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Background: Walnut consumption counteracts oxidative stress and inflammation, 2 drivers of cognitive decline. Clinical data concerning effects on cognition are lacking., Objectives: The Walnuts And Healthy Aging study is a 2-center (Barcelona, Spain; Loma Linda, CA) randomized controlled trial examining the cognitive effects of a 2-y walnut intervention in cognitively healthy elders., Methods: We randomly allocated 708 free-living elders (63-79 y, 68% women) to a diet enriched with walnuts at ∼15% energy (30-60 g/d) or a control diet (abstention from walnuts). We administered a comprehensive neurocognitive test battery at baseline and 2 y. Change in the global cognition composite was the primary outcome. We performed repeated structural and functional brain MRI in 108 Barcelona participants., Results: A total of 636 participants completed the intervention. Besides differences in nutrient intake, participants from Barcelona smoked more, were less educated, and had lower baseline neuropsychological test scores than those from Loma Linda. Walnuts were well tolerated and compliance was good. Modified intention-to-treat analyses (n = 657) uncovered no between-group differences in the global cognitive composite, with mean changes of -0.072 (95% CI: -0.100, -0.043) in the walnut diet group and -0.086 (95% CI: -0.115, -0.057) in the control diet group (P = 0.491). Post hoc analyses revealed significant differences in the Barcelona cohort, with unadjusted changes of -0.037 (95% CI: -0.077, 0.002) in the walnut group and -0.097 (95% CI: -0.137, -0.057) in controls (P = 0.040). Results of brain fMRI in a subset of Barcelona participants indicated greater functional network recruitment in a working memory task in controls., Conclusions: Walnut supplementation for 2 y had no effect on cognition in healthy elders. However, brain fMRI and post hoc analyses by site suggest that walnuts might delay cognitive decline in subgroups at higher risk. These encouraging but inconclusive results warrant further investigation, particularly targeting disadvantaged populations, in whom greatest benefit could be expected.This trial was registered at clinicaltrials.gov as NCT01634841., (Copyright © The Author(s) 2020.)

Background: Non-alcoholic fatty liver disease (NAFLD) affects 25-30% of the general population and is characterized by the presence of non-alcoholic fatty liver (NAFL) that can progress to non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis leading to hepatocellular carcinoma. To date, liver biopsy is the gold standard for the diagnosis of NASH and for staging liver fibrosis. This study aimed to train models for the non-invasive diagnosis of NASH and liver fibrosis based on measurements of lipids, glycans and biochemical parameters in peripheral blood and with the use of different machine learning methods., Methods: We performed a lipidomic, glycomic and free fatty acid analysis in serum samples of 49 healthy subjects and 31 patients with biopsy-proven NAFLD (15 with NAFL and 16 with NASH). The data from the above measurements combined with measurements of 4 hormonal parameters were analyzed with two different platforms and five different machine learning tools., Results: 365 lipids, 61 glycans and 23 fatty acids were identified with mass-spectrometry and liquid chromatography. Robust differences in the concentrations of specific lipid species were observed between healthy, NAFL and NASH subjects. One-vs-Rest (OvR) support vector machine (SVM) models with recursive feature elimination (RFE) including 29 lipids or combining lipids with glycans and/or hormones (20 or 10 variables total) could differentiate with very high accuracy (up to 90%) between the three conditions. In an exploratory analysis, a model consisting of 10 lipid species could robustly discriminate between the presence of liver fibrosis or not (98% accuracy)., Conclusion: We propose novel models utilizing lipids, hormones and glycans that can diagnose with high accuracy the presence of NASH, NAFL or healthy status. Additionally, we report a combination of lipids that can diagnose the presence of liver fibrosis. Both models should be further trained prospectively and validated in large independent cohorts., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The world's population is aging as a consequence of an increased global life expectancy. Identifying simple strategies to promote healthy aging (i.e., absence of major chronic diseases, preserved physical and cognitive functions, intact mental health, and good quality of life) have emerged as a major public health concern. Identifying biomarkers to better characterize the aging process is a research priority. Telomeres are repetitive DNA sequences at chromosome ends that prevent the loss of genomic DNA, protecting its physical integrity. Telomere length (TL) is considered a biomarker of aging: shorter telomeres are associated with a decreased life expectancy and increased rates of age-related chronic diseases. Telomere attrition has been shown to be accelerated by oxidative stress and inflammation. Since edible plants contain plenty of compounds with antioxidant and anti-inflammatory properties, it is plausible that their sustained consumption might help counteract telomere attrition. In this narrative review, we update evidence on the association between plant-rich dietary patterns and plant-based foods and TL. First, we summarize findings from observational studies on the association between TL and 1) adherence to plant-rich dietary patterns (mainly, but not only, focused on the Mediterranean diet); 2) consumption of seeds (mostly focused on nuts, grains, and coffee); and 3) intake of carotenoids, one of the plant-derived bioactives most studied in health and disease. Second, we summarize the main randomized controlled trials evaluating the effect on TL of dietary interventions involving either plant-rich dietary patterns or plant foods. Even though evidence from trials is very limited, several observational studies have reinforced the suggestive benefits of adherence to the Mediterranean diet (a plant-rich dietary pattern), consumption of seeds (and its derivatives), and dietary intake of carotenoids on TL, which further supports the research benefits of plant-rich dietary patterns and plant foods to promote health and longevity., (Copyright © The Author(s) 2019.)

