In cohort studies, consumption of nuts has been consistently associated with reduced rates of coronary heart disease (CHD) and total cancer, as well as lower all-cause, cardiovascular and cancer mortality [1,2,3▪]. Of note, there is evidence of a dose–response relationship between nut consumption and reduced cardiometabolic risk. Recent meta-analyses included dose–response analyses that showed significant reductions in the relative risk of CVD and all-cause and CVD mortality for increased daily servings of total nuts [2,3▪]. A recent very large prospective study [4▪] describes findings from the prospective Nurses’ Health Study (NHS) I and II and Health Professionals Follow-Up Study assessing not only total nut consumption but also separated walnut consumption in relation to CVD after follow-up for up to 32 years. Results showed a multivariable-adjusted hazard ratio of 0.71 [95% confidence interval (CI) 0.52–0.97] for CVD per each serving increase in walnuts. Randomized controlled trials (RCTs) have also uncovered a consistent cholesterol-lowering effect of nuts, but no effect on blood pressure . Concerning walnuts, a recent meta-analysis of 24 RCTs of walnuts for outcomes on blood lipids uncovered a significant continuous dose–response relationship between walnut-intake and blood cholesterol reduction . Nut consumption also beneficially influences oxidative stress, inflammation and vascular reactivity . The optimal nutrient composition of nuts probably explains their salutary effects. Nuts contain sizable amounts of fat, but fatty acids are mainly unsaturated; they are also rich in fiber, protein and various bioactive micronutrients [1,7]. The nutrient composition of walnuts differs from that of all other nuts by three important aspects: they contain ≈10% of energy as alpha-linolenic acid (ALA), the main vegetable polyunsaturated n-3 fatty acid (n-3PUFA), are a rich source of phytomelatonin and possess more polyphenols than any other nut type [1,8▪]. Because of their differential composition, walnuts may have specific health effects not observed with other nuts. This review focuses on the latest findings concerning health effects of walnuts and ALA and relevant micronutrients such as nonsodium minerals, phytosterols, γ-tocopherol, melatonin and polyphenols, albeit one should consider that any benefit derived from the consumption of a healthy food with a complex matrix such as walnuts is likely because of the synergy of several or all of its bioactive components acting on multiple metabolic and vascular physiology pathways, rather than to any single nutrient .
Walnuts are the common food with the highest content of ALA , the vegetable n-3 fatty acid. The bioavailability of ALA is almost complete as, like other unsaturated fatty acids, it is nearly 100% absorbed from the diet. Once absorbed, the metabolism of ALA involves a modest conversion to its longer chain counterparts, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) [11▪▪]. Although there is much evidence on the cardioprotective properties of dietary EPA and DHA, mostly supplied by fatty fish and fish oils , the role of ALA in cardiovascular health has been less explored. Recent experimental studies have begun to uncover the benefits of ALA on the arterial tree and in the brain, akin to those observed for EPA and DHA. They include neuroprotection, vasodilation of brain arteries and neuroplasticity . However, results of cohort studies focusing on exposure to ALA and clinical outcomes and RCTs testing ALA-rich foods or supplements for intermediate risk factors have provided inconsistent results [11▪▪].
Alpha-linolenic acid-derived oxylipins
Oxylipins are PUFA metabolites obtained by the action of cyclooxygenase, lipoxygenase and cytochrome P450 epoxygenase. As oxylipins play a role in cardiovascular disease (CVD) and aging, there is an emerging interest on dietary strategies to improve their status [14▪]. Holt et al.  treated hypercholesterolemic women with walnuts (5 or 40 g/day) for 4 weeks and reported that those receiving 40 g/day improved microvascular function in relation to changes in plasma epoxides, particularly arachidonic-acid-derived 14 (15)-epoxyeicosatrienoic acid. Similarly, a raise in circulating ALA-derived oxylipins was observed in 19 healthy men with low intake of marine n-3PUFA who consumed 14 g/day of ALA from linseed oil for 12 weeks . The notion that dietary ALA modifies the oxylipin profile beyond mere changes of its own derivatives was also observed in a study with rats fed diets enriched with either ALA, EPA or DHA .
Experimental and clinical studies indicate that marine n-3PUFA promote the formation of anti-inflammatory and vasodilatory oxylipins, but ALA-derived oxylipins have been little studied. In this regard, challenge with ALA of THP-1-derived M1-like macrophages induced a reduction in lipopolysaccharide (LPS)-induced cytokine production . Of note, in an interesting study conducted in Caenorhabditis elegans, concomitant exposure to ALA and its derived oxylipin 9S-hydroperoxy-10E,12Z,15Z-octadecatrienoic acid induced an increase in the worm's lifespan [19▪].
