Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies.

BACKGROUND: A healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how they relate to mortality and longevity are unclear. We aimed to identify and replicate a healthy lifestyle metabolomic signature and examine how it is related to total and cause-specific mortality risk and longevity. METHODS: In four large cohorts with 13,056 individuals and 28-year follow-up, we assessed five healthy lifestyle factors, used liquid chromatography mass spectrometry to profile plasma metabolites, and ascertained deaths with death certificates. The unique healthy lifestyle metabolomic signature was identified using an elastic regression. Multivariable Cox regressions were used to assess associations of the signature with mortality and longevity. FINDINGS: The identified healthy lifestyle metabolomic signature was reflective of lipid metabolism pathways. Shorter and more saturated triacylglycerol and diacylglycerol metabolite sets were inversely associated with the healthy lifestyle score, whereas cholesteryl ester and phosphatidylcholine plasmalogen sets were positively associated. Participants with a higher healthy lifestyle metabolomic signature had a 17% lower risk of all-cause mortality, 19% for cardiovascular disease mortality, and 17% for cancer mortality and were 25% more likely to reach longevity. The healthy lifestyle metabolomic signature explained 38% of the association between the self-reported healthy lifestyle score and total mortality risk and 49% of the association with longevity. CONCLUSIONS: This study identifies a metabolomic signature that measures adherence to a healthy lifestyle and shows prediction of total and cause-specific mortality and longevity. FUNDING: This work was funded by the NIH, CIHR, AHA, Novo Nordisk Foundation, and SciLifeLab.

Should we remove wine from the Mediterranean diet?: a narrative review.

Moderate alcohol intake (or, more specifically, red wine) represents one of the postulated beneficial components of the traditional Mediterranean diet. Many well-conducted nonrandomized studies have reported that light-to-moderate alcohol intake is not only associated with reduced risk of cardiovascular disease, but also of all-cause mortality. Nonetheless, alcohol is an addictive substance imposing huge threats for public health. Alcohol consumption is associated with increased risks of cancer, neurological harms, injuries, and other adverse outcomes. Both the Global Burden of Disease (2016) and Mendelian randomization studies recently supported that the healthiest level of alcohol intake should be 0. Therefore, despite findings of conventional observational epidemiologic studies supporting a potential beneficial role of wine in the context of a healthy Mediterranean dietary pattern, a strong controversy remains on this issue. Age, sex, and drinking patterns are likely to be strong effect modifiers. In this context, a new 4-y noninferiority pragmatic trial in Spain (University of Navarra Alumni Trialist Initiative or "UNATI"), publicly funded by the European Research Council, will randomly assign >10,000 current drinkers (males, 50-70 y; females, 55-75 y) to repeatedly receive advice on either abstention or moderation in alcohol consumption. The recruitment will begin in mid-2024. The primary endpoint is a composite of the main clinical outcomes potentially related to alcohol intake including all-cause mortality. Clinical trial registry number: PREDIMED, ISRCTN35739639, www.predimed.es; SUN, clinicaltrials.gov identifier: NCT02669602, https://medpreventiva.es/i2CmeL.

Consumption of olive oil and risk of breast cancer in U.S. women: results from the Nurses' Health Studies.

BACKGROUND: Olive oil consumption may reduce breast cancer risk, but it is unclear whether olive oil is beneficial for breast cancer prevention in populations outside of Mediterranean regions, namely in the U.S., where the average consumption of olive oil is low compared with Mediterranean populations. We examined whether olive oil intake was associated with breast cancer risk in two prospective cohorts of U.S. women. METHODS: We used multivariable-adjusted time-varying Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence interval (CI) for breast cancer among 71,330 (Nurses' Health Study, 1990-2016) and 93,295 women (Nurses' Health Study II, 1991-2017) who were free of cancer at baseline. Diet was assessed by a validated semi-quantitative food frequency questionnaire every 4 years. RESULTS: During 3,744,068 person-years of follow-up, 9,638 women developed invasive breast cancer. The multivariable-adjusted HR (95% CI) for breast cancer among women who had the highest consumption of olive oil (>1/2 tablespoon/d or >7 g/d) compared with those who never or rarely consumed olive oil, was 1.01 (0.93, 1.09). Higher olive oil consumption was not associated with any subtype of breast cancer. CONCLUSION: We did not observe an association between higher olive oil intake and breast cancer risk in two large prospective cohorts of U.S. women, whose average olive oil consumption was low. Prospective studies are needed to confirm these findings and to further investigate whether different varieties of olive oil (e.g., virgin and extra virgin olive oil) may play a role in breast cancer risk.