Ischemic heart disease (IHD) is a leading cause of mortality in the United States. There is substantial evidence that a sustained intake of industrially-produced trans fatty acids (IP-TFA) is associated with increased risk of fatal IHD. This has led many regulatory agencies to pressure dietary oil producers to remove IP-TFA from their products. That this has resulted in lower blood levels of IP-TFA in the United States is clear, but whether this has been accompanied by a reduction in the incidence of fatal IHD is unknown. To test the hypothesis that declining IP-TFA levels are associated with declining rates of fatal IHD, we compared the IP-TFA levels in red blood cells (RBC) analyzed in our laboratory between 2009 and 2016 (n = 53 194) with yearly US-specific IHD mortality rates. We found that decreasing RBC IP-TFA levels were strongly correlated with decreasing rates of fatal IHD (R 2  = 0.9552, P < .0001). Recognizing the limitations of observational studies in addressing causation questions, our findings nevertheless support our hypothesis and suggest that efforts to remove IP-TFA from the food supply in the United States may be having the desired effect., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Nut consumption lowers blood cholesterol and is associated with reduced cardiovascular disease, but effects on blood pressure (BP) are inconsistent. We assessed the 2-year effects of a walnut diet versus a control diet on office BP and 24-hours ambulatory BP in free-living elders participating in the Walnuts and Healthy Aging study, a randomized trial testing the effects of walnuts at ≈15% energy on age-related disorders. In a prespecified analysis, we enrolled 305 participants, of whom 236 (75%) completed the study (65% women; age, 69 years; 60% with mild hypertension). Walnuts were well tolerated, and compliance was >98%. Mean baseline office BP was 128/79 mm Hg. Adjusted changes from baseline in mean office systolic BP were -4.61 mm Hg (95% CI, -7.43 to -1.79 mm Hg) in the walnut group and -0.59 mm Hg (-3.38 to 2.21 mm Hg) in controls ( P=0.051). Respective changes in mean systolic 24-hour ambulatory BP were -3.86 mm Hg (CI, -5.45 to -2.26 mm Hg) and -2.00 mm Hg (CI, -3.58 to -0.42 mm Hg; P=0.111). No changes in diastolic BP were observed. In participants in the upper tertile of baseline 24-hour ambulatory systolic BP (>125 mm Hg), mean 2-year systolic 24-hour BP was -8.5 mm Hg (CI, -12 to -5.0 mm Hg) in the walnut group and -2.5 mm Hg (CI, -6.3 to 1.3 mm Hg) in controls ( P=0.034). During the trial, participants in the walnut group required less uptitration of antihypertensive medication and had better overall BP regulation than controls. Walnut consumption reduces systolic BP in elderly subjects, particularly in those with mild hypertension. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT01634841 .

Background & Aims: Shortening of leukocyte telomere length (LTL) is a biomarker of aging. Epidemiologic studies of LTL in relation to dietary fatty acids have reported conflicting results. The red blood cell (RBC) fatty acid status is a valid objective biomarker of long-term dietary intake of C18:2n-6, C18:3n-3 and long-chain n-3 polyunsaturated fatty acids (C20:5n-3 and C22:6n-3). In healthy older individuals, we investigated whether LTL relates to the RBC proportions of the main dietary polyunsaturated fatty acids (PUFA), and to the RBC proportion of arachidonic acid (C20:4n-6), a fatty acid that can generate pro-inflammatory lipid mediators once released from cell membranes., Design: Cross-sectional study in 344 subjects (mean age 68.8 y, 68.6% women) who participated in a randomized controlled trial testing whether a diet enriched in walnuts can delay the onset of age-related diseases (https://clinicaltrials.gov/ct2/show/NCT01634841). At baseline, we assessed LTL by high-throughput quantitative fluorescence and determined fatty acids in RBCs by gas chromatography., Results: In multivariate models adjusted for age and gender, the RBC proportions of dietary PUFA were unrelated to LTL. In contrast, the RBC proportion of arachidonic acid inversely related to LTL (regression coefficient [95% confidence interval], -0.10 (-0.19 to -0.01), P = 0.023)., Conclusion: An increasing proportion of C20:4n-6 in RBCs is associated with shorter telomeres. Further research is needed to investigate the role of this fatty acid and its derived lipid mediators in the aging process., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective- To examine the associations between baseline levels of fatty acids in blood cell membranes and their 1-year changes with the incidence of coronary heart disease (CHD) in older adults at high cardiovascular disease risk. Approach and Results- This is a case-control study nested in the PREDIMED trial (Prevención con Dieta Mediterránea), with 136 CHD cases and 272 controls (matched on age, sex, body mass index, intervention group, and time of permanence in the study to the time event). We used gas chromatography to measure the proportion of 22 fatty acids in blood cell membranes at baseline and after 1 year. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% CIs. After adjustment for classical CHD risk factors and multiple testing, 1 SD increase in baseline levels of C22:0, C24:0 and the sum of individual very long chain saturated fatty acids was associated with 56% (OR, 0.44 [95% CI, 0.28-0.69]), 59% (OR, 0.41 [95% CI, 0.25-0.65]), and 55% (OR, 0.45 [95% CI, 0.29-0.70]) a decreased odds of developing CHD, respectively. Baseline C20:1n9 was associated with higher odds of CHD (OR, 1.58 [95% CI, 1.25-2.00]). Conclusions- Higher levels of C22:0 and C24:0 were associated with a lower CHD incidence, whereas higher levels of C20:1n9 were associated with a higher risk. This study adds to the growing body of evidence suggesting potential differences in the cardiovascular disease effects of different types of circulating saturated fatty acids.

