Plasma metabolite profile of legume consumption and future risk of type 2 diabetes and cardiovascular disease.

BACKGROUND: Legume consumption has been linked to a reduced risk of type 2 diabetes (T2D) and cardiovascular disease (CVD), while the potential association between plasma metabolites associated with legume consumption and the risk of cardiometabolic diseases has never been explored. Therefore, we aimed to identify a metabolite signature of legume consumption, and subsequently investigate its potential association with the incidence of T2D and CVD. METHODS: The current cross-sectional and longitudinal analysis was conducted in 1833 PREDIMED study participants (mean age 67 years, 57.6% women) with available baseline metabolomic data. A subset of these participants with 1-year follow-up metabolomics data (n = 1522) was used for internal validation. Plasma metabolites were assessed through liquid chromatography-tandem mass spectrometry. Cross-sectional associations between 382 different known metabolites and legume consumption were performed using elastic net regression. Associations between the identified metabolite profile and incident T2D and CVD were estimated using multivariable Cox regression models. RESULTS: Specific metabolic signatures of legume consumption were identified, these included amino acids, cortisol, and various classes of lipid metabolites including diacylglycerols, triacylglycerols, plasmalogens, sphingomyelins and other metabolites. Among these identified metabolites, 22 were negatively and 18 were positively associated with legume consumption. After adjustment for recognized risk factors and legume consumption, the identified legume metabolite profile was inversely associated with T2D incidence (hazard ratio (HR) per 1 SD: 0.75, 95% CI 0.61-0.94; p = 0.017), but not with CVD incidence risk (1.01, 95% CI 0.86-1.19; p = 0.817) over the follow-up period. CONCLUSIONS: This study identified a set of 40 metabolites associated with legume consumption and with a reduced risk of T2D development in a Mediterranean population at high risk of cardiovascular disease. TRIAL REGISTRATION: ISRCTN35739639.

Association of adiposity and its changes over time with COVID-19 risk in older adults with overweight/obesity and metabolic syndrome: a longitudinal evaluation in the PREDIMED-Plus cohort.

BACKGROUND: Cross-sectionally, older age and obesity are associated with increased coronavirus disease-2019 (COVID-19) risk. We assessed the longitudinal associations of baseline and changes in adiposity parameters with COVID-19 incidence in older adults at high cardiovascular risk. METHODS: This analysis included 6874 men and women (aged 55-75 years) with overweight/obesity and metabolic syndrome in the PREDIMED-Plus lifestyle intervention trial for cardiovascular risk reduction. Body weight, body-mass-index (BMI), waist circumference, waist-to-height ratio (WHtR), and a body shape index (ABSI) were measured at baseline and annual follow-up visits. COVID-19 was ascertained by an independent Event Committee until 31 December 2021. Cox regression models were fitted to evaluate the risk of COVID-19 incidence based on baseline adiposity parameters measured 5-6 years before the pandemic and their changes at the visit prior to censoring. RESULTS: At the time of censoring, 653 incident COVID-19 cases occurred. Higher baseline body weight, BMI, waist circumference, and WHtR were associated with increased COVID-19 risk. During the follow-up, every unit increase in body weight (HRadj (95%CI): 1.01 (1.00, 1.03)) and BMI (HRadj: 1.04 (1.003, 1.08)) was associated with increased COVID-19 risk. CONCLUSIONS: In older adults with overweight/obesity, clinically significant weight loss may protect against COVID-19. TRIAL REGISTRATION: This study is registered at the International Standard Randomized Controlled Trial (ISRCT; http://www.isrctn.com/ISRCTN89898870 ).

Plasma metabolite profiles associated with the World Cancer Research Fund/American Institute for Cancer Research lifestyle score and future risk of cardiovascular disease and type 2 diabetes.