Predictors of total mortality and their differential association on premature or late mortality in the SUN cohort.

Several studies have tried to analyse the association between all-cause mortality and different risk factors, (especially those which are modifiable, such as smoking, diet or exercise), to develop public health preventive strategies. However, a specific analysis of predictors of premature and late mortality is needed to give more precise recommendations. Considering that there are risk factors which exert an influence on some diseases and not on others, we expect that, similarly, they may have a different impact depending on the timing of mortality, separating premature (≤65 years) from late mortality (>65 years). Thus, we prospectively followed-up during a median of 12 years a cohort of 20,272 university graduates comprising an ample range of ages at inception. Time-dependent, covariate-adjusted Cox models were used to estimate adjusted hazard ratios (HR) and their 95 % confidence intervals (CI) for each predictor. The strongest independent predictor of mortality at any age was physical activity which was associated with reduced risk of total, premature and late mortality (range of HRs when comparing the highest vs. the lowest level: 0.24 to 0.48). Specific strong predictors for premature mortality were smoking, HR: 4.22 (95 % CI: 2.42-7.38), and the concurrence of ≥2 metabolic conditions at baseline, HR: 1.97 (1.10-3.51). The habit of sleeping a long nap (≥30 min/d), with HR: 2.53 (1.30-4.91), and poor adherence to the Mediterranean Diet (≤3 points in a 0 to 8 score vs. ≥6 points), with HR: 2.27 (1.08-4.76), were the strongest specific predictors for late mortality. Smoking, diet quality or lifestyles, probably should be differentially assessed as specific predictors for early and late mortality. In the era of precision medicine, this approach will allow tailored recommendations appropriate to each person's age and baseline condition.

Loss of Visceral Fat is Associated with a Reduction in Inflammatory Status in Patients with Metabolic Syndrome.

SCOPE: Excessive visceral adipose tissue (VAT) is associated with higher secretion of pro-inflammatory molecules, contributing to systemic inflammation and obesity-related metabolic disturbances. METHODS AND RESULTS: This prospective analysis includes 117 overweight/obese adults (55-75 years) from the PREDIMED-Plus study. Fourteen inflammatory markers and adipokines are measured using a Bio-Plex assay with multiplex technology: insulin, glucagon, IL-6, visfatin, ghrelin, GLP-1, TNF-α, MCP-1, PAI-1, resistin, C-peptide, leptin, adipsin, and adiponectin. Participants are categorized into tertiles according to changes in VAT after 1-year of follow-up, determined by dual-energy X-Ray absorptiometry. Participants allocate in tertile 3, which represent an increase of VAT content after 1-year of follow-up compared to tertile 1, show significant differences in insulin (T3 vs T1, fully adjusted model: p = 0.037, p for trend 0.042), PAI-1 (fully adjusted model: p = 0.05, p for trend 0.06), c-peptide (fully adjusted model: p = 0.037, p for trend 0.042), and TNF-α (fully adjusted model p = 0.037, p for trend 0.042). CONCLUSION: The results evidence that a reduction in VAT is associated with clinical improvements in several inflammatory and adiposity markers, mainly in insulin, c-peptide, and PAI-1 levels, and these improvements may contribute to a reduction in cardiometabolic disturbances observe in obesity.

Only virgin type of olive oil consumption reduces the risk of mortality. Results from a Mediterranean population-based cohort.