There is limited evidence from epidemiological studies for the inflammatory or anti-inflammatory properties of fatty acids in blood cell membranes. Therefore, this study examined associations between baseline ( n = 282) and 1-year ( n = 143) changes in the levels of fatty acids in blood cell membranes with circulating inflammatory markers in older adults at high cardiovascular risk. The data for this cross-sectional analysis was obtained from a case-control study within the PREDIMED study. Linear regression with elastic net penalty was applied to test associations between measured fatty acids and inflammatory markers. Several fatty acids were associated with interferon-γ (IFNγ) and interleukins (ILs) IL-6, IL-8, and IL-10 at baseline and additionally also with IL-1b at 1 year. Omega-6 fatty acids were consistently positively associated with pro-inflammatory IL-6 and IL-8 at baseline. Omega-3 fatty acids including C20:5n3 and C18:3n3 were negatively associated with IFN-γ at 1 year. It is interesting to note that the cis and trans forms of C16:1n7 at 1 year were oppositely associated with the inflammatory markers. C16:1n7trans was negatively associated with IFN-γ, IL-6, IL-8, IL-10, and IL-1b, whereas C16:1n7cis was positively associated with IL-1b. This study adds to the growing body of evidence suggesting potential differences in inflammatory or anti-inflammatory properties of fatty acids in blood cell membranes.

Purpose of Review: There is increasing interest in exploring whether age-related diseases can be prevented by dietary means through nutrients or food bioactives, whole foods, or specific dietary patterns. Because of the slow nature of the aging process, biomarkers such as telomere length are helpful for this purpose. Here we update the developments in the area during the last 2 years., Recent Findings: Most data stem from epidemiologic studies, often cross-sectional in design. Recent articles strengthened the link between consumption of sugar-sweetened beverages and telomere shortening, whereas a novel association between telomere length and drinking coffee has been uncovered. Controversy on meat consumption and telomere length persists, mostly because of the presumed different effects of total meat and processed meat. In general terms, increasing consumption of antioxidant-rich plant foods relates to maintained telomere length. Feeding intervention trials with outcomes on telomere length are few and thus far have contributed little to further knowledge on this topic., Summary: Epidemiologic studies provide support for the putative effects of diet components on telomere length and on the aging process in general. Dietary associations with telomere length should be confirmed with adequately powered randomized controlled trials.

Purpose of Review: Nuts in general and walnuts in particular are in the limelight for the association of their consumption with improved health outcomes. Walnuts have an optimal composition in bioactive nutrients and recent clinical and experimental studies have uncovered a number of beneficial effects of walnut micronutrients, working in isolation or in concert, on metabolic pathways and clinical outcomes that make this review timely and relevant., Recent Findings: Alpha-linolenic acid, a critical walnut component, is metabolized into bioactive oxylipins, has been shown to protect microglial cells from inflammation, and is associated with lower fatal myocardial infarction rates through a putative antiarrhythmic effect. Phytosterols relate to the cholesterol-lowering effect of nut consumption. Nonsodium minerals are associated with better cardiometabolic health. Walnut phytomelatonin has anticancer effects that are shared by the main walnut polyphenols and their metabolites, ellagitannins and urolithins, respectively., Summary: This review highlights new evidence on the health-promoting properties of walnuts and their main micronutrient components. The conclusion is that walnuts are optimal healthful foods.