BACKGROUND: A healthy lifestyle (HL) has been inversely related to type 2 diabetes (T2D) and cardiovascular disease (CVD). However, few studies have identified a metabolite profile associated with HL. The present study aims to identify a metabolite profile of a HL score and assess its association with the incidence of T2D and CVD in individuals at high cardiovascular risk. METHODS: In a subset of 1833 participants (age 55-80y) of the PREDIMED study, we estimated adherence to a HL using a composite score based on the 2018 Word Cancer Research Fund/American Institute for Cancer Research recommendations. Plasma metabolites were analyzed using LC-MS/MS methods at baseline (discovery sample) and 1-year of follow-up (validation sample). Cross-sectional associations between 385 known metabolites and the HL score were assessed using elastic net regression. A 10-cross-validation procedure was used, and correlation coefficients or AUC were assessed between the identified metabolite profiles and the self-reported HL score. We estimated the associations between the identified metabolite profiles and T2D and CVD using multivariable Cox regression models. RESULTS: The metabolite profiles that identified HL as a dichotomous or continuous variable included 24 and 58 metabolites, respectively. These are amino acids or derivatives, lipids, and energy intermediates or xenobiotic compounds. After adjustment for potential confounders, baseline metabolite profiles were associated with a lower risk of T2D (hazard ratio [HR] and 95% confidence interval (CI): 0.54, 0.38-0.77 for dichotomous HL, and 0.22, 0.11-0.43 for continuous HL). Similar results were observed with CVD (HR, 95% CI: 0.59, 0.42-0.83 for dichotomous HF and HR, 95%CI: 0.58, 0.31-1.07 for continuous HL). The reduction in the risk of T2D and CVD was maintained or attenuated, respectively, for the 1-year metabolomic profile. CONCLUSIONS: In an elderly population at high risk of CVD, a set of metabolites was selected as potential metabolites associated with the HL pattern predicting the risk of T2D and, to a lesser extent, CVD. These results support previous findings that some of these metabolites are inversely associated with the risk of T2D and CVD. TRIAL REGISTRATION: The PREDIMED trial was registered at ISRCTN ( http://www.isrctn.com/ , ISRCTN35739639).

Olive oil consumption, plasma metabolites, and risk of type 2 diabetes and cardiovascular disease.

BACKGROUND: Olive oil consumption has been inversely associated with the risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, the impact of olive oil consumption on plasma metabolites remains poorly understood. This study aims to identify plasma metabolites related to total and specific types of olive oil consumption, and to assess the prospective associations of the identified multi-metabolite profiles with the risk of T2D and CVD. METHODS: The discovery population included 1837 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) trial with available metabolomics data at baseline. Olive oil consumption was determined through food-frequency questionnaires (FFQ) and adjusted for total energy. A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation sample. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known candidate metabolites and olive oil consumption were assessed using elastic net regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite-weighted models and FFQ-derived olive oil consumption in each pair of training-validation data sets within the discovery sample. We further estimated the prospective associations of the identified plasma multi-metabolite profile with incident T2D and CVD using multivariable Cox regression models. RESULTS: We identified a metabolomic signature for the consumption of total olive oil (with 74 metabolites), VOO (with 78 metabolites), and COO (with 17 metabolites), including several lipids, acylcarnitines, and amino acids. 10-CV Pearson correlation coefficients between total olive oil consumption derived from FFQs and the multi-metabolite profile were 0.40 (95% CI 0.37, 0.44) and 0.27 (95% CI 0.22, 0.31) for the discovery and validation sample, respectively. We identified several overlapping and distinct metabolites according to the type of olive oil consumed. The baseline metabolite profiles of total and extra virgin olive oil were inversely associated with CVD incidence (HR per 1SD: 0.79; 95% CI 0.67, 0.92 for total olive oil and 0.70; 0.59, 0.83 for extra virgin olive oil) after adjustment for confounders. However, no significant associations were observed between these metabolite profiles and T2D incidence. CONCLUSIONS: This study reveals a panel of plasma metabolites linked to the consumption of total and specific types of olive oil. The metabolite profiles of total olive oil consumption and extra virgin olive oil were associated with a decreased risk of incident CVD in a high cardiovascular-risk Mediterranean population, though no associations were observed with T2D incidence. TRIAL REGISTRATION: The PREDIMED trial was registered at ISRCTN ( http://www.isrctn.com/ , ISRCTN35739639).

Nut consumption is associated with a shift of the NMR lipoprotein subfraction profile to a less atherogenic pattern among older individuals at high CVD risk.

BACKGROUND: Scientific evidence has accumulated on the beneficial effects of nut consumption on cardiovascular risk and cholesterol reduction, but few studies have examined the effects of nuts on advanced measures of lipoprotein atherogenicity determined by nuclear magnetic resonance (NMR) spectroscopy. We analyzed associations between the amount and type of of nuts consumed and advanced measures of lipoprotein atherogenity and insulin resistance in older individuals at high cardiovascular risk. METHODS: The present observational study was carried out within the framework of the Prevención con Dieta Mediterránea (PREDIMED) trial. Cross-sectional and longitudinal analyses after 1-year of follow-up were conducted in 196 men and women recruited in the PREDIMED-Reus (Spain) center. Dietary intake was assessed using a validated semi-quantitative food questionnaire. Baseline and 1-year fasting plasma lipoprotein and metabolite profiling were performed in plasma using NMR spectra Vantera® Clinical Analyzer. Associations by tertiles of nut consumption between baseline and 1-year changes and advanced measures of lipoprotein atherogenicity, branched chain amminoacids, and measures of insulin resistance were tested by multivariable-adjusted ANCOVA models. RESULTS: Compared to paticipants in the bottom tertile, those in the top tertile of total nut consumption showed higher levels of large HDL particles and HDL-cholesterol, lower levels of branched-chain amino acids (BCAA) and GlycA, and reduced lipoprotein insulin resistance and diabetes risk index. Participants in the top tertile of walnut consumption disclosed lower levels of very large VLDL, total LDL particles, LDL-cholesterol, and GlycA. Participants in the top tertile of non-walnut nut consumption displayed higher levels of total HDL particles, HDL-cholesterol and apoliporotein A1, lower BCAA and GlycA, and reduced lipoprotein insulin resistance. Participants in the top tertile of 1-year changes in walnut consumption showed increases in medium-sized HDL particles in comparison to the bottom tertile. CONCLUSIONS: In older individuals at high cardiovascular risk, increasing nut consumption was associated with a shift of the NMR lipoprotein subfraction profile to a less atherogenic pattern, as well as lower circulating concentrations of BCAA and decreased insulin resistance. These results provide novel mechanistic insight into the cardiovascular benefit of nut consumption. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003.