BACKGROUND: Evidence on the association between virgin olive oil (OO) and mortality is limited since no attempt has previously been made to discern about main OO varieties. OBJECTIVE: We examined the association between OO consumption (differentiating by common and virgin varieties) and total as well as cause-specific long-term mortality METHODS: 12,161 individuals, representative of the Spanish population ≥18 years old, were recruited between 2008 and 2010 and followed up through 2019. Habitual food consumption was collected at baseline with a validated computerized dietary history. The association between tertiles of OO main varieties and all-cause, cardiovascular and cancer mortality were analyzed using Cox models. RESULTS: After a mean follow-up of 10.7 years (129,272 person-years), 143 cardiovascular deaths, and 146 cancer deaths occurred. The hazard ratio (HR) (95% confidence interval) for all-cause mortality in the highest tertile of common and virgin OO consumption were 0.96 (0.75-1.23; P-trend 0.891) and 0.66 (0.49-0.90; P-trend 0.040). The HR for all-cause mortality per a 10 g/day increase in virgin OO was 0.91 (0.83-1.00). Virgin OO consumption was also inversely associated with cardiovascular mortality, with a HR of 0.43 (0.20-0.91; P-trend 0.017), but common OO was not, with a HR of 0.88 (0.49-1.60; P-trend 0.242). No variety of OO was associated with cancer mortality. CONCLUSION: Daily moderate consumption of virgin OO (1 and 1/2 tablespoons) was associated with a one-third lower risk of all-cause as well as half the risk of cardiovascular mortality. These effects were not seen for common OO. These findings may be useful to reappraise dietary guidelines.

Mortality prediction of the nutrient profile of the Chilean front-of-pack warning labels: Results from the Seguimiento Universidad de Navarra prospective cohort study.

Background and aims: Front-of-Pack (FoP) nutrition labelling has been established as a policy, empowering consumers to choose healthy food options for preventing diet-related non-communicable diseases. This study aimed to evaluate the association between the nutrient profile underlying the Chilean warning label score and all-cause mortality and to conduct a calibration with the Nutri-Score in a large cohort of Spanish university graduates. Materials and methods: This prospective cohort study analysed 20,666 participants (8,068 men and 12,598 women) with a mean (standard deviation) age of 38 years (±12.4) from the SUN cohort. Dietary food intake was assessed by a validated semi-quantitative food-frequency questionnaire at baseline and after 10 years of follow-up. The warning label score was calculated by considering the threshold of nutrients (sugar, saturated fat, and sodium) and energy density per 100 g/ml of product, as established by Chilean Legislation. Participants were classified according to quartiles of consumption of daily label score: Q1 (≤5.0), Q2 (>5.0-7.1), Q3 (>7.1-9.8), and Q4 (>9.8). Time-dependent, multivariable-adjusted Cox models were applied. To compare the performance of the warning label score and Nutri-Score to predict mortality, we used the Akaike information criterion (AIC) and Bayesian information criterion (BIC) methods. Results: During a median of 12.2 years of follow-up, 467 deaths were identified. A higher score in the warning label values (lower nutritional quality) was associated with an increased risk of all-cause mortality [HR (95% CI) Q4 vs. Q1: 1.51 (1.07-2.13); p-trend = 0.010] and cancer mortality [HR (95% CI) Q4 vs. Q1: 1.91 (1.18-3.10); p-trend = 0.006]. However, no statistically significant association was found for cardiovascular mortality. Furthermore, the warning label score and Nutri-Score exhibited comparable AIC and BIC values, showing similar power of prediction for mortality. Conclusion: A diet with a higher warning label score (>9.8 per day) was a good predictor of all cases and cancer mortality in a large Spanish cohort of university graduates. Also, the warning label score was capable to predict mortality as well as the Nutri-Score. Our findings support the validity of the warning label score as a FoP nutrition labelling policy since it can highlight less healthy food products.

Effect of olive oil consumption on cardiovascular disease, cancer, type 2 diabetes, and all-cause mortality: A systematic review and meta-analysis.

