**6. Phytochemicals and Mechanisms Responsible for the Beneficial Activity**

Biologically active antioxidant compounds found in nuts can modulate essential physiological processes inside human bodies and influence key mechanisms of actions involved in aging and age-associated diseases [154].

Nut antioxidant polyphenols, the majority of which are found in the pellicle of nuts, can have anti-carcinogenic potential. They retard the initiation, differentiation, and proliferation of cancer cells, modulate signaling pathways related to cell survival, attenuate the growth of tumors, diminish angiogenesis and metastasis, and stimulate the expression of detoxification enzymes and antioxidants [155,156].

Some polyphenols are found in significant amounts in certain types of nuts, giving them specific biological actions. Thus, ellagic acid (EA), physiologically hydrolyzed from ellagitannins (ETs) abundant in walnuts, found also in pecans and pine nuts, could reduce adipocyte expansion and might be beneficial in the management of obesity and the metabolic complications related to obesity [157]. Another example is anacardic acid, a strong antioxidant polyphenol contained in cashew nut shells, which was shown to have anticancer potential, inhibited prostate tumor angiogenesis, cell proliferation, and prompted apoptosis [158–160].

Other polyphenols, found only in very small amounts in nuts, can contribute to beneficial health effects through their hormetic and/or synergistic actions with other polyphenols. In pistachios, the small amounts of genistein, (-) epigallocatechin-3-gallate (EGCG) or resveratrol can act synergistically through common or complementary action pathways with proven antioxidant and anti-aging activity. Thus, the flavonoid (isoflavone) genistein has demonstrated antioxidant, chemopreventive, and chemotherapeutic effects [161]. Growing evidence suggests that EGCG, also present in pecans and hazelnuts, can contribute to the anti-cancer potential [162]. It has an inhibitory proliferation effect on human pancreatic cancer cells [163]. In oral cancer, EGCG exerted an apoptotic therapeutic role, controlling cancer cell proliferation, and in breast cancer showed an anti-angiogenic effect [164]. Resveratrol, another antioxidant phytochemical also found in peanuts besides pistachios, proved to have neurogenesis activity and cancer chemoprevention potential [165,166]. Pterostilbene (PTS), a natural dimethylated analog of resveratrol, had the capability to significantly inhibit secretion of TNF-α and alter the cytokine production in IGROV-1 ovarian cancer cell line [167].

Melatonin, found in walnuts in quantities of 3.5 ± 1.0 ng/g, could be protective against CV damage and cancer initiation and propagation [168].

Selenium, a trace element supplied mostly by Brazil nuts, is associated with reduced risks for prostate cancer [169] and hepatocellular carcinoma [170].

Nuts are characterized as fatty foods, with total lipid content ranging from 46% in cashew to 76% in macadamia (Table 7). However, the healthy lipid profile of tree nuts and peanuts, mostly MUFAs and PUFAs and low or very low amounts of saturated fatty acids, is a key mechanism of action in the prevention of several age-related diseases [154,171].

Lipophilic bioactive compounds found in nuts can also influence the aging process. Among those compounds, phytosterols can reduce CV risk [172]. Increasing evidence recommends phytosterols for lowering LDL-C [173–175]. Phytosterols, being more hydrophobic than cholesterol, can dislocate cholesterol from intestinal micelles and reduce LDL-C absorption [176]. In combination with *n*-3 PUFAs, phytosterols show both complementary and synergistic lipid-lowering effects in hyperlipidemic mature adults [177].

Lipophilic isomers of vitamin E (tocopherols and tocotrienols), via their antioxidant properties, might inhibit the propagation of free radical damage in biological membranes and enhance immune functions [91]. Oxidation stress and inflammation, processes involved in the decline of cognitive function and neural capacity of the aging brain, can be reduced by tocols through their antioxidant and anti-inflammatory properties [178,179]. It was suggested that dietary intake of tocotrienols could be sufficient to support neuroprotection [180,181].

The lipophilic antioxidant phytochemicals, even in minute amounts, showed increased bioavailability and bioaccessibility, with their intestinal absorption being favored by the presence of lipids in tree nuts and peanuts. Lutein, the most abundant antioxidant carotenoid in the human retina and brain, can be found in pistachios [182]. Age-related macular degeneration (AMD), the primary cause of blindness and vision impairment in old age, can be amended or prevented by lutein [183]. Data indicated the significant impact macular pigment density, a biomarker of brain lutein, might also have on the brain health and cognition in the elderly by improving neurobiological efficiency, neural structure and efficacy, visual perception, and decision-making [184,185]. Recent scientific evidence showed that lutein could stop neuroinflammation, a pathological condition of many neurodegenerative disorders, diminish lipid peroxidation, and, by down-regulation of the NF-κB (the nuclear factor kappa-light-chain-enhancer of activated B cells) pathway, decrease the release of pro-inflammatory cytokines [186]. Compared to other sources, the amount of lutein found in pistachios is low, but as mentioned before, the intestinal absorption of lutein is enhanced by the presence of fatty acids in the tree nut.

Two mechanisms of actions, increased cholesterol efflux and improved endothelial function, favorably affected by whole walnuts and walnut oil, may answer in part the CV benefits of walnut consumption [187]. The favorable effect walnuts have on endothelial function could be credited to ALA, oxylipins (PUFA metabolites with a protective role in CVD and aging), polyphenols, L-arginine, and magnesium [176]. Walnut kernels provide ~9% ALA, while walnut oil provides ~10% ALA [81].

Similarly, ALA might be the factor for the decreased number of atherogenic small and dense LDL-C particles and increased number of large HDL-C particles noticed after walnut intake, as well as the reduction of detrimental lipid classes, such as ceramides and sphingomyelins, associated with CVD risk [188].

The synergistic influence exerted by MUFAs and PUFAs, antioxidant polyphenols and lipophilic compounds, and fiber in the modulation of specific miRNAs, have resulted in the improvement of insulin sensitivity via the PI3K-AKT signaling pathway in pre-diabetic and diabetic population [189].

In pathological conditions, such as AD, there is a diminished expression of glucose transporters, which apparently contributes to a reduced utilization of glucose in cognition-critical brain areas. However, transport and metabolism of ketone bodies (KBs), metabolites produced by the liver as alternative energy sources, are not affected in AD [190]. For that reason, periods of ketogenic diets (KDs) can possibly be effective preventive or treatment measures for neurological disorders [191]. We argue that nuts, due to their phytochemical profile (fat content between 49 and 75%, low amounts

of carbohydrates, and high content of ketogenic amino acids including leucine) and strong antioxidant potential, can be part of KDs. Important actions of KDs are related to decrease oxidative stress and inflammatory activity and improve mitochondrial function [192].

As seen in this review, higher nut intake by mature adults was associated with a reduced risk of diabetes, CHD, CVD, several types of cancer, and cognitive disorders. For most of these outcomes, there were indications of nonlinear associations between tree nut and peanut consumption and decreased risk noticed up to an intake of around 15–20 g per day, or 4–5 servings per week, with no further decrease with higher intakes. One study revealed that walnuts had a beneficial effect against diabetes at about 5 grams per day, a little more than one serving per week, with again no additional results for greater intake amount. The intake of both tree nuts and peanuts was linked with reduced risks of diabetes, CHD, CVD, and cancer, as well as increased cognitive function and performance. Although, only tree nuts showed increase in flow-mediated dilation and decrease in LDL-C or certain biochemical and anthropometric parameters (fasting insulin, HOMA-IR, HbA1c, BW, Wc). The results of our study are in line with other analyses that have investigated the relationship between nut intake and chronic diseases [22,94].