Inflammatory potential of diet and bone mineral density in a senior Mediterranean population: a cross-sectional analysis of PREDIMED-Plus study.

PURPOSE: Inflammation could play a key role in tissue damage and bone metabolism. The modified dietary inflammatory score (M-DIS) is a validated tool to estimate the inflammatory potential of the diet. In the present study, we evaluate the associations between the M-DIS and bone mineral density (BMD) in a senior Mediterranean population with overweight/obesity and metabolic syndrome. METHODS: Baseline cross-sectional association between the M-DIS and bone mineral density was assessed in 1134 participants of the multicenter PREDIMED-Plus trial (aged 55-75 with overweight/obesity and metabolic syndrome). BMD was measured using Dual-energy X-ray Absorptiometry scans and participants answered a food frequency questionnaire to determine the M-DIS. BMD was categorized as low BMD when T score was equal or lower than -1 and normal BMD in another case. Associations between BMD and M-DIS were evaluated by using linear and logistic regressions adjusted by other co-variates. RESULTS: Participants in the top tertile of the M-DIS had a lower BMD at total femur [ß (95% CI) - 0.02 (- 0.04, - 0.01)], trochanter areas [ß (95% CI) - 0.03 (- 0.05, - 0.01)] and lumbar spine area [ß (95% CI) - 0.03 (- 0.07, 0.01)] (but in the last case, measures were less precise and hence not statistically significant) compared to those in the lower M-DIS tertile. Multiple logistic regression analyses showed that the odds of the total femur and femoral trochanter osteopenia/osteoporosis were higher in participants in the top tertile compared to those in the lowest tertile of M-DIS [OR (95% CI) 1.71 (1.12, 2.64), P for trend 0.015; 2.02 (1.29, 3.21), P for trend 0.002, respectively]. CONCLUSION: A high pro-inflammatory diet, measured by the M-DIS, is associated with lower BMD in a senior Mediterranean population with metabolic syndrome.

Factors associated with successful dietary changes in an energy-reduced Mediterranean diet intervention: a longitudinal analysis in the PREDIMED-Plus trial.

PURPOSE: Long-term nutrition trials may fail to respond to their original hypotheses if participants do not comply with the intended dietary intervention. We aimed to identify baseline factors associated with successful dietary changes towards an energy-reduced Mediterranean diet (MedDiet) in the PREDIMED-Plus randomized trial. METHODS: Longitudinal analysis of 2985 participants (Spanish overweight/obese older adults with metabolic syndrome) randomized to the active intervention arm of the PREDIMED-Plus trial. Dietary changes were assessed with a 17-item energy-reduced MedDiet questionnaire after 6 and 12 months of follow-up. Successful compliance was defined as dietary changes from baseline of ≥ 5 points for participants with baseline scores < 13 points or any increase if baseline score was ≥ 13 points. We conducted crude and adjusted multivariable logistic regression models to identify baseline factors related to compliance. RESULTS: Consistent factors independently associated with successful dietary change at both 6 and 12 months were high baseline perceived self-efficacy in modifying diet (OR6-month: 1.51, 95% CI 1.25-1.83; OR12-month: 1.66, 95% CI 1.37-2.01), higher baseline fiber intake (OR6-month: 1.62, 95% CI 1.07-2.46; OR12-month: 1.62, 95% CI 1.07-2.45), having > 3 chronic conditions (OR6-month: 0.65, 95% CI 0.53-0.79; OR12-month: 0.76, 95% CI 0.62-0.93), and suffering depression (OR6-month: 0.80, 95% CI 0.64-0.99; OR12-month: 0.71, 95% CI 0.57-0.88). CONCLUSION: Our results suggested that recruitment of individuals with high perceived self-efficacy to dietary change, and those who initially follow diets relatively richer in fiber may lead to greater changes in nutritional recommendations. Participants with multiple chronic conditions, specifically depression, should receive specific tailored interventions. TRIAL REGISTRATION: ISRCTN registry 89898870, 24th July 2014 retrospectively registered http://www.isrctn.com/ISRCTN89898870 .