BACKGROUND: Some large prospective studies on olive oil consumption and risk of chronic disease suggested protective effects. OBJECTIVE: We conducted an outcome-wide systematic review and meta-analysis of prospective cohort studies and randomized controlled trials (RCT) assessing the association between olive oil consumption and the primary risk of 4 different outcomes: cardiovascular disease (CVD), cancer, type 2 diabetes (T2D) or all-cause mortality through January 2022. METHODS: Thirty-six studies were included in the systematic review and twenty-seven studies (24 prospective cohorts and 3 different reports from one RCT) were assessed in 4 quantitative random-effects meta-analyses. They included a total of 806,203 participants with 49,223 CVD events; 1,285,064 participants with 58,892 incident cases of cancer; 680,239 participants with 13,389 incident cases of T2D; and 733,420 participants with 174,081 deaths. Olive oil consumption was most frequently measured with validated food frequency questionnaires. Studies follow-up ranged between 3.7 and 28 years. RESULTS: A 16% reduced risk of CVD (relative risk [RR]: 0.84; 95% confidence interval [CI]: 0.76 to 0.94), standardized for every additional olive oil consumption of 25 g/d was found. No significant association with cancer risk was observed (RR: 0.94; 95% CI: 0.86 to 1.03, per 25 g/d). Olive oil consumption was associated with a 22% lower relative risk of T2D (RR: 0.78; 95% CI: 0.69 to 0.87, per 25 g/d) without evidence of heterogeneity. Similarly, it was inversely associated with all-cause mortality (RR: 0.89; 95% CI: 0.85 to 0.93, per 25 g/d). Only the results for T2D were homogeneous. Specific sources of heterogeneity for the other 3 outcomes were not always apparent. CONCLUSIONS: Prospective studies supported a beneficial association of olive oil consumption with CVD, T2D and all-cause mortality, but they did not show any association with cancer risk.

One-year longitudinal association between changes in dietary choline or betaine intake and cardiometabolic variables in the PREvención con DIeta MEDiterránea-Plus (PREDIMED-Plus) trial.

BACKGROUND: Choline and betaine intakes have been related to cardiovascular health. OBJECTIVES: We aimed to explore the relation between 1-y changes in dietary intake of choline or betaine and 1-y changes in cardiometabolic and renal function traits within the frame of the PREDIMED (PREvención con DIeta MEDiterránea)-Plus trial. METHODS: We used baseline and 1-y follow-up data from 5613 participants (48.2% female and 51.8% male; mean ± SD age: 65.01 ± 4.91 y) to assess cardiometabolic traits, and 3367 participants to assess renal function, of the Spanish PREDIMED-Plus trial. Participants met ≥3 criteria of metabolic syndrome and had overweight or obesity [BMI (in kg/m2) ≥27 and ≤40]. These criteria were similar to those of the PREDIMED parent study. Dietary intakes of choline and betaine were estimated from the FFQ. RESULTS: The greatest 1-y increase in dietary choline or betaine intake (quartile 4) was associated with improved serum glucose concentrations (-3.39 and -2.72 mg/dL for choline and betaine, respectively) and HbA1c levels (-0.10% for quartile 4 of either choline or betaine intake increase). Other significant changes associated with the greatest increase in choline or betaine intake were reduced body weight (-2.93 and -2.78 kg, respectively), BMI (-1.05 and -0.99, respectively), waist circumference (-3.37 and -3.26 cm, respectively), total cholesterol (-4.74 and -4.52 mg/dL, respectively), and LDL cholesterol (-4.30 and -4.16 mg/dL, respectively). Urine creatinine was reduced in quartile 4 of 1-y increase in choline or betaine intake (-5.42 and -5.74 mg/dL, respectively). CONCLUSIONS: Increases in dietary choline or betaine intakes were longitudinally related to improvements in cardiometabolic parameters. Markers of renal function were also slightly improved, and they require further investigation.This trial was registered at https://www.isrctn.com/ as ISRCTN89898870.

Vitamin D and Risk of Obesity-Related Cancers: Results from the SUN ('Seguimiento Universidad de Navarra') Project.