Among different nuts tested for effects on vascular reactivity in RCTs, only walnuts have been shown to improve endothelial function, as indicated in a recent meta-analysis . This beneficial effect could be ascribed to ALA itself and/or derived oxylipins, but polyphenols, magnesium and L-arginine in walnuts probably play a role.
Alpha-linolenic acid in brain function
As DHA is an integral compound of the membrane phospholipids of neural tissues, there has been interest in exploring whether intake of DHA or its parent foods protects against neurological diseases. The role of ALA on brain function has been little studied, although the picture is beginning to change. In an in-vitro study, primary cultures of embryonic E14 mice neural stem cells were challenged with different doses of linoleic acid and ALA . Authors found that ALA had the highest potential to induce differentiation of neural stem cells toward astrocytes and oligodendrocytes, in parallel to changes in the expression of Notch-1, Hes-1 and Ki-67 genes.
Activation of microglia mediates chronic inflammation-associated brain aging, injury and neurodegeneration. Fisher et al.  investigated the cellular mechanisms underlying walnuts’ protective effects on brain microglial-associated inflammation. To this purpose, they fed walnuts or control diets to aged rats and collected serum, which contained ALA and other walnut-derived bioactives. Added to the medium used to pretreat BV-2 microglial cells subjected to LPS-induced injury, serum from walnut-fed animals protected microglial cells from LPS-induced inflammation. In line with this finding, Lee et al.  recently reported that addition of ALA to the cell culture medium attenuated the over-production of nitric oxide, release of pro-inflammatory cytokines and generation of reactive oxygen species in C6 glial cells treated with a neurotoxin, translating into increased cell viability.
Finally, the potential of ALA to prevent the anxiety disorder ensuing traumatic brain injury was tested in a rat model of mild controlled cortical impact, whereby administration of ALA by subcutaneous injection resulted in a significant reduction in contusion volume and protected against anxiety-like behavior .
Dietary alpha-linolenic acid and chronic disease: updated epidemiology
In contrast with the vast information collected for marine n-3PUFA, epidemiologic data on dietary ALA in relation to prevalent diseases has been scarce and contradictory [11▪▪]. In this respect, a global consortium of 19 cohort studies constituting 45 637 unique individuals and 7973 cases of CHD with data on blood or tissue biomarkers of intake of seafood-derived n-3PUFA and ALA reported a similarly reduced risk of fatal (but not nonfatal) coronary events per 1-SD increases in all biomarkers, the relative risk for ALA being of 0.91 (CI 0.84–0.98) [25▪▪]. Such beneficial effect against cardiac death suggests an antiarrhythmic effect of ALA similar to that of marine n-3PUFA.
Most prospective studies have assessed effects of total nuts on CVD risk. Confirming prior findings, the recent report of Guasch-Ferré et al. [4▪] of a large prospective study shows that participants consuming nuts at least five times per week had 14% lower risk of CVD and 20% lower risk of CHD, but not lower risk of stroke, compared with those with the lowest nut consumption. Interestingly, total nut consumption was more strongly associated with reduced rates of fatal CHD (−31%), but not nonfatal myocardial infarction (−3%), pointing again to an antiarrhythmic effect of nuts, the best candidate being ALA. In that study, walnut consumption was more strongly related to a lower risk of CVD than total nuts, and was also associated with a lower risk of stroke, suggesting an additional effect of walnuts . In addition to its antiarrhythmic potential, ALA may exert beneficial cardiovascular effects by way of cholesterol-lowering, antithrombotic and anti-inflammatory action, and vasculoprotection via improved endothelial function and reduced atherosclerosis .
Like all plant foods, nuts are cholesterol-free but contain chemically related phytosterols, nonnutritive molecules that play a structural role in plant membranes similar to that of cholesterol in animal membranes. These compounds are also believed to have antioxidant properties. Phytosterols are more hydrophobic than cholesterol, a reason why they displace cholesterol from intestinal micelles, thereby interfering with cholesterol absorption, which leads to a reduction of low-density lipoprotein (LDL)-cholesterol [27▪▪]. The phytosterols content of nuts in general (from 95 to 279 mg/100 g) and walnuts in particular (113 mg/100 g)  place them among the whole foods richest in these molecules. Phytosterols, together with unsaturated fatty acids and fiber, justify in part the cholesterol-lowering properties of nuts. Indeed, a pooled analysis of 61 nut RCTs with outcomes on lipid changes reported that the total phytosterol dose from nuts correlated inversely to LDL-cholesterol reduction (r = −0.60) .