Pro-vegetarian food patterns and cardiometabolic risk in the PREDIMED-Plus study: a cross-sectional baseline analysis.

PURPOSE: We explored the cross-sectional association between the adherence to three different provegetarian (PVG) food patterns defined as general (gPVG), healthful (hPVG) and unhealthful (uPVG), and the cardiometabolic risk in adults with metabolic syndrome (MetS) of the PREDIMED-Plus randomized intervention study. METHODS: We performed a cross-sectional analysis of baseline data from 6439 participants of the PREDIMED-Plus randomized intervention study. The gPVG food pattern was built by positively scoring plant foods (vegetables/fruits/legumes/grains/potatoes/nuts/olive oil) and negatively scoring, animal foods (meat and meat products/animal fats/eggs/fish and seafood/dairy products). The hPVG and uPVG were generated from the gPVG by adding four new food groups (tea and coffee/fruit juices/sugar-sweetened beverages/sweets and desserts), splitting grains and potatoes and scoring them differently. Multivariable-adjusted robust linear regression using MM-type estimator was used to assess the association between PVG food patterns and the standardized Metabolic Syndrome score (MetS z-score), a composed index that has been previously used to ascertain the cardiometabolic risk, adjusting for potential confounders. RESULTS: A higher adherence to the gPVG and hPVG was associated with lower cardiometabolic risk in multivariable models. The regression coefficients for 5th vs. 1st quintile were - 0.16 (95% CI: - 0.33 to 0.01) for gPVG (p trend: 0.015), and - 0.23 (95% CI: - 0.41 to - 0.05) for hPVG (p trend: 0.016). In contrast, a higher adherence to the uPVG was associated with higher cardiometabolic risk, 0.21 (95% CI: 0.04 to 0.38) (p trend: 0.019). CONCLUSION: Higher adherence to gPVG and hPVG food patterns was generally associated with lower cardiovascular risk, whereas higher adherence to uPVG was associated to higher cardiovascular risk.

Vitamin K dietary intake is associated with cognitive function in an older adult Mediterranean population.

BACKGROUND: In the last years, evidence that dietary vitamin K could have a role in the cognitive domain has increased. However, data from large trials are limited. The objective of this study was to assess the association of 2 year changes in the dietary intake of vitamin K with cognitive function measured through neuropsychological performance tests. METHODS: In 5,533 participants of the multicentre PREDIMED-Plus study (48.1% women, age 65.1 ± 4.9 years with overweight/obesity and metabolic syndrome), we assessed the adjusted odds ratios of cognitive function decline according to 2 year changes in vitamin K intake. Participants answered a battery of cognitive function tests and Food Frequency Questionnaires (FFQs) in order to estimate the vitamin K dietary intake. RESULTS: After adjusting for potential cofounders, the highest tertile of change of dietary vitamin K intake (median [IQR]; 194.4 µg/d [120.9, 373.1]) was inversely associated with a Mini-Mental State Examination (MMSE) score ≤24 (OR [95% CI]; 0.53 [0.35, 0.79] P for trend = 0.002) compared with a decrease in the intake of vitamin K (median [IQR]; -97.8 µg/d [-292.8, -51.5]). A significant positive association between changes in dietary vitamin K intake and the semantic verbal fluency test scores (OR [95% CI]; 0.69 [0.51, 0.94] P for trend = 0.019) was found. CONCLUSIONS: An increase of the intake of dietary vitamin K was associated with better cognitive function scores, independently of recognised risk factors for cognitive decline, in an older adult Mediterranean population with high cardiovascular risk.

Circulating Amino Acids and Risk of Peripheral Artery Disease in the PREDIMED Trial.