Obesity is associated with a higher risk of several types of cancer, grouped as obesity-related cancers (ORC). Vitamin D deficiency is more prevalent in obese subjects, and it has been suggested to play a role in the association between obesity and cancer risk. The aim of the study was to analyze the association between vitamin D intake and the subsequent risk of ORC in a prospective Spanish cohort of university graduates. The SUN Project, initiated in 1999, is a prospective dynamic multipurpose cohort. Participants answered a 556-item lifestyle baseline questionnaire that included a validated food-frequency questionnaire. We performed Cox regression models to estimate the hazard ratios (HRs) of ORC according to quartiles of energy-adjusted vitamin D intake (diet and supplements). We included 18,017 participants (mean age = 38 years, SD = 12 years), with a median follow-up of 12 years. Among 206,783 person-years of follow-up, we identified 225 cases of ORC. We found no significant associations between vitamin D intake and ORC risk after adjusting for potential confounders: HRQ2vsQ1 = 1.19 (95% CI 0.81-1.75), HRQ3vsQ1 = 1.20 (95% CI 0.81-1.78), and HRQ4vsQ1 = 1.02 (95% CI 0.69-1.51). Dietary and supplemented vitamin D do not seem to be associated with ORC prevention in the middle-aged Spanish population.

Alcohol, Drinking Pattern, and Chronic Disease.

This review discusses the inconsistent recommendations on alcohol consumption and its association with chronic disease, highlighting the need for an evidence-based consensus. Alcohol is an addictive substance consumed worldwide, especially in European countries. Recommendations on alcohol consumption are controversial. On one hand, many nonrandomized studies defend that moderate consumption has a beneficial cardiovascular effect or a lower risk of all-cause mortality. On the other hand, alcohol is associated with an increased risk of cancer, neurological diseases, or injuries, among others. For years, efforts have been made to answer the question regarding the safe amount of alcohol intake, but controversies remain. Observational studies advocate moderate alcohol consumption following a Mediterranean pattern (red wine with meals avoiding binge drinking) as the best option for current drinkers. However, agencies such as the IARC recommend abstention from alcohol as it is a potent carcinogen. In this context, more randomized trial with larger sample size and hard clinical endpoints should be conducted to clarify the available evidence and provide clinicians with support for their clinical practice.

Prospective associations between a priori dietary patterns adherence and kidney function in an elderly Mediterranean population at high cardiovascular risk.

PURPOSE: To assess the association between three different a priori dietary patterns adherence (17-item energy reduced-Mediterranean Diet (MedDiet), Trichopoulou-MedDiet and Dietary Approach to Stop Hypertension (DASH)), as well as the Protein Diet Score and kidney function decline after one year of follow-up in elderly individuals with overweight/obesity and metabolic syndrome (MetS). METHODS: We prospectively analyzed 5675 participants (55-75 years) from the PREDIMED-Plus study. At baseline and at one year, we evaluated the creatinine-based estimated glomerular filtration rate (eGFR) and food-frequency questionnaires-derived dietary scores. Associations between four categories (decrease/maintenance and tertiles of increase) of each dietary pattern and changes in eGFR (ml/min/1.73m2) or ≥ 10% eGFR decline were assessed by fitting multivariable linear or logistic regression models, as appropriate. RESULTS: Participants in the highest tertile of increase in 17-item erMedDiet Score showed higher upward changes in eGFR (ß: 1.87 ml/min/1.73m2; 95% CI: 1.00-2.73) and had lower odds of ≥ 10% eGFR decline (OR: 0.62; 95% CI: 0.47-0.82) compared to individuals in the decrease/maintenance category, while Trichopoulou-MedDiet and DASH Scores were not associated with any renal outcomes. Those in the highest tertile of increase in Protein Diet Score had greater downward changes in eGFR (ß: - 0.87 ml/min/1.73m2; 95% CI: - 1.73 to - 0.01) and 32% higher odds of eGFR decline (OR: 1.32; 95% CI: 1.00-1.75). CONCLUSIONS: Among elderly individuals with overweight/obesity and MetS, only higher upward change in the 17-item erMedDiet score adherence was associated with better kidney function after one year. However, increasing Protein Diet Score appeared to have an adverse impact on kidney health. TRIAL REGISTRATION NUMBER: ISRCTN89898870 (Data of registration: 2014).

Changes in plasma total saturated fatty acids and palmitic acid are related to pro-inflammatory molecule IL-6 concentrations after nutritional intervention for one year.

