Test (CPT) in multivariate-adjusted models, and, in total, 13 bacterial genera associated with CPT. Erysipelotrichaceae UCG 003 showed the highest association with CPT and known butyrate producers such as Butyricicoccus spp., Roseburia spp., and Eubacterium hallii were among the identified bacteria. The bacteria Lachnospiraceae UCG 001, Anaerostipes and Blautia were associated with CPT and also the adherence to healthy and unhealthy plant-based diets. In addition, functional analysis showed a significant negative association between the CPT and the glucuronate and galacturonate metabolic pathways. From the other impulsivity assessments, two more associations were identified, for the genus Phascolarctobacterium with the Stroop test, and the genus Lachnospiraceae GAG 54 with the positive urgency subscore of UPPS-P Impulsive Behaviour Scale. Overall, our findings suggest potential links between the faecal microbiota composition and function with behavioural impulsive inattention as determined by the CPT.

There is growing interest in relating taste perception to diet and healthy aging. However, there is still limited information on the influence of age, sex and genetics on taste acuity as well as on the relationship between taste perception and taste preferences. We have analysed the influence of age on the intensity rating of the five basic tastes: sweet, salty, bitter, sour and umami (separately and jointly in a “total taste score”) and their modulation by sex and genetics in a relatively healthy population (men and women) aged 18–80 years (n = 1020 Caucasian European participants). Taste perception was determined by challenging subjects with solutions of the five basic tastes using standard prototypical tastants (6-n-propylthiouracil (PROP), NaCl, sucrose, monopotassium glutamate and citric acid) at 5 increasing concentrations (I to V). We also measured taste preferences and determined the polymorphisms of the genes taste 2 receptor member 38 (TAS2R38), taste 1 receptor member 2 (TAS2R38) and sodium channel epithelial 1 beta subunit (SCNN1B), as TAS2R38-rs713598, TAS1R2-rs35874116 and SCNN1B-rs239345 respectively. We found a statistically significant decrease in taste perception (“total taste score”) with increasing age for all the concentrations analysed. This association was stronger for the higher concentrations (p = 0.028; p = 0.012; p = 0.005; p = 4.20 × 10−5 and p = 1.48 × 10−7, for I to V in the multivariable-adjusted models). When we analysed taste qualities (using concentration V), the intensity rating of all the 5 tastes was diminished with age (p < 0.05 for all). This inverse association differed depending on the test quality, being higher for bitter (PROP) and sour. Women perceived taste significantly more intense than men (p = 1.4 × 10−8 for total taste score). However, there were differences depending on the taste, umami being the lowest (p = 0.069). There was a complex association between the ability to perceive a taste and the preference for the same. Significant associations were, nevertheless, found between a higher perception of sour taste and a higher preference for it in women. In contrast, the higher perception of sweet was significantly associated with a higher preference for bitter in both, men and women. The TAS2R38-rs713598 was strongly associated with bitter (PROP) taste (p = 1.38 × 10−50), having a significant interaction with sex (p = 0.030). The TAS1R2-rs35874116 was not significantly associated with sweet, whereas the SCNN1B-rs239345 was associated (p = 0.040) with salty taste. In conclusion, the inverse association between age and perceived taste intensity as well as the additional influence of sex and some genetic polymorphisms give rise to large inter-individual differences in taste perception and taste preferences that should be taken into account in future studies and for applications in precision nutrition for healthy aging.