Effective prevention and risk prediction are important for peripheral artery disease (PAD) due to its poor prognosis and the huge disease burden it produces. Circulating amino acids (AA) and their metabolites may serve as biomarkers of PAD risk, but they have been scarcely investigated. The objective was to prospectively analyze the associations of baseline levels of plasma AA (and their pathways) with subsequent risk of PAD and the potential effect modification by a nutritional intervention with the Mediterranean diet (MedDiet). A matched case-control study was nested in the PREDIMED trial, in which participants were randomized to three arms: MedDiet with tree nut supplementation group, MedDiet with extra-virgin olive oil (EVOO) supplementation group or control group (low-fat diet). One hundred and sixty-seven PAD cases were matched with 250 controls. Plasma AA was measured with liquid chromatography/mass spectrometry at the Broad Institute. Baseline tryptophan, serine and threonine were inversely associated with PAD (ORfor 1 SD increase = 0.78 (0.61-0.99); 0.67 (0.51-0.86) and 0.75 (0.59-0.95), respectively) in a multivariable-adjusted conditional logistic regression model. The kynurenine/tryptophan ratio was directly associated with PAD (ORfor 1 SD increase = 1.50 (1.14-1.98)). The nutritional intervention with the MedDiet+nuts modified the association between threonine and PAD (p-value interaction = 0.018) compared with the control group. However, subjects allocated to the MedDiet+EVOO group were protected against PAD independently of baseline threonine. Plasma tryptophan, kynurenine/tryptophan ratio, serine and threonine might serve as early biomarkers of future PAD in subjects at a high risk of cardiovascular disease. The MedDiet supplemented with EVOO exerted a protective effect, regardless of baseline levels of threonine.

U-Shaped Association between Dietary Acid Load and Risk of Osteoporotic Fractures in 2 Populations at High Cardiovascular Risk.

BACKGROUND: Bone contributes to maintaining the acid-base balance as a buffering system for blood pH. Diet composition also affects acid-base balance. Several studies have linked an imbalance in the acid-base system to changes in the density and structure of bone mass, although some prospective studies and meta-analyses suggest that acid load has no deleterious effect on bone. OBJECTIVE: The aim of this study was to examine the associations between potential renal acid load (PRAL) and net endogenous acid production (NEAP) and the risk of osteoporotic fractures and bone mineral density (BMD) in 2 middle-aged and elderly Mediterranean populations. METHODS: We conducted a longitudinal analysis including 870 participants from the PREvención con DIeta MEDiterranea (PREDIMED) Study and a cross-sectional analysis including 1134 participants from the PREDIMED-Plus study. Participants were adults, aged 55-80 y, either at high cardiovascular risk (PREDIMED) or overweight/obese with metabolic syndrome (PREDIMED-Plus), as defined by the International Diabetes Federation, the American Heart Association, and the National Heart Association. PRAL and NEAP were calculated from validated food-frequency questionnaires. BMD was measured using DXA scans. Fracture information was obtained from medical records. The association between mean PRAL and NEAP and fracture risk was assessed using multivariable-adjusted Cox models. BMD differences between tertiles of baseline PRAL and NEAP were evaluated by means of ANCOVA. RESULTS: A total 114 new fracture events were documented in the PREDIMED study after a mean of 5.2 y of intervention and 8.9 y of total follow-up. Participants in the first and third PRAL and NEAP tertiles had a higher risk of osteoporotic fracture compared with the second tertile, showing a characteristically U-shaped association [HR (95% CI): 1.73 (1.03, 2.91) in tertile 1 and 1.91 (1.14, 3.19) in tertile 3 for PRAL, and 1.83 (1.08, 3.09) in tertile 1 and 1.87 (1.10, 3.17) in tertile 3 for NEAP]. Compared with the participants in tertile 1, the participants in the top PRAL and NEAP tertiles had lower BMD [PRAL: mean total femur BMD: 1.029 ± 0.007 and 1.007 ± 0.007 g/cm2; P = 0.006 (tertiles 1 and 3); NEAP: mean total femur BMD: 1.032 ± 0.007 and 1.009 ± 0.007 g/cm2; P = 0.017 (tertiles 1 and 3)]. CONCLUSIONS: The results of our study suggest that both high and low dietary acid are associated with a higher risk of osteoporotic fractures, although only high dietary acid was found to have a negative relation to BMD in senior adults with existing chronic health conditions. This trial was registered at http://www.isrctn.com/ as ISRCTN3573963 (PREDIMED) and ISRCTN89898870 (PREDIMED-Plus).

Predictors of successful weight loss with relative maintenance of fat-free mass in individuals with overweight and obesity on an 8-week low-energy diet.