Systemic inflammation is associated with an increased risk of non-communicable diseases, such as cardiovascular diseases and diabetes. Circulating fatty acids (FA) are known to be related to these conditions, possibly through their role in inflammation, although different types of FAs can have opposite effects on inflammatory mediators. The aim of the present study was to analyze the association of plasma FAs with inflammatory biomarkers in a PREDIMED trial subsample after one year of intervention. In a one-year longitudinal study of 91 participants of the PREDIMED trial (Barcelona-Clinic center), plasma FAs and inflammatory biomarkers were analyzed using gas chromatography and ELISA, respectively. In baseline plasma, a multivariable-adjusted ordinary least squares regression model showed that n-3 polyunsaturated FAs concentrations were inversely associated with concentrations of soluble intercellular adhesion molecule-1 (sICAM-1) and E-selectin, whereas the level of the most abundant saturated FA, palmitic acid, was directly associated with concentrations of interleukin-6 (IL-6) (ß = 0.48 pg/mL, 95% CI: 0.03, 0.93 per 1-SD increase, p-value = 0.037). After one year of nutritional intervention, changes of plasma diet-derived total saturated FAs and palmitic acid were directly associated with changes in IL-6 (ß = 0.59 pg/mL [95% CI: 0.28, 0.89] per 1-SD, p-value = 0.001; ß = 0.64 pg/mL, 95% CI: 0.31, 0.98, p-value = 0.001), respectively, after correction for multiple testing. Our findings suggest that saturated FAs of dietary origin, especially palmitic acid, are directly involved in the increase of IL-6 in plasma.

Consumption of Olive Oil and Risk of Total and Cause-Specific Mortality Among U.S. Adults.

BACKGROUND: Olive oil consumption has been shown to lower cardiovascular disease risk, but its associations with total and cause-specific mortality are unclear. OBJECTIVES: The purpose of this study was to evaluate whether olive oil intake is associated with total and cause-specific mortality in 2 prospective cohorts of U.S. men and women. METHODS: The authors used multivariable-adjusted Cox proportional-hazards models to estimate HRs for total and cause-specific mortality among 60,582 women (Nurses' Health Study, 1990-2018) and 31,801 men (Health Professionals Follow-up Study, 1990-2018) who were free of cardiovascular disease or cancer at baseline. Diet was assessed by a semiquantitative food frequency questionnaire every 4 years. RESULTS: During 28 years of follow-up, 36,856 deaths occurred. The multivariable-adjusted pooled HR for all-cause mortality among participants who had the highest consumption of olive oil (>0.5 tablespoon/day or >7 g/d) was 0.81 (95% CI: 0.78-0.84) compared with those who never or rarely consumed olive oil. Higher olive oil intake was associated with 19% lower risk of cardiovascular disease mortality (HR: 0.81; 95% CI: 0.75-0.87), 17% lower risk of cancer mortality (HR: 0.83; 95% CI: 0.78-0.89), 29% lower risk of neurodegenerative disease mortality (HR: 0.71; 95% CI: 0.64-0.78), and 18% lower risk of respiratory disease mortality (HR: 0.82; 95% CI: 0.72-0.93). In substitution analyses, replacing 10 g/d of margarine, butter, mayonnaise, and dairy fat with the equivalent amount of olive oil was associated with 8%-34% lower risk of total and cause-specific mortality. No significant associations were observed when olive oil was compared with other vegetable oils combined. CONCLUSIONS: Higher olive oil intake was associated with lower risk of total and cause-specific mortality. Replacing margarine, butter, mayonnaise, and dairy fat with olive oil was associated with lower risk of mortality.

Association between ideal cardiovascular health and telomere length in participants older than 55 years old from the SUN cohort.