Background Metabolic syndrome (MetS) is a multimorbid long-term condition without consensual medical definition and a diagnostic based on compatible symptomatology. Here we have investigated the molecular signature of MetS in urine. Methods We used NMR-based metabolomics to investigate a European cohort including urine samples from 11,754 individuals (18–75 years old, 41% females), designed to populate all the intermediate conditions in MetS, from subjects without any risk factor up to individuals with developed MetS (4–5%, depending on the definition). A set of quantified metabolites were integrated from the urine spectra to obtain metabolic models (one for each definition), to discriminate between individuals with MetS. Results MetS progression produces a continuous and monotonic variation of the urine metabolome, characterized by up- or down-regulation of the pertinent metabolites (17 in total, including glucose, lipids, aromatic amino acids, salicyluric acid, maltitol, trimethylamine N -oxide, and p -cresol sulfate) with some of the metabolites associated to MetS for the first time. This metabolic signature, based solely on information extracted from the urine spectrum, adds a molecular dimension to MetS definition and it was used to generate models that can identify subjects with MetS (AUROC values between 0.83 and 0.87). This signature is particularly suitable to add meaning to the conditions that are in the interface between healthy subjects and MetS patients. Aging and non-alcoholic fatty liver disease are also risk factors that may enhance MetS probability, but they do not directly interfere with the metabolic discrimination of the syndrome. Conclusions Urine metabolomics, studied by NMR spectroscopy, unravelled a set of metabolites that concomitantly evolve with MetS progression, that were used to derive and validate a molecular definition of MetS and to discriminate the conditions that are in the interface between healthy individuals and the metabolic syndrome.

DNA-methylation has been associated with biological age and several epigenetic clocks have been reported (Hovarth) MicroRNA (miRNA) are short single-stranded RNA molecules implicated in the regulation of gene expression. As well as protein-coding genes, miRNA-coding genes may be targets for DNA methylation. However, the role of this methylation on aging and cardiovascular risk is still poorly studied. Our aim is to analyze the DNA methylation in miRNA-coding genes in a high-cardiovascular risk Mediterranean population, and its association with age considering sex-specific differences. A DNA-methylation analysis of miRNA genes was analyzed using the EPIC850K array, in high-cardiovascular risk 414 subjects aged 55-75y. We obtained Beta and M-values for CpGs located in the miRNA genes and their association with age in multivariate models adjusted for confounders (sex, leukocytes, batch-effect, diabetes, BMI). Sex-specific analyses were conducted. In the whole population, significant associations between miRNA-gene methylation and chronological age were obtained. Outstanding the MIR34B (cg26561785; p=3,9 × 10-8; hypermethylation associated with higher age; r=0.28). Previous studies have linked miR-34a to vascular aging and arteriosclerosis. The following most significant associations (p=4,7 × 10-7-1,5 × 10-6) were obtained with CpG in MIR663(r=0.26), MIR9-3(r=0.26), MIR495(r=-0.26) and MIR203A(r=0.25), as main components of the methylation signature in the whole population. Sex-specific analysis detected sex-specific differences. The top-ranked CpGs in men were MIR34B (cg26561785;p=9.2 × 10-6) and MIR9-3 (cg12530503;p=1.8 × 10-05); whereas in women were MIR376B (cg05348084;p=4.3 × 10-7) and MIR203A (cg24454784;p=3.9 × 10-06). Altered methylation in MIR genes is associated with chronological age, and this association may be different between men and women with high-cardiovascular risk.