A low-energy diet (LED) is an effective approach to induce a rapid weight loss in individuals with overweight. However, reported disproportionally large losses of fat-free mass (FFM) after an LED trigger the question of adequate protein content. Additionally, not all individuals have the same degree of weight loss success. After an 8-week LED providing 5020 kJ/d for men and 4184 kJ/d for women (84/70 g protein/d) among overweight and obese adults, we aimed to investigate the relationship between protein intake relative to initial FFM and proportion of weight lost as FFM as well as the individual characteristics associated with weight loss success. We assessed all outcomes baseline and after the LED. A total of 286 participants (sixty-four men and 222 women) initiated the LED of which 82 % completed and 70 % achieved a substantial weight loss (defined as ≥8 %). Protein intake in the range 1·0-1·6 g protein/d per kg FFM at baseline for men and 1·1-2·2 g protein/d per kg FFM at baseline for women was not associated with loss of FFM (P = 0·632). Higher Three-Factor Eating Questionnaire (TFEQ) hunger at baseline and reductions in TFEQ disinhibition and hunger during the LED were associated with larger weight loss (all P ≤ 0·020); whereas lower sleep quality at baseline predicted less successful weight loss using intention to treat analysis (P = 0·021), possibly driven by those dropping out (n 81, P = 0·067 v. completers: n 198, P = 0·659). Thus, the protein intakes relative to initial FFM were sufficient for maintenance of FFM and specific eating behaviour characteristics were associated with weight loss success.

Dairy products intake and the risk of incident cataracts surgery in an elderly Mediterranean population: results from the PREDIMED study.

PROPOSAL: The aim of this study was to examine the association between the consumption of total and specific types of dairy products and the risk of incident cataracts in an elderly Mediterranean population at high cardiovascular risk. METHODS: We prospectively analyzed 5860 subjects from the PREvención con DIeta MEDiterránea (PREDIMED) Study. The time to cataract surgery was calculated as the time between recruitment and the date of the surgery, last visit of the follow-up, date of death, or until the end of the study. Dairy products intake was assessed using validated food frequency questionnaires. We used Cox proportional hazard regression to assess the risk of cataract surgery according to average dietary energy-adjusted total dairy products, milk, yogurt and cheese consumption. RESULTS: We documented a total of 768 new cataract events after a median of 5.6 years of follow-up. Subjects in the second [hazard ratio (HR) 0.62; 95% CI 0.52, 0.74] and third tertile (HR: 0.71; 95% CI 0.60, 0.85) of skimmed yogurt intake had a significantly lower risk of cataracts after adjusting for potential confounders. No significant associations were observed for total dairy products, whole and skimmed milk, whole yogurt and cheese consumption. CONCLUSION: The intake of skimmed yogurt was associated with a reduced risk of cataracts in an elderly Mediterranean population with high cardiovascular risk. No significant associations were observed for other type of dairy product. CLINICAL TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 35739639. Registration date: 5 October 2005.

Adherence to the Mediterranean diet and nuclear magnetic resonance spectroscopy biomarkers in older individuals at high cardiovascular disease risk: cross-sectional and longitudinal analyses.

BACKGROUND: The Mediterranean diet (MedDiet) has been related to a decreased risk of cardiovascular disease (CVD) and diabetes. OBJECTIVES: We aimed to prospectively assess the relationship between adherence to the MedDiet and advanced lipoprotein subclass profiles and glucose metabolism and inflammation markers, as determined by nuclear magnetic resonance (NMR) spectroscopy. DESIGN: We conducted cross-sectional and longitudinal analyses within the framework of the PREvención con DIeta MEDiterránea study in 196 participants from the Reus-Tarragona center. Adherence to the MedDiet was assessed using a 14-item validated questionnaire [Mediterranean Diet Adherence Score (MEDAS)]. Plasma lipoprotein subclasses and molecular metabolite profiles were determined using NMR spectra collected on a Vantera Clinical Analyzer at baseline and after 1 y of follow-up. Baseline and 1-y categories of MEDAS were related to measures of lipoprotein atherogenicity and diabetes risk using multivariable-adjusted analysis of covariance models. RESULTS: Compared with participants in the lowest category of baseline MEDAS, those in the highest category showed higher concentrations of total high-density lipoprotein (HDL) particles and H1P HDL, lower concentrations of very low-density lipoprotein (VLDL)-triglyceride, smaller size of VLDL, and lower concentrations of very large VLDL, as well as lower concentrations of branched-chain amino acids, leucine, and GlycA and reduced Diabetes Risk Index (DRI) scores. In addition, participants who increased by 3 or more points in their 1-y MEDAS showed an increase in concentrations of H7P-HDL, H5P-HDL, and citrate, and reduced acetone and DRI scores compared with those with lesser adherence increases. CONCLUSIONS: In older adults at high cardiometabolic risk, higher MEDAS was associated with modest beneficial changes in lipoprotein and glucose metabolism. The results suggest that lipoprotein subclass distribution and glycemic control are potential mechanisms behind the well-known salutary effects of MedDiet on CVD and diabetes risk. Future clinical trials exploring the effects of the MedDiet on advanced lipoprotein subclass profiles and glucose metabolism markers are needed to confirm the results of our study. TRIAL REGISTRATION NUMBER: This trial was registered at controlled-trials.com as ISRCTN35739639.