Objective : To assess the effects of chronic walnut consumption on body weight and adiposity in elderly individuals. Methods : The Walnuts and Healthy Aging study is a dual-center (Barcelona, Spain and Loma Linda University (LLU)), 2-year randomized parallel trial. This report concerns only the LLU cohort. Healthy elders (mean age 69 year, 67% women) were randomly assigned to walnut ( n = 183) or control diets ( n = 173). Subjects in the walnut group received packaged walnuts (28⁻56 g/day), equivalent to ≈15% of daily energy requirements, to incorporate into their habitual diet, while those in the control group abstained from walnuts. Adiposity was measured periodically, and data were adjusted for in-trial changes in self-reported physical activity. Results : After 2 years, body weight significantly decreased ( p = 0.031), while body fat significantly increased ( p = 0.0001). However, no significant differences were observed between the control and walnut groups regarding body weight (-0.6 kg and -0.4 kg, respectively, p = 0.67) or body fat (+0.9% and +1.3%, respectively, p = 0.53). Lean body mass, waist circumference, and waist-to-hip ratio remained essentially unchanged. Sensitivity analyses were consistent with the findings of primary analysis. Conclusion : Our findings indicate that walnuts can be incorporated into the daily diet of healthy elders without concern for adverse effects on body weight or body composition.

Background: Cell membrane fatty acid (FA) composition may play a role in human metabolic diseases. However, the modulatory effect of nutrients other than fat is poorly explored., Objective: To investigate the effect of moderate-carbohydrate diets with different glycemic indices (GI) and a low-fat diet (LF) on red blood cell (RBC) FA membrane composition., Design: The RBC FA profile was measured in 87 subjects from the GLYNDIET study. Participants were randomly assigned to one of the following energy-restricted diet for 6 months: moderate-carbohydrate/low-GI diet (LGI, n = 31), moderate-carbohydrate/high-GI diet (HGI, n = 30) or LF-diet (n = 26)., Results: We observed a significant increase in C20:0 and decrease in C20:3n-6 in the LGI and HGI groups compared to LF group. Compared to LF-diet, C22:4n-6 was lower after the HGI while C22:6n-3 was higher after LGI diet. Also, a tendency was found for higher concentrations of long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) in LGI compared to HGI and LF groups. The intra-group analysis showed significantly increased levels of total monounsaturated fatty acids (MUFA) after LGI and HGI interventions, as well as a significant increase in C22:5n-6 and a decrease in LCn-3PUFA and omega-3-index after the LF diet. The decrease in C20:5n-3 after HGI and LF diets was also significant., Conclusion: Diets with a moderate amount of carbohydrates and healthy fat, mainly with LGI, modify the RBC fatty acid membrane composition., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: The activity of stearoyl-CoA desaturase-1 (SCD1), the central enzyme in the synthesis of monounsaturated fatty acids (MUFA), has been associated with de novo lipogenesis. In experimental models SCD1 is down-regulated by polyunsaturated fatty acids (PUFA), but clinical studies are scarce. The effect of long-chain n-3 PUFA (LCn-3PUFA) supplied by the regular diet, in the absence of fatty fish or fish oil supplementation, remains to be explored., Methods: We related 1-y changes in plasma SCD1 index, as assessed by the C16:1n-7/C16:0 ratio, to both adiposity traits and nutrient intake changes in a sub-cohort (n = 243) of non-hypertriglyceridemic subjects of the PREDIMED (PREvención con DIeta MEDiterranea) trial., Results: After adjustment for confounders, including changes in fasting triglycerides, plasma SCD1 index increased in parallel with body weight (0.221 [95% confidence interval, 0.021 to 0.422], P = 0.031) and BMI (0.115 [0.027 to 0.202], P = 0.011). Additionally, dietary LCn-3PUFA (but not MUFA or plant-derived PUFA) were associated with decreased plasma SCD1 index (-0.544 [-1.044 to -0.043], P = 0.033, for each 1 g/d-increase in LCn-3PUFA). No associations were found for other food groups, but there was a trend for fatty fish intake (-0.083 [-0.177 to 0.012], P = 0.085, for each 10 g/d-increase)., Conclusions: Our data add clinical evidence on the down-regulation of plasma SCD1 index by LCn-3PUFA in the context of realistic changes in fish consumption in the customary, non-supplemented diet., Clinical Trial Registration: http://www.Controlled-trials.com/ISRCTN35739639., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Animal models support dietary omega-3 fatty acids protection against abdominal aortic aneurysm (AAA), but clinical data are scarce. The sum of red blood cell proportions of the omega-3 eicosapentaenoic and docosahexaenoic acids, known as omega-3 index, is a valid surrogate for long-term omega-3 intake. We investigated the association between the omega-3 index and the prevalence and progression of AAA. We also investigated associations between AAA and arachidonic acid, an omega-6 fatty acid that is a substrate for proinflammatory lipid mediators., Methods and Results: We obtained blood samples from 498 AAA patients (maximal aortic diameter ≥30 mm) within a population-based ultrasound-screening trial in men and from 199 age-matched controls who screened negative. We determined the fatty acids of red blood cells by gas chromatography. During a median follow-up of 4.85 years, 141 AAA patients reached criteria for vascular surgical repair. Participants were high consumers of omega-3 (average omega-3 index: 7.6%). No significant associations were found for omega-3 index. In contrast, arachidonic acid in AAA patients was higher than in controls ( P <0.001), and individuals in the upper tertile of arachidonic acid at baseline had higher probability of having AAA (odds ratio: 1.309; 95% confidence interval, 1.021-1.678; P =0.033). AAA patients at the upper tertile of arachidonic acid at baseline had a 54% higher risk of needing surgical repair during follow-up (hazard ratio: 1.544; 95% confidence interval, 1.127-2.114; P =0.007)., Conclusions: Omega-3 index is unrelated to men with AAA from a country in which fish consumption is customarily high. Arachidonic acid is associated with AAA presence and progression., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00662480., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Subtle cognitive decline preceding cognitive impairment can be self-perceived, referred to as subjective cognitive decline (SCD), or go unrecognized., Objective: To study the clinical, cognitive, and structural neuroimaging characteristics of psychometrically normal subjects without self-awareness of cognitive decline (unaware decliners, UD) and to compare them with SCD participants and controls., Methods: 2,640 participants from the ALFA cohort, 1,899 controls, 173 UD (decline reported by the informant only), and 568 SCD underwent clinical and cognitive explorations. A subset of 530 underwent structural MRI (379 Controls; 43 UD; 108 SCD). Linear models adjusting for confounders (age, sex, education, and mood state) were used to assess group differences on cognition and voxel-wise grey matter (GM) volumes., Results: 6.6% were UD while 21.5% SCD. No differences in anxiety and depression were observed between controls and UD, while SCD did (p < 0.01). UD showed lower performance in the Memory Binding Test free recall (p < 0.005) than controls, but no differences compared to SCD. Right medial frontal and insular increments of GM volumes were observed in UD with respect to controls. Informant report of decline in UD and SCD was associated with lower left hippocampal GM volume but related to memory performance only in UD (rho = 0.46, p = 0.002)., Conclusions: UD had worse memory performance than controls which correlated with hippocampal GM volume and presented brain volume increments in self-appraisal areas (medial frontal and insula). Individuals unaware of cognitive decline may represent a distinct group at risk for cognitive impairment and support the usefulness of informant-reported cognitive decline.