There is considerable interest in the connection between alcohol-induced oxidative stress, DNA methylation, antioxidants, and accelerated aging across diverse populations. Nevertheless, self-reported alcohol consumption is prone to bias, and objective biomarkers of alcohol intake are needed. Our aims were to investigate the performance of an epigenomic biomarker of alcohol consumption in a Mediterranean population using self-reported data and the biomarker gamma-glutamyl transferase (GGT); to examine the effects of alcohol (self-reported and biomarker-assessed) on epigenome-wide methylation; to analyze the association between alcohol (self-reported and biomarker-assessed) and telomere length and other aging biomarkers; and to explore the modulating effect of the Mediterranean diet (MedDiet). We performed blood epigenome-wide methylation studies (EWAS) in a Mediterranean cohort (aged 55–75 years). Self-reported alcohol consumption and MedDiet were assessed by questionnaires. A replication cohort (cohort 2) from the same area was also analyzed. For both cohorts, the DNA methylation-based biomarker (450-CpGs) was computed alongside epigenetic clocks for the following biological age acceleration metrics: DNAm telomere length, GrimAgeAcceleration, PhenoAgeAcceleration, and CausalityAgeYing (cohort 1). The association between the epigenomic biomarker and self-reported alcohol consumption was significant (p < 0.001) in both cohorts, but modest. However, the association was stronger when predicting high alcohol intake (AUC: 0.76; 95%CI: 0.65–0.86; p < 0.0001). In the EWAS, the hit (cg06690548-SLC7A11, in a cystine transporter that enhances glutathione production for antioxidant defense) was shared among the self-reported alcohol consumption, GGT, and the epigenomic biomarker, with alcohol linked to hypomethylation. We detected differential methylation in pre-selected oxidative stress-related genes. Enrichment analysis revealed “Rap1 signaling pathway” as the hit (p < 0.00001). High self-reported alcohol consumption and the epigenomic biomarker were associated with shorter telomere length (p < 0.05) in cohort 1. Additionally, a modulation by Mediterranean diet adherence was hypothesized. No significant associations were found between self-reported alcohol intake and the other aging biomarkers; however, the epigenomic score was directly associated with GrimAge, PhenoAge and CausAgeYing biomarkers in cohort 1 (p < 0.001), and two were replicated in cohort 2. In conclusion, alcohol intake has an impact on DNA methylation at the epigenome-wide level in this Mediterranean population, replicating the main hits from other populations and validating the epigenomic biomarker for intake, although improvement is needed. Moreover, several associations with aging biomarkers were observed.

Background Fat mass and obesity (FTO) and melanocortin-4 receptor (MC4R) and are relevant genes associated with obesity. This could be through food intake, but results are contradictory. Modulation by diet or other lifestyle factors is also not well understood. Objective To investigate whether MC4R and FTO associations with body-weight are modulated by diet and physical activity (PA), and to study their association with alcohol and food intake. Methods Adherence to Mediterranean diet (AdMedDiet) and physical activity (PA) were assessed by validated questionnaires in 7,052 high cardiovascular risk subjects. MC4R rs17782313 and FTO rs9939609 were determined. Independent and joint associations (aggregate genetic score) as well as statistical and biological gene-lifestyle interactions were analyzed. Results FTO rs9939609 was associated with higher body mass index (BMI), waist circumference (WC) and obesity (P<0.05 for all). A similar, but not significant trend was found for MC4R rs17782313. Their additive effects (aggregate score) were significant and we observed a 7% per-allele increase of being obese (OR = 1.07; 95%CI 1.01-1.13). We found relevant statistical interactions (P<0.05) with PA. So, in active individuals, the associations with higher BMI, WC or obesity were not detected. A biological (non-statistical) interaction between AdMedDiet and rs9939609 and the aggregate score was found. Greater AdMedDiet in individuals carrying 4 or 3-risk alleles counterbalanced their genetic predisposition, exhibiting similar BMI (P = 0.502) than individuals with no risk alleles and lower AdMedDiet. They also had lower BMI (P = 0.021) than their counterparts with low AdMedDiet. We did not find any consistent association with energy or macronutrients, but found a novel association between these polymorphisms and lower alcohol consumption in variant-allele carriers (B+/−SE: −0.57+/−0.16 g/d per-score-allele; P = 0.001). Conclusion Statistical and biological interactions with PA and diet modulate the effects of FTO and MC4R polymorphisms on obesity. The novel association with alcohol consumption seems independent of their effects on BMI.