Gut microbiota dynamics and association with chronic kidney disease: A longitudinal study within the PREDIMED-Plus trial.

AIMS: Chronic kidney disease (CKD) represents a global health concern, disproportionately affecting the elderly with heightened cardiovascular risk. The emerging focus on the gut microbiota's role in CKD pathophysiology represents a pivotal area in nephrology; however, the evidence on this topic is limited. This observational prospective study, in the framework of the PREDIMED-Plus trial, investigates associations between gut microbiota composition and the 1-year trajectory of CKD in 343 participants aged 55-75 years with high cardiovascular risk. MATERIALS AND METHODS: Kidney function was assessed at baseline and at 1-year of follow-up through the estimated glomerular filtration rate based on cystatin C (eGFR-CysC) and CKD defined by eGFR-CysC <60 mL/min/1.73 m2. Participants were grouped based on their 1-year CKD trajectory: Group 1 maintained normal status or improved from CKD to normal, while Group 2 maintained CKD or worsened from normal to CKD. Fecal microbiota composition was assessed through 16S sequencing. KEY FINDINGS: We observed differences in gut microbiota composition between CKD trajectory groups. Notably, the baseline relative abundance of Lachnoclostridium and Lachnospira, both butyrate-producing genera, was lower in participants maintaining or progressing to CKD. Longitudinally, a decrease in Lachnospira abundance was associated with CKD progression. The improved Chao1 index after 1-year follow-up suggests a link between enhanced microbial richness and stable/better kidney function. SIGNIFICANCE: The findings underscore the potential of gut microbiota analysis in non-invasively monitoring CKD, especially in older populations, and hint at future interventions targeting gut microbiota to manage CKD progression. Further research is needed for causal relationships and generalizability.

Plasma metabolite predictors of metabolic syndrome incidence and reversion.

BACKGROUND: Metabolic Syndrome (MetS) is a progressive pathophysiological state defined by a cluster of cardiometabolic traits. However, little is known about metabolites that may be predictors of MetS incidence or reversion. Our objective was to identify plasma metabolites associated with MetS incidence or MetS reversion. METHODS: The study included 1468 participants without cardiovascular disease (CVD) but at high CVD risk at enrollment from two case-cohort studies nested within the PREvención con DIeta MEDiterránea (PREDIMED) study with baseline metabolomics data. MetS was defined in accordance with the harmonized International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute criteria, which include meeting 3 or more thresholds for waist circumference, triglyceride, HDL cholesterol, blood pressure, and fasting blood glucose. MetS incidence was defined by not having MetS at baseline but meeting the MetS criteria at a follow-up visit. MetS reversion was defined by MetS at baseline but not meeting MetS criteria at a follow-up visit. Plasma metabolome was profiled by LC-MS. Multivariable-adjusted Cox regression models and elastic net regularized regressions were used to assess the association of 385 annotated metabolites with MetS incidence and MetS reversion after adjusting for potential risk factors. RESULTS: Of the 603 participants without baseline MetS, 298 developed MetS over the median 4.8-year follow-up. Of the 865 participants with baseline MetS, 285 experienced MetS reversion. A total of 103 and 88 individual metabolites were associated with MetS incidence and MetS reversion, respectively, after adjusting for confounders and false discovery rate correction. A metabolomic signature comprised of 77 metabolites was robustly associated with MetS incidence (HR: 1.56 (95 % CI: 1.33-1.83)), and a metabolomic signature of 83 metabolites associated with MetS reversion (HR: 1.44 (95 % CI: 1.25-1.67)), both p < 0.001. The MetS incidence and reversion signatures included several lipids (mainly glycerolipids and glycerophospholipids) and branched-chain amino acids. CONCLUSION: We identified unique metabolomic signatures, primarily comprised of lipids (including glycolipids and glycerophospholipids) and branched-chain amino acids robustly associated with MetS incidence; and several amino acids and glycerophospholipids associated with MetS reversion. These signatures provide novel insights on potential distinct mechanisms underlying the conditions leading to the incidence or reversion of MetS.

Effect of 1-year lifestyle intervention with energy-reduced Mediterranean diet and physical activity promotion on the gut metabolome and microbiota: a randomized clinical trial.