Objective: Bilirubin is a potent antioxidant that has been inversely related to cardiovascular disease. There is little information on serum total bilirubin (TB) in relation to atherosclerosis in familial dyslipidemia. We assessed the association between TB and carotid and femoral atherosclerosis in this high-risk group., Approach and Results: We evaluated 464 individuals with familial dyslipidemia (56% men; median age, 48 years), 322 with familial hypercholesterolemia, and 142 with familial combined hyperlipidemia. Carotid and femoral arteries were imaged bilaterally with a standardized ultrasonographic protocol. Mean and maximum intima-media thickness and plaque presence (≥1.2 mm) and height were recorded. Cross-sectional associations between TB and atherosclerosis variables were investigated in multivariable-adjusted models, including lipid values and hypolipidemic drug use. Inflammatory markers (C-reactive protein, total leukocyte count, and lipoprotein[a]) were also determined. Increasing TB levels were associated with decreasing intima-media thickness of all carotid segments ( P <0.05, all). TB also related to carotid plaque, present in 78% of individuals, and to plaque burden (≥3 plaques), with odds ratios (95% confidence interval) 0.59 (0.36-0.98) and 0.57 (0.34-0.96) for each increase of 0.5 mg in TB, respectively. Findings were confirmed in a validation cohort of 177 subjects with nonfamilial dyslipidemia. Only the familial combined hyperlipidemia group, with higher inflammation-related markers, showed an inverse association between TB and femoral plaque height (β=-0.183; P =0.030)., Conclusions: TB was inversely and independently associated with carotid plaque burden in familial and nonfamilial dyslipidemia. These findings support the use of TB as a biomarker of atherosclerosis in this high-risk group., (© 2017 American Heart Association, Inc.)