Like many plant foods, nuts contain little sodium but are rich in potassium, magnesium and calcium . These three minerals are involved in many aspects of cellular metabolism and other biological processes, including insulin sensitivity, blood pressure regulation and vascular reactivity. Obviously, no cohort studies have related the specific mineral content of walnuts to health outcomes, but much evidence on the beneficial role of nonsodium minerals as contributed by the overall diet is available and the latest findings are briefly reviewed here.
Whereas high-sodium (salt) intake is associated with hypertension, CVD and all-cause mortality, nonsodium minerals generally have the opposite effect . The low-sodium and high-potassium content of nuts (2 mg/100 g and 441 mg/100 g, respectively, in walnuts) is one of the most beneficial of all common vegetable foods. As detailed in a recent comprehensive review , raising dietary K+ blunts the effects of high dietary Na+, indicating that modest sodium restriction with increasing potassium intake is a good general strategy to control blood pressure, prevent stroke and reduce CVD mortality.
Concerning dietary magnesium, the latest meta-analysis with data from 40 cohort studies concludes that increasing intake is associated with a reduced risk of stroke, heart failure, diabetes and all-cause mortality, but not CHD or total CVD . These findings are confirmed by a recent comprehensive review on the topic , which lists walnuts among the plant foods with highest magnesium content (158 mg/100 g) and concludes that high dietary magnesium intake relates to a lower risk of major cardiovascular risk factors (mainly metabolic syndrome, diabetes and hypertension) and is associated with improved endothelial function.
Nuts are among the foods with the highest calcium content (walnuts contain 98 mg/100 g) . A 2015 meta-analysis found no relationship between dietary calcium and risk of CVD mortality  and a recent study from a large prospective cohort reported that dietary calcium was unrelated to all-cause mortality . However, a recent meta-analysis of nine intervention studies lasting from 1 to 7 years demonstrates the potential of dietary calcium with vitamin D in the prevention of total fractures, particularly hip fractures . A combined diet score of potassium, magnesium and calcium was associated with reduced stroke risk in the NHS I and II cohorts , suggesting synergy among these minerals in influencing disease risk.
VITAMIN E (γ-TOCOPHEROL)
The term ‘vitamin E’ comprises four tocopherols (α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol), but only RRR-α-tocopherol satisfies the criteria of being a vitamin. As long as intestinal function is preserved, tocopherols are bioavailable because, being small fatty molecules, they are absorbed along with dietary fat in the intestine and enter the circulation via chylomicron particles . Walnuts are an excellent source of γ-tocopherol, supplying 21 mg/100 g , and there is evidence that the liver hydroxylation and oxidation products of this form of vitamin E are potent free radical scavengers and reduce pro-inflammatory eicosanoids and the inflammatory response, actions that are not shared by α-tocopherol. For these reasons, γ-tocopherol and not α-tocopherol is believed to be the cardioprotective form of vitamin E . A similar effect of γ-tocopherol over α-tocopherol has been observed in relation to cancer, both in experimental and epidemiological studies .
At night, the mammalian pineal gland synthetizes melatonin, a hormone with experimental evidence of pleiotropic effects, such as antioxidant, anti-inflammatory, antiobesity and anticancer activities, and neuroprotection, that is best known for its sleep-regulatory role. Many plants contain sizable amounts of bioavailable melatonin [39▪]. Walnuts are one of the main food sources of phytomelatonin, with an average content of 350 ng/100 g, and this together with ALA and antioxidants was believed to underlie the beneficial effect on mood observed in a small 6-week trial of walnut supplementation in healthy young men . There is evidence that melatonin from walnuts is absorbed, as shown by a roughly four-fold rise in serum melatonin levels in an experiment with rats fed exclusively walnuts . A sound experimental study comparing diets with walnut flour (containing 7.5 ng/g melatonin), synthetic melatonin and control in a murine model of breast cancer provides new insight into the antitumorigenic and immunomodulatory actions of walnut phytomelatonin . Concerning the primary function of melatonin, evidence is lacking to support the claim that walnuts improve sleep quality, an interesting topic for future research.