BACKGROUND: The health benefits of the Mediterranean diet (MedDiet) have been linked to the presence of beneficial gut microbes and related metabolites. However, its impact on the fecal metabolome remains poorly understood. OBJECTIVES: Our goal was to investigate the weight-loss effects of a 1-y lifestyle intervention based on an energy-reduced MedDiet coupled with physical activity (intervention group), compared with an ad libitum MedDiet (control group), on fecal metabolites, fecal microbiota, and their potential association with cardiovascular disease risk factors. METHODS: A total of 400 participants (200 from each study group), aged 55-75 y, and at high cardiovascular disease risk, were included. Dietary and lifestyle information, anthropometric measurements, blood biochemical parameters, and stool samples were collected at baseline and after 1 y of follow-up. Liquid chromatography-tandem mass spectrometry was used to profile endogenous fecal metabolites, and 16S amplicon sequencing was employed to profile the fecal microbiota. RESULTS: Compared with the control group, the intervention group exhibited greater weight loss and improvement in various cardiovascular disease risk factors. We identified intervention effects on 4 stool metabolites and subnetworks primarily composed of bile acids, ceramides, and sphingosines, fatty acids, carnitines, nucleotides, and metabolites of purine and the Krebs cycle. Some of these were associated with changes in several cardiovascular disease risk factors. In addition, we observed a reduction in the abundance of the genera Eubacterium hallii group and Dorea, and an increase in alpha diversity in the intervention group after 1 y of follow-up. Changes in the intervention-related microbiota profiles were also associated with alterations in different fecal metabolite subnetworks and some cardiovascular disease risk factors. CONCLUSIONS: An intervention based on an energy-reduced MedDiet and physical activity promotion, compared with an ad libitum MedDiet, was associated with improvements in cardiometabolic risk factors, potentially through modulation of the fecal microbiota and metabolome. This trial was registered at https://www.isrctn.com/ as ISRCTN89898870 (https://doi.org/10.1186/ISRCTN89898870).

Plasma levels of neurology-related proteins are associated with cognitive performance in an older population with overweight/obesity and metabolic syndrome.

Cognitive impairment is present in a broad spectrum of medical conditions and in aging. Here, we aimed to identify plasma proteins related to cognitive function in a sample of older adults with overweight/obesity and metabolic syndrome. A total of 129 subjects (mean age 64.7 years; 36% females) were grouped according to low (l-GCF, N=65) or high (h-GCF, N=64) global cognitive function and matched according to education, sex, age, and body mass index. Cognitive performance was assessed using neuropsychological tests. Plasma levels of 92 neurology-related proteins were assessed using a proximity extension assay. An elastic net regression analysis was used to identify proteins more associated with cognitive performance. Additionally, the protein expression levels were compared between the two groups by means of a t-test with false discovery rate correction. Pearson correlations were used to assess associations between the protein levels and scores from the neurocognitive tests. Six proteins (alpha-2-MRAP, HAGH, Siglec-9, MDGA1, IL12, and EDA2R) were identified as potential contributors to cognitive performance, remaining significantly increased in l-GCF compared to h-GCF participants after correction for multiple testing. Negative correlations (r= -0.23 to -0.18, i.e., lower protein levels, higher cognitive function) were found between global cognitive function and Siglec-9, NMNAT1, HAGH, LXN, gal-8, alpha-2-MRAP, IL12, PDGF-R-alpha, NAAA, EDA2R, CLEC1B, and LAT. Mini-mental state examination z scores showed the strongest correlations with protein levels, specifically negative correlations with CLEC1b, LXN, LAT, PLXNB3, NMNAT1, gal-8, HAGH, NAAA, CTSS, EZR, KYNU, MANF (r=-0.38 to -0.26) and a positive correlation with ADAM23 (r= 0.26). In summary, we identified several plasma proteins that were significantly associated with cognitive performance in older adults with obesity and metabolic syndrome, although further research is needed to replicate the results in larger samples and to include a predictive perspective.

Cross-sectional and longitudinal assessment of the association between DDR1 variants and processing speed in patients with early psychosis and healthy controls.

Recent evidence indicates that DDR1 participates in myelination and that variants of DDR1 are associated with decreased cognitive processing speed (PS) in schizophrenia (SZ). Here, we explored whether DDR1 variants were associated with PS in subjects diagnosed with an early psychosis (EP), a condition often preceding SZ. Data from two Spanish independent samples (from Reus and Santander) including patients with EP (n = 75 and n = 312, respectively) and healthy controls (HCs; n = 57 and n = 160) were analyzed. The Trail Making Test part A was used to evaluate PS. Participants underwent genotyping to identify DDR1 variants rs1264323 and rs2267641. Cross-sectional data were analyzed with general linear models and longitudinal data were analyzed using mixed models. We examined the combined rs1264323AA-rs2267641AC/CC genotypes (an SZ-risk combination) on PS. The SZ-risk combined genotypes were associated with increased PS in EP patients but not in HCs in the cross-sectional analysis. In the longitudinal analysis, the SZ-risk combined genotypes were significantly associated with increased PS in both HCs and EP patients throughout the 10-year follow-up but no genotype × time interaction was observed. These results provide further evidence that DDR1 is involved in cognition and should be replicated with other samples.