INTRODUCTION AND OBJECTIVES: Telomeres are noncoding regions located at the end of chromosomes and their shortening has been associated with risk factors and cardiovascular disease. The aim of this study was to evaluate the association between ideal cardiovascular health (Life's simple 7) and the odds of having short telomeres in a subsample of participants older than 55 years from the Seguimiento Universidad de Navarra (SUN) study. METHODS: We included 886 participants older than 55 years (645 men and 241 women). Telomere length was measured using a real-time quantitative polymerase chain reaction. Cardiovascular health score was defined by the American Heart Association as a composite score of 7 key risk factors (smoking status, physical activity, diet, body mass index, blood pressure, total cholesterol, and fasting blood glucose) with 0 to 2 points for each factor. We categorized this score in tertiles as poor (0-9 points), intermediate (10-11 points) and ideal (12-14 points). The odds of having short telomeres was defined as telomere length below the 20th percentile. RESULTS: Individuals with higher ideal cardiovascular health had a lower prevalence of having short telomeres (adjusted OR, 0.60; 95%CI, 0.34-1.05; P trend=.052). This association was statistically significant in men (adjusted OR, 0.37; 95%CI, 0.17-0.83; P trend=.025) but not in women. CONCLUSIONS: An inverse association between cardiovascular health score and short telomeres was found especially for men older than 55 years in the SUN population. The SUN project was registered at ClinicalTrials.gov (Identifier: NCT02669602).

Cross-Sectional Associations between HDL Structure or Function, Cell Membrane Fatty Acid Composition, and Inflammation in Elderly Adults.

BACKGROUND: Cell membrane fatty acid composition has been related to inflammation and cardiovascular disease (CVD) risk. Dysregulation of HDL function is also considered a CVD risk factor. OBJECTIVES: We aimed to investigate whether the content of cell membrane fatty acids and HDL functionality are linked to each other as well as to inflammation. METHODS: This cross-sectional analysis involved 259 participants (mean age: 67.9 y) with overweight/obesity (mean BMI: 29.5 kg/m2) from a coronary artery disease case-control study nested within the PREDIMED (PREvención con DIeta MEDiterránea) trial for which HDL functional parameters [apoA-I, apoA-IV, and apoC-III; cholesterol efflux capacity (CEC); HDL oxidative inflammatory index (HOII); sphingosine-1-phosphate (S1P); serum amyloid A (SAA); and complement-3 (C3) protein] were quantified. We also assessed 22 fatty acids in blood cell membranes using GC and inflammatory markers (IFN-γ and IL-1b, IL-6, IL-8, and IL-10) in serum. Associations of HDL-related variables with cell membrane fatty acids and with inflammatory markers were assessed using multivariable linear regression analyses with elastic net penalty. RESULTS: ApoA-I, apoC-III, CEC, HOII, S1P, and SAA, but not apoA-IV and C3 protein, were associated with membrane fatty acids. S1P and SAA were directly associated with IL-6, whereas apoA-I and C3 protein showed inverse associations with IL-6. Specific fatty acids including myristic acid (14:0) and long-chain n-6 fatty acids being negatively and positively associated with IL-8, respectively, were also found to be positively associated with SAA. CONCLUSIONS: This study suggests interrelations between indicators of inflammation and both blood cell membrane fatty acid composition and HDL structure/functional parameters in a Mediterranean population at high CVD risk.This trial was registered at www.isrctn.com as ISRCTN35739639.

Tricarboxylic acid cycle related-metabolites and risk of atrial fibrillation and heart failure.

BACKGROUND: Tricarboxylic acid (TCA) cycle deregulation may predispose to cardiovascular diseases, but the role of TCA cycle-related metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unexplored. This study sought to investigate the association of TCA cycle-related metabolites with risk of AF and HF. METHODS: We used two nested case-control studies within the PREDIMED study. During a mean follow-up for about 10 years, 512 AF and 334 HF incident cases matched by age (±5 years), sex and recruitment center to 616 controls and 433 controls, respectively, were included in this study. Baseline plasma levels of citrate, aconitate, isocitrate, succinate, malate and d/l-2-hydroxyglutarate were measured with liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression models were fitted to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for metabolites and the risk of AF or HF. Potential confounders included smoking, family history of premature coronary heart disease, physical activity, alcohol intake, body mass index, intervention groups, dyslipidemia, hypertension, type 2 diabetes and medication use. RESULTS: Comparing extreme quartiles of metabolites, elevated levels of succinate, malate, citrate and d/l-2-hydroxyglutarate were associated with a higher risk of AF [ORQ4 vs. Q1 (95% CI): 1.80 (1.21-2.67), 2.13 (1.45-3.13), 1.87 (1.25-2.81) and 1.95 (1.31-2.90), respectively]. One SD increase in aconitate was directly associated with AF risk [OR (95% CI): 1.16 (1.01-1.34)]. The corresponding ORs (95% CI) for HF comparing extreme quartiles of malate, aconitate, isocitrate and d/l-2-hydroxyglutarate were 2.15 (1.29-3.56), 2.16 (1.25-3.72), 2.63 (1.56-4.44) and 1.82 (1.10-3.04), respectively. These associations were confirmed in an internal validation, except for aconitate and AF. CONCLUSION: These findings underscore the potential role of the TCA cycle in the pathogenesis of cardiac outcomes.

