Given the evidence of the health benefits of plant-based diets and long-chain n–3 (ω-3) fatty acids, there is keen interest in better understanding the role of α-linolenic acid (ALA), a plant-derived n–3 fatty acid, on cardiometabolic diseases and cognition. There is increasing evidence for ALA largely based on its major food sources (i.e., walnuts and flaxseed); however, this lags behind our understanding of long-chain n–3 fatty acids. Meta-analyses of observational studies have shown that increasing dietary ALA is associated with a 10% lower risk of total cardiovascular disease and a 20% reduced risk of fatal coronary heart disease. Three randomized controlled trials (RCTs) [AlphaOmega trial, Prevención con Dieta Mediterránea (PREDIMED) trial, and Lyon Diet Heart Study] all showed benefits of diets high in ALA on cardiovascular-related outcomes, but the AlphaOmega trial, designed to specifically evaluate ALA effects, only showed a trend for benefit. RCTs have shown that dietary ALA reduced total cholesterol, LDL cholesterol, triglycerides, and blood pressure, and epidemiologic studies and some trials also have shown an anti-inflammatory effect of ALA, which collectively account for, in part, the cardiovascular benefits of ALA. A meta-analysis reported a trend toward diabetes risk reduction with both dietary and biomarker ALA. For metabolic syndrome and obesity, the evidence for ALA benefits is inconclusive. The role of ALA in cognition is in the early stages but shows promising evidence of counteracting cognitive impairment. Much has been learned about the health benefits of ALA and with additional research we will be better positioned to make strong evidence-based dietary recommendations for the reduction of many chronic diseases.

Oxidative stress contributes not only to the pathogenesis of type 2 diabetes (T2D) but also to diabetic vascular complications. It follows that antioxidants might contribute to limiting the diabetes burden. In this review we focus on ellagic acid (EA), a compound that can be obtained upon intestinal hydrolysis of dietary ellagitannins, a family of polyphenols naturally found in several fruits and seeds. There is increasing research on cardiometabolic effects of ellagitannins, EA, and urolithins (EA metabolites). We updated research conducted on these compounds and (I) glucose metabolism; (II) inflammation, oxidation, and glycation; and (III) diabetic complications. We included studies testing EA in isolation, extracts or preparations enriched in EA, or EA-rich foods (mostly pomegranate juice). Animal research on the topic, entirely conducted in murine models, mostly reported glucose-lowering, antioxidant, anti-inflammatory, and anti-glycation effects, along with prevention of micro- and macrovascular diabetic complications. Clinical research is incipient and mostly involved non-randomized and low-powered studies, which confirmed the antioxidant and anti-inflammatory properties of EA-rich foods, but without conclusive results on glucose control. Overall, EA-related compounds might be potential agents to limit the diabetes burden, but well-designed human randomized controlled trials are needed to fill the existing gap between experimental and clinical research.

Oxidative stress and inflammation are mediators in the pathophysiology of several non-communicable diseases (NCDs). Tree nuts and peanuts lower risk factors of cardiometabolic disease, including blood lipids, blood pressure and insulin resistance, among others. Given their strong antioxidant/anti-inflammatory potential, it is plausible that nuts may also exert a favorable effect on inflammation and oxidative stress. Evidence from systematic reviews and meta-analyses of cohort studies and randomized controlled trials (RCTs) suggest a modest protective effect of total nuts; however, the evidence is inconsistent for specific nut types. In this narrative review, the state of evidence to date is summarized for the effect of nut intake on biomarkers of inflammation and oxidative stress, and an attempt is made to define the gaps in research while providing a framework for future research. Overall, it appears that some nuts, such as almonds and walnuts, may favorably modify inflammation, and others, such as Brazil nuts, may favorably influence oxidative stress. There is a pressing need for large RCTs with an adequate sample size that consider different nut types, and the dose and duration of nut intervention, while evaluating a robust set of biomarkers for inflammation and oxidative stress. Building a stronger evidence base is important, especially since oxidative stress and inflammation are mediators of many NCDs and can benefit both personalized and public health nutrition.