Supplemental marine omega-3 eicosapentaenoic acid (EPA) has an anti-atherosclerotic effect. Clinical research on EPA supplied by the regular diet and atherosclerosis is scarce. In the framework of the PREvención con DIeta MEDiterránea (PREDIMED) trial, we conducted a cross-sectional study in 161 older individuals at high vascular risk grouped into different stages of carotid atherosclerosis severity, including those without ultrasound-detected atheroma plaque ( n = 38), with plaques <2.0 mm thick ( n = 65), and with plaques ≥2.0 mm ( n = 79). The latter were asked to undergo contrast-enhanced 3T magnetic resonance imaging (MRI) and were subsequently grouped into absence ( n = 31) or presence ( n = 27) of MRI-detectable plaque lipid, a main feature of unstable atheroma plaques. We determined the red blood cell (RBC) proportion of EPA (a valid marker of long-term EPA intake) at enrolment by gas chromatography. In multivariate models, EPA related inversely to MRI-assessed plaque lipid volume, but not to maximum intima-media thickness of internal carotid artery, plaque burden, or MRI-assessed normalized wall index. The inverse association between EPA and plaque lipid content in patients with advanced atherosclerosis supports the notion that this fatty acid might improve cardiovascular health through stabilization of advanced atheroma plaques., Competing Interests: Philip C. Calder is an advisor to Pronova BioPharma. Jordi Salas-Salvadó has received research funding and is a non-paid member of the scientific advisory committee of the International Nut Council. Emilio Ros has received research funding from the California Walnut Commission and is also a non-paid member of its scientific advisory committee. No other authors declare a conflict of~interest.

Background: Cataract is a leading cause of vision impairment worldwide, and surgery is the only available treatment. The process that initiates lens opacification is dependent on the oxidative stress experienced by the lens components. A healthy overall dietary pattern, with the potential to reduce oxidative stress, has been suggested as a means to decrease the risk of developing cataract. We aimed to investigate the hypothesis that an intervention with a Mediterranean diet (MedDiet) rather than a low-fat diet could decrease the incidence of cataract surgery in elderly subjects., Methods: We included 5802 men and women (age range: 55-80 years) from the Prevención con Dieta Mediterránea study (multicenter, parallel-group, randomized controlled clinical trial) who had not undergone cataract surgery. They were randomly assigned to one of three intervention groups: (1) a MedDiet enriched with extra-virgin olive oil (EVOO) ( n = 1998); (2) a MedDiet enriched with nuts ( n = 1914), and a control group recommended to follow a low-fat diet ( n = 1890). The incidence of cataract surgery was recorded yearly during follow-up clinical evaluations. Primary analyses were performed on an intention-to-treat basis. Cox regression analyses were used to assess the relationship between the nutritional intervention and the incidence of cataract surgery., Results: During a follow-up period of 7.0 years (mean follow-up period: 5.7 years; median: 5.9 years), 559 subjects underwent cataract surgery. Two hundred and six participants from the MedDiet + EVOO group, 174 from the MedDiet + Nuts group, and 179 from the control group underwent cataract surgery. We did not observe a reduction in the incidence of cataract surgery in the MedDiet groups compared to the control group. The multivariable adjusted hazard ratios were 1.03 (95% confidence interval [CI]: 0.84-1.26, p = 0.79) for the control group versus the MedDiet + EVOO group and 1.06 (95% CI: 0.86-1.31, p = 0.58) for the control group versus the MedDiet + Nuts group., Conclusions: To our knowledge, this is the first large randomized trial assessing the role of a MedDiet on the incidence of cataract surgery. Our results showed that the incidence of cataract surgery was similar in the MedDiet with EVOO, MedDiet with nuts, and low-fat diet groups. Further studies are necessary to investigate whether a MedDiet could have a preventive role in cataract surgery.

Background: Marine omega-3 eicosapentaenoic acid (EPA) is readily incorporated into cardiomyocyte membranes, partially displacing the omega-6 arachidonic acid (AA). Whereas AA is a substrate for pro-inflammatory eicosanoids, the release of EPA from cell membranes generates anti-inflammatory lipid mediators, contributing to the infarct-limiting effect observed experimental models. Clinical data are lacking., Methods: In this observational study conducted in 100 patients with a reperfused anterior ST-elevation myocardial infarction (STEMI), at hospital admission we quantified by gas-chromatography the red blood cell proportions of AA, EPA, and the AA:EPA ratio, a valid surrogate for cardiomyocyte membrane content. Patients underwent cardiac magnetic resonance imaging in the acute phase (one week post-STEMI), and at long-term (6 months) follow-up. Infarct size (delayed gadolinium enhancement) and cardiac function (left ventricular ejection fraction [LVEF]) were correlated with exposures of interest by multivariate regression analysis., Results: AA:EPA ratio directly related to acute infarct size (coefficient [95% CI]: 6.19 [1.68 to 10.69], P = 0.008) and inversely to long-term LVEF (coefficient [95% CI]: − 4.02 [− 7.15 to − 0.89], P = 0.012). EPA inversely related to acute infarct size (coefficient [95% CI]: − 6.58; [− 11.46 to − 1.70]; P = 0.009), while a direct association with LVEF at follow-up (coefficient [95% CI]: 3.67 [0.25 to 7.08]; P = 0.036) was observed., Conclusions: A low AA:EPA ratio in red blood cells at the time of STEMI is associated with smaller acute infarct size and preserved long-term ventricular function. Our results are consistent with prior work in experimental models and add to the notion of omega-3 fatty acids as a healthy fat., Trial Registration: http://www.clinicaltrials.gov/NCT01311700