Among common foods, walnuts are one of the most important sources of total polyphenols, with a reported content of up to 2500 mg/100 g [8▪,43▪▪]. The most abundant are ellagitannins, mainly pedunculagin [43▪▪]. Indeed, walnuts are the richest plant source of ellagitannins (∼1600 mg/100 g) [44▪]. Upon hydrolysis, ellagitannins release ellagic acid, which is further metabolized by intestinal bacteria to urolithins, in a process influenced by individual differences in gut microbiota [45▪▪,46]. Urolithins are much better absorbed than ellagitannins, reach the bloodstream and target many organs and tissues. Ellagitannins and urolithins disclose many biological activities, such as antioxidant, anti-inflammatory, anticancer and prebiotic effects, suggesting a range of beneficial effects on human health [43▪▪]. However, the mechanisms of action supporting such benefits are still under debate. A recent meta-analysis reported a reduction of adiposity, LDL-cholesterol and glucose following consumption of ellagitannin-rich foods, particularly walnuts [44▪].
The most widely investigated effects of ellagic acid and urolithins concern inhibition of cancer-cell proliferation. Research in vitro and in animal models has shown that phenolic walnut extracts induce a dose-dependent inhibition of the growth of colon, breast, and prostate cancer cells [43▪▪,47,48]. Modulation of cell signaling, cell cycle arrest and key cellular processes such as mitogen-activated protein kinases signaling appear to underlie the antitumor activity of walnut extracts [43▪▪]. A recent study in a mice model of obesity showed that a diet containing 6.7% walnuts protected against intestinal tumorigenesis and growth, along with preservation of intestinal stem cell function . For the particular case of colon cancer, other likely contributors to the chemopreventive effect of walnuts are changes of the gut microbiome. Both in animal experiments [48,50] and RCTs [51▪,52], walnut feeding promoted bacterial diversity and enriched the microbiota with probiotic-type bacteria, including Lactobacillus spp. and Roseburia spp., and increased the abundance of butyrate-producing Firmicutes whereas reducing Bacteriodetes. Walnut consumption was also associated with reduced fecal concentrations of toxic secondary bile acids deoxycholate and lithocholate [51▪]. Such beneficial effects on the intestinal microbiota can likely be ascribed to nondigestible material from walnuts, mainly ellagitannins and fiber polysaccharides.
All nuts are rich sources of bioactive nutrients, but walnuts have a distinct composition (high ALA, melatonin and polyphenol content). Recent findings from clinical studies suggest that ALA metabolism gives rise to vasodilatory and anti-inflammatory oxylipins, which might underlie the beneficial effect of walnut consumption on endothelial function. Incipient experimental research also suggests that ALA is neuroprotective, although polyphenols from walnuts probably synergize for beneficial effects on brain function. Recent epidemiological observations have related the blood or tissue content of ALA as biomarker of intake to protection from fatal CHD to the same degree as that afforded by EPA and DHA, pointing to a similar antiarrhythmic effect of both vegetable and marine n-3PUFA. Given that dose–response relationships exist between walnut consumption and both reduced CVD rates and blood cholesterol reduction, dose appears to be a relevant factor when recommending walnuts to improve cardiometabolic risk. Phytosterols in nuts are responsible in part for their cholesterol-lowering effect, as indicated by a recent meta-analysis of nut-feeding trials. Nonsodium minerals such as potassium and magnesium, shared by all nuts, have beneficial effects on cardiometabolic risk, as confirmed by recent reviews. Walnuts are rich in γ-tocopherol, a form of vitamin E that has anti-inflammatory and anticancer properties in addition to being a potent antioxidant. Evidence is emerging on antitumorigenic actions of walnut phytomelatonin, but its sleep-promoting effects have not been tested in humans. Finally, recent experimental evidence suggests that the main polyphenols in walnuts, ellagitannins and their metabolites (urolithins), have beneficial effects against oxidation, inflammation, and tumor growth and also positively influence the intestinal microbiota. As shown in part in Fig. 1, most bioactive walnut micronutrients synergize to affect multiple metabolic pathways leading to protection from chronic noncommunicable diseases. For simplicity, the scheme cannot include all the described effects of particular molecules. Given their highly bioactive micronutrient content, walnuts may be considered as natural health capsules that can be incorporated into the usual diet to promote overall health.
CIBEROBN is an initiative of ISCIII, Spain.
Financial support and sponsorship
This work was supported by the Instituto de Salud Carlos III Miguel Servet fellowship (grant CP12/03299) and by The Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (grant PI15/01014).
Conflicts of interest
E.R., M.I.-P. and A.S.-V. have received funds for research from the California Walnut Commission (CWC) through their institutions. E.R. has also received fees for presentations from the CWC and is a nonpaid member of its Scientific Advisory Board.
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