Simple sugar intake and cancer incidence, cancer mortality and all-cause mortality: A cohort study from the PREDIMED trial.

OBJECTIVE: To examine associations between intake of simple sugars and cancer incidence, cancer mortality, and total mortality in a prospective cohort study based on the PREDIMED trial conducted from 2003 to 2010. METHODS: Participants were older individuals at high cardiovascular risk. Exposures were total sugar, glucose and fructose from solid or liquid sources, and fructose from fruit and 100% fruit juice. Cancer incidence was the primary outcome; cancer mortality and all-cause mortality were secondary outcomes. Multivariable-adjusted, time-dependent Cox proportional hazard models were used. RESULTS: Of 7447 individuals enrolled, 7056 (94.7%) were included (57.6% women, aged 67.0 ± 6.2 years). 534 incident cancers with 152 cancer deaths and 409 all-cause deaths were recorded after a median follow-up of 6 years. Intake of simple sugars in solid form was unrelated to outcomes. Higher cancer incidence was found per 5 g/day increase in intake of liquid sugars, with multivariable-adjusted HR of 1.08 (95% CI, 1.03-1.13) for total liquid sugar, 1.19 (95% CI, 1.07-1.31) for liquid glucose, 1.14 (95% CI, 1.05-1.23) for liquid fructose, and 1.39 (95% CI, 1.10-1.74) for fructose from fruit juice. Cancer and all-cause mortality increased to a similar extent with intake of all sugars in liquid form. In categorical models, cancer risk was dose-related for all liquid sugars. CONCLUSIONS: Simple sugar intake in drinks and fruit juice was associated with an increased risk of overall cancer incidence and mortality and all-cause mortality. This suggests that sugary beverages are a modifiable risk factor for cancer and all-cause mortality.

Dietary calcium, vitamin D, and breast cancer risk in women: findings from the SUN cohort.

PURPOSE: Epidemiological evidence concerning the relationship between calcium and vitamin D intake and breast cancer (BC) is inconclusive. Moreover, the association according to menopausal status remains unclear. We aimed to assess whether total intakes from dietary and supplemental sources of calcium and vitamin D were associated with the incidence of BC in a Mediterranean cohort. METHODS: We prospectively evaluated the association between intakes of calcium and vitamin D and BC risk among 10,812 women in the Seguimiento Universidad de Navarra (SUN) Project, a Spanish cohort of university graduates. RESULTS: During a mean follow-up of 10.7 years, 101 incident BC cases were confirmed. Evidence of a non-linear association between total calcium intake and BC risk was found (Pnon-linearity = 0.011) with risk reductions associated with higher intake up to approximately 1400 mg/day. Moderate intake [Tertile 2 (T2)] of total calcium was associated with lower overall BC risk [HR for T2 vs. Tertile 1 (T1): 0.55; 95% CI 0.33-0.91] and also among postmenopausal women (HRT2 vs. T1 = 0.38; 95% CI 0.16-0.92). Intake of vitamin D was not associated with BC risk. CONCLUSIONS: Our findings suggest an L-shaped association between total calcium intake and BC incidence. Moderate calcium intake may be associated with lower BC risk among overall and postmenopausal women, but not among premenopausal women. No evidence for any association between vitamin D intake and BC was found. Adherence to current guidelines recommendations for calcium intake may help to reduce BC risk.