Introduction: An unwanted consequence of population aging is the growing number of elderly at risk of neurodegenerative disorders, including dementia and macular degeneration. As nutritional and behavioral changes can delay disease progression, we designed the Walnuts and Healthy Aging (WAHA) study, a two-center, randomized, 2-year clinical trial conducted in free-living, cognitively healthy elderly men and women. Our interest in exploring the role of walnuts in maintaining cognitive and retinal health is based on extensive evidence supporting their cardio-protective and vascular health effects, which are linked to bioactive components, such as n-3 fatty acids and polyphenols. Methods: The primary aim of WAHA is to examine the effects of ingesting walnuts daily for 2 years on cognitive function and retinal health, assessed with a battery of neuropsychological tests and optical coherence tomography, respectively. All participants followed their habitual diet, adding walnuts at 15% of energy (≈30-60 g/day) (walnut group) or abstaining from walnuts (control group). Secondary outcomes include changes in adiposity, blood pressure, and serum and urinary biomarkers in all participants and brain magnetic resonance imaging in a subset. Results: From May 2012 to May 2014, 708 participants (mean age 69 years, 68% women) were randomized. The study ended in May 2016 with a 90% retention rate. Discussion: The results of WAHA might provide high-level evidence of the benefit of regular walnut consumption in delaying the onset of age-related cognitive impairment and retinal pathology. The findings should translate into public health policy and sound recommendations to the general population (ClinicalTrials.gov identifier NCT01634841).

Summary There is a hypothesis causally linking excess intake of n-6 polyunsaturated fatty acids (PUFAs) to atopic disease. Under most dietary conditions, the main precursor of eicosanoids is the n-6 PUFA arachidonic acid (AA). AA-derived eicosanoids play many roles in sensitization to allergens and in allergic inflammation. Long chain n-3 PUFAs inhibit AA incorporation into cell membranes and inhibit AA metabolism to eicosanoids. It is hypothesized that atopy is associated with a higher n-6 PUFA status and with a low n-3 PUFA status. However, measurements of fatty acid composition do not provide a clear picture that such fatty acid abnormalities exist in atopy with no really clear pattern of altered status of a particular fatty acid or a particular fatty acid family. There are few reports of elevated linoleic acid in atopy. Some studies report lower amounts of the n-6 PUFAs, including AA, and of long chain n-3 PUFAs in atopy, although observations on this are not consistent. Taken together these data clearly do not support the hypothesis that atopy is somehow associated with a high exposure to, and status of, n-6 PUFAs. Intervention studies with n-3 PUFAs in pregnant women, infants and children suggest some clinical benefits, although how long lasting these are remains to be determined. The observation that there may be low AA status in atopy suggests that fish oil intervention, which targets AA status and metabolism, may not be ideal and that a combination of fish oil with some longer chain n-6 PUFAs may be more efficacious.

Background: The lipid-modulatory effects of high intakes of the fish-oil fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are well established and likely to contribute to cardioprotective benefits., Objectives: We aimed to determine the effect of moderate EPA and DHA intakes (<2 g EPA+DHA/d) on the plasma fatty acid profile, lipid and apolipoprotein concentrations, lipoprotein subclass distribution, and markers of oxidative status. We also aimed to examine the effect of age, sex, and apolipoprotein E (APOE) genotype on the observed responses., Design: Three hundred twelve adults aged 20-70 y, who were prospectively recruited according to age, sex, and APOE genotype, completed a double-blind placebo-controlled crossover study. Participants consumed control oil, 0.7 g EPA+DHA/d (0.7FO), and 1.8 g EPA+DHA/d (1.8FO) capsules in random order, each for an 8-wk intervention period, separated by 12-wk washout periods., Results: In the group as a whole, 8% and 11% lower plasma triacylglycerol concentrations were evident after 0.7FO and 1.8FO, respectively (P < 0.001): significant sex x treatment (P = 0.038) and sex x genotype x treatment (P = 0.032) interactions were observed, and the greatest triacylglycerol-lowering responses (reductions of 15% and 23% after 0.7FO and 1.8FO, respectively) were evident in APOE4 men. Furthermore, lower VLDL-cholesterol (P = 0.026) and higher LDL-cholesterol (P = 0.010), HDL-cholesterol (P < 0.001), and HDL2 (P < 0.001) concentrations were evident after fish-oil intervention., Conclusions: Supplements providing EPA+DHA at doses as low as 0.7 g/d have a significant effect on the plasma lipid profile. The results of the current trial, which used a prospective recruitment approach to examine the responses in population subgroups, are indicative of a greater triacylglycerol-lowering action of long-chain n-3 polyunsaturated fatty acids in males than in females.