There is adherence to a healthy Mediterranean diet (MedDiet), but adherence varies widely. Precision nutrition is increasingly interested in individual characteristics influencing diet adherence, but few studies have examined personality traits. Our main aim was to investigate the association between personality traits and MedDiet adherence. Our secondary aims were to explore genome-wide genetic variants associated with neuroticism, including replication of previous findings, as well as to explore gene-MedDiet interactions. We analyzed participants (aged 55-75) in the PREDIMED-Plus-Valencia study and measured clinical, lifestyle, and genetic factors. The Eysenck Personality Questionnaire-Revised (EPQ-R) was used to measure neuroticism, psychoticism, and extraversion. Genotyping was undertaken, and associations with candidate SNPs, genome-wide association studies (GWAS), genetic risk scores (GRS), and gene-MedDiet interactions were explored. Neuroticism was inversely (beta = -0.09; = 0.001) associated with adherence to the Mediterranean diet (MEDAS-17). Likewise, the probability of low MedDiet adherence increased neuroticism (OR: 1.27; 95% CI: 1.02-1.60; = 0.031 per SD). In the GWAS for this trait, several SNPs surpassed the suggestive level of statistical significance. The most strongly associated was rs10181407- (NADH dehydrogenase 1 alpha subcomplex subunit 10) (beta = -2.39; = 2.70 × 10 ). The GRS for neuroticism was significantly associated with MedDiet adherence (beta = -0.18; = 0.020), increasing the causality level. We replicated some candidate SNPs, and among them, the rs2243873- (euchromatic histone lysine methyltransferase 2) gene. The analysis of gene-MedDiet interactions revealed the role of these dietary modulations. Neuroticism was the personality trait most inversely associated with MedDiet adherence, suggesting its integration in precision nutrition analysis. Moreover, neuroticism-related genetics and MedDiet modulations will also be important.

The gut microbiota plays a potential role in the pathophysiology of depression through the gut–brain axis. This cross-sectional study in 400 participants from the PREDIMED-Plus study investigates the interplay between gut microbiota and depression using a multi-omics approach. Depression was defined as antidepressant use or high Beck Depression Inventory-II scores. Gut microbiota was characterized by 16S rRNA sequencing, and faecal metabolites were analysed via liquid chromatography-tandem mass spectrometry. Participants with depression exhibited significant differences in gut microbial composition and metabolic profiles. Differentially abundant taxa included Acidaminococcus, Christensenellaceae R-7 group , and Megasphaera , among others. Metabolomic analysis revealed 15 significantly altered metabolites, primarily lipids, organic acids, and benzenoids, some of which correlated with gut microbial features. This study highlights the interplay between the gut microbiota and depression, paving the way for future research to determine whether gut microbiota influences depression pathophysiology or reflects changes associated with depression.

Background Over the past decade, emerging evidence has shed light on the role of the gut microbiota in the interface between diet and brain health. Olive oil, particularly virgin olive oil, a key component and major fat source in the Mediterranean diet, has exhibited widespread healthful benefits, including improvements in gut microbiota and cognitive health. Despite insights from preclinical studies into the relationship between virgin olive oil consumption, gut microbiota, and cognitive function, human research in this area remains limited. Therefore, our study aims to investigate the interplay between total olive oil consumption and its subtypes, gut microbiota, and changes in cognitive function in older adults who were cognitively healthy at baseline but at high risk of cognitive decline. Methods In this prospective cohort study, we assessed a total of 656 participants aged 55 to 75y (mean age 65.0 ± 4.9y, 47.9% women) with overweight/obesity and metabolic syndrome who provided stool samples and completed a validated semi-quantitative food frequency questionnaire at baseline and a comprehensive battery of neuropsychological tests at baseline and at a 2-y follow-up. Results Results from the multivariable linear regression models showed that higher consumption of virgin olive oil was associated with improved cognitive function over a 2-y follow-up, and a more diverse gut microbiota overall structure at baseline. Conversely, increased consumption of common olive oil is linked to lower alpha diversity of the microbial communities, and accelerated cognitive decline. Mediation analysis suggests that gut microbiota and particularly the Adlercreutzia , may serve as a mediator taxon in the association between virgin olive oil consumption and positive changes in general cognitive function. Conclusions Higher consumption of virgin olive oil was associated with cognitive preservation, possibly mediated by favorable alterations in gut microbiota composition. Our study provides novel insights into the complex interplay between different types of olive oil consumption, gut microbiota, and changes in cognitive function. These findings underscore the potential of microbiota-targeted dietary strategies to promote cognitive health in aging populations, though further high-quality and clinical cohort studies are required. DPFhB-m7M3fFKDUWwEQESz Video Abstract