Non-alcoholic fatty liver disease is a highly prevalent condition without specific pharmacological treatment, characterized in the initial stages by hepatic steatosis. It was suggested that lipid infiltration in the liver might be reduced by caffeine through anti-inflammatory, antioxidative, and fatty acid metabolism-related mechanisms. We investigated the effects of caffeine (CAF) and green coffee extract (GCE) on hepatic lipids in lean female rats with steatosis. For three months, female Sprague-Dawley rats were fed a standard diet or a cocoa butter-based high-fat diet plus 10% liquid fructose. In the last month, the high-fat diet was supplemented or not with CAF or a GCE, providing 5 mg/kg of CAF. Plasma lipid levels and the hepatic expression of molecules involved in lipid metabolism were determined. Lipidomic analysis was performed in liver samples. The diet caused hepatic steatosis without obesity, inflammation, endoplasmic reticulum stress, or hepatic insulin resistance. Neither CAF nor GCE alleviated hepatic steatosis, but GCE-treated rats showed lower hepatic triglyceride levels compared to the CAF group. The GCE effects could be related to reductions of hepatic (i) mTOR phosphorylation, leading to higher nuclear lipin-1 levels and limiting lipogenic gene expression; (ii) diacylglycerol levels; (iii) hexosylceramide/ceramide ratios; and (iv) very-low-density lipoprotein receptor expression. In conclusion, a low dose of CAF did not reduce hepatic steatosis in lean female rats, but the same dose provided as a green coffee extract led to lower liver triglyceride levels.

Docosahexaenoic acid (DHA) might help prevent Alzheimer’s disease (AD). Red blood cell (RBC) status of DHA is an objective measure of long-term dietary DHA intake. In this prospective observational study conducted within the Framingham Offspring Cohort (1490 dementia-free participants aged ≥65 years old), we examined the association of RBC DHA with incident AD, testing for an interaction with APOE-ε4 carriership. During the follow-up (median, 7.2 years), 131 cases of AD were documented. In fully adjusted models, risk for incident AD in the highest RBC DHA quintile (Q5) was 49% lower compared with the lowest quintile (Q1) (Hazard ratio [HR]: 0.51, 95% confidence interval [CI]: 0.27, 0.96). An increase in RBC DHA from Q1 to Q5 was predicted to provide an estimated 4.7 additional years of life free of AD. We observed an interaction DHA × APOE-ε4 carriership for AD. Borderline statistical significance for a lower risk of AD was observed per standard deviation increase in RBC DHA (HR: 0.71, 95% CI: 0.51, 1.00, p = 0.053) in APOE-ε4 carriers, but not in non-carriers (HR: 0.85, 95% CI: 0.65, 1.11, p = 0.240). These findings add to the increasing body of literature suggesting a robust association worth exploring dietary DHA as one strategy to prevent or delay AD.

RBC long-chain omega-3 (n–3) fatty acid (FA) percentages (of total fatty acids) are associated with lower risk for total mortality, but it is unknown if a suite of FAs could improve risk prediction. The objective of this study was to compare a combination of RBC FA levels with standard risk factors for cardiovascular disease (CVD) in predicting risk of all-cause mortality. Framingham Offspring Cohort participants without prevalent CVD having RBC FA measurements and relevant baseline clinical covariates (n = 2240) were evaluated during 11 y of follow-up. A forward, stepwise approach was used to systematically evaluate the association of 8 standard risk factors (age, sex, total cholesterol, HDL cholesterol, hypertension treatment, systolic blood pressure, smoking status, and prevalent diabetes) and 28 FA metrics with all-cause mortality. A 10-fold cross-validation process was used to build and validate models adjusted for age and sex. Four of 28 FA metrics [14:0, 16:1n–7, 22:0, and omega-3 index (O3I; 20:5n–3 + 22:6n–3)] appeared in ≥5 of the discovery models as significant predictors of all-cause mortality. In age- and sex-adjusted models, a model with 4 FA metrics was at least as good at predicting all-cause mortality as a model including the remaining 6 standard risk factors (C-statistic: 0.778; 95% CI: 0.759, 0.797; compared with C-statistic: 0.777; 95% CI: 0.753, 0.802). A model with 4 FA metrics plus smoking and diabetes (FA + Sm + D) had a higher C-statistic (0.790; 95% CI: 0.770, 0.811) compared with the FA (P < 0.01) or Sm + D models alone (C-statistic: 0.766; 95% CI: 0.739, 0.794; P < 0.001). A variety of other highly correlated FAs could be substituted for 14:0, 16:1n–7, 22:0, or O3I with similar predicted outcomes. In this community-based population in their mid-60s, RBC FA patterns were as predictive of risk for death during the next 11 y as standard risk factors. Replication is needed in other cohorts to validate this FA fingerprint as a predictor of all-cause mortality.