Docosahexaenoic acid (DHA) plays an important role in normal development of the brain and retina in the human. In utero, DHA is incorporated in the fetus, and its accretion continues throughout early postnatal life. Although human breast milk contains this fatty acid, several organizations recommend supplementing infant formulas with DHA for infants and premature infants. Traditionally, certain types of fish oil have been used for fortifying some infant formulas, but with the decline in world fisheries, the search for alternative sources of DHA continues. Among the viable ingredient sources of DHA is oil derived from single-cell organisms (marine microorganisms); however, these oil sources display different positional specificity of DHA in the glycerol lipids compared with that found in human breast milk lipids. In the latter, the DHA is mainly esterified in the central position of the glycerol backbone. Because of these differences in human milk and oils derived from single-cell organisms, recent research in biotechnology has focused on developing new structured triacylglycerols with an intramolecular structure resembling that found in human milk lipids. This research is justified by the potential differences in metabolism of DHA based on the hypothetical bioavailability and benefits in DHA found in human milk lipids. Presented herein is a review of the published research on the metabolism of DHA from different triacylglycerol sources including in vitro studies and animal studies. Despite small differences observed in digestion, the current data reveal a minimal effect on the parameters of development studied for the intramolecular position in which DHA is esterified.

Objective: To determine possible differences of composition in the course of lactation, phospholipid (PL) classes (phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylcholine, and sphingomyelin) and fatty acid composition of PL and triacylglycerol (TGs) fractions of milk fat were analyzed in 66 samples from mothers from Granada (Spain) who gave birth to full-term infants. Analyses included colostrum, transitional milk, and mature milk., Methods: After milk fat extraction, PLs and TGs were separated by thin-layer chromatography and fatty acids of each fraction were converted into their methyl esters, which were analyzed by gas chromatography. PL classes were determined by high-performance liquid chromatography using an evaporative light-scattering detector., Results: Mature human milk showed a lower content (P = 0.020) of PLs than did the other milks. Percentage of sphingomyelin was constant for all stages of lactation, whereas the percentage of phosphatidylcholine in mature milk was significantly lower (P < 0.05) than in colostrum and transitional milk. TGs in mature human milk contained lower percentages (P < 0.001) of arachidonic acid, docosahexaenoic acid, and nervonic acid. Docosahexaenoic acid and nervonic acid also showed a significant decrease (P < 0.001) in total PLs from colostrum and mature milk., Conclusions: The composition of PL classes and fatty acids in PLs and TGs in milk of mothers in Granada (Southern Europe) is different from that in milk from mothers in other parts of the world. In addition, the ratio of long-chain polyunsaturated fatty acids delivered in the form of PLs to long-chain polyunsaturated fatty acids delivered in the form of triacylglycerols diminishes as lactation proceeds.

Supplementation of formulas for full-term infants with long-chain (LC) PUFA [arachidonic acid (AA) and docosahexaenoic acid (DHA)] at levels resembling human milk is recommended because they provide biochemical and functional benefits to the neonate. The objective of this work was to determine whether the source of dietary LC-PUFA affects the bioavailability in full-term infants. Treatment groups were as follows: full-term infants were fed from birth to 3 mo breast-milk (n = 11, 0.4 and 0.3 g/100 g total fatty acids as AA and DHA, respectively), formula containing LC-PUFA in the form of egg phospholipids (n = 12), or a formula supplemented with LC-PUFA in the form of triglycerides synthesized by single cells of algal and fungal microorganisms (n = 12). Both formulas provided 0.4 and 0.1 g/100 g total fatty acids as AA and DHA, respectively. We compared the fatty acid compositions of the main plasma lipid fractions (phospholipids, triglycerides, and cholesteryl esters) at birth and 3 mo. At 3 mo, lower levels of nervonic acid (NA), docosapentaenoic (DPA) acid, and DHA were found in all plasma lipid fractions from infants fed formula compared with those in the human milk-fed infants, irrespective of the source of the formula supplement (P < 0.02). These data demonstrate that the form of dietary LC-PUFA (triglycerides or phospholipids) does not influence their bioavailability. Similarly, absorption of LC-PUFA depends mainly on the lipid composition of the diet fed. These results suggest that the levels of NA, DPA, and DHA in formulas for full-term infants should be increased.

We developed and validated a new high-performance liquid chromatographic method for the separation of phospholipid classes in human milk, infant formulas and phospholipidic sources of long-chain polyunsaturated fatty acids (LC-PUFAs) used in paediatric nutrition. Phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine and sphingomyelin were separated in less than 25 min using an Extrasil silica column (150 x 4.0 mm I.D., 3-microm particle size) by isocratic elution with a mixture of isopropanol-hexane-water. Phospholipids were determined by an evaporative light-scattering detector. Several chromatographic conditions were assayed to optimise the method, whose suitability is shown by the detection limits, linearity ranges and precision rates obtained. The main advantages of the proposed method are its speed and the direct determination of the main phospholipids present in human milk, infant formulas and the phospholipid sources of LC-PUFAs used in paediatric nutrition.