Recent advances on the effect of nut consumption on cognitive improvement

Abstract

Cognitive disorders, including dementia, Parkinson's and Alzheimer's disease, pose significant public health issues. Preventing/delaying their onset is essential as effective medical treatments are unavailable. Nuts contain bioactive compounds, including fatty acids, macronutrients such as proteins and dietary fibers, micronutrients, and polyphenols; these act synergistically preventing age-related diseases. Epidemiological investigations have established that high nut consumption reduces cognitive impairment risk, suggesting it is useful for cognitively impaired individuals; however, clinical data on the effects of nut consumption on cognitive function are lacking. This review summarized nut consumption effects on oxidative stress, inflammatory response, and gut microbiota. Nuts reduce oxidative stress; their active substances, including glansreginin A, proanthocyanidins, quercetin, and nut oil, have significant anti-inflammatory effects. Furthermore, they comprise complex mixtures, which synergistically induce beneficial changes in the intestinal microbial community.

INTRODUCTION

Cognitive disorders such as dementia, Parkinson's and Alzheimer's disease, are chronic conditions associated with neuronal and synaptic losses, inflammation, oxidative stress, and disturbances of the immune function, among others (Neher, 2021). The lack of effective pharmacological agents to treat dementia and prevent or delay its onset poses a primary global concern. Therefore, choosing an appropriate diet and healthy lifestyle, which are potentially beneficial to chronic diseases, is essential.

Several previous studies have described the phytochemical composition and bioactivity of nuts. Although different nuts contain varying nutrients, their overall nutritional profiles are similar: they contain high concentrations of unsaturated fatty acids, proteins, and polyphenols. These constituents exhibit high nutritional value and health benefit effects (Alasalvar et al., 2020; Ros et al., 2021) (Figure 1a) and may act synergistically to prevent age-related diseases (Arslan et al., 2020). Epidemiological studies have established the beneficial effects of nut consumption on many age-related diseases, such as cognitive disorders, cancer, coronary artery disease, type 2 diabetes mellitus (T2DM), and cardiovascular disease (Grosso & Estruch, 2016). Furthermore, these diseases are related to behavioral risk factors, such as suboptimal diet (X. Liu et al., 2020; Naghshi et al., 2021). Additionally, regular nut consumption seems to prevent cellular senescence and contribute to telomere health, which is related to biological age and chronic diseases (Tan, Tey et al., 2021).

FIGURE 1. (a) The health benefit effects of nuts. (b) The number of publications on “nuts and cognitive,” “nuts and memory,” “nuts and neuroprotective,” “nuts and brain health,” and “nuts and neurodegenerative disease” indexed by Pubmed since 2011.

The number of publications on “nuts and cognitive,” “nuts and memory,” “nuts and neuroprotective,” “nuts and brain health,” and “nuts and neurodegenerative disease” indexed by Pubmed has increased since 2011 (Figure 1b). In PubMed database, over 20 countries have conducted research on the neural protective effects of nuts, with the top five countries being The United States, Spain, China, Australia, and Italy. Population studies have reached inconsistent conclusions on the beneficial effects of dietary nut intake on cognitive dysfunction. Thus, the effects of nut consumption on oxidative stress, inflammatory response, and gut microbiota were summarized and comprehensively reviewed.

BIOACTIVE COMPOUNDS CONTAINED IN NUTS

Nuts are widely consumed all over the world (Ghosh et al., 2020; Guasch-Ferré & Willett, 2021). A systematic review study has been conducted on the nutritional compositions and bioactive compounds of nuts, which is shown in Table 1 (Rusu et al., 2018). The most common edible nuts are walnuts, hazelnuts, Brazil nuts, cashews, pecans, pistachios, almonds, macadamias, and pine nuts. Nuts with a low digestible carbohydrate concentration contain various nutrients such as dietary fibers, proteins, unsaturated fatty acids, vitamins, micronutrients, minerals, and phytochemicals (Polmann et al., 2022).

TABLE 1 Nutritional composition of nuts.

Nuts	Protein (g/100 g)	Lipids (g/100 g)	Total fiber (g/ 100 g)	Carbohydrate (g/100 g)	Phytosterols (mg/100 g)	Total polyphenols (mg/100 g)
Almond	19.5–26.0	43.4–67.0	2.5–14.0	2.1–12.0	452.0	287.9
Walnut	13.5–15.2	64.5–65.2	6.7	2.1–13.7	321.1	1574.8
Cashews	18.2–36.3	43.8–51.2	2.5–4.2	7.9–30.1	1714.8	232.9
Pistachios	19.8–20.2	45.1–45.3	10.6	1.5–27.2	291.0	1420.0
Hazelnuts	14.1–15.0	60.8–61.5	9.7	1.4–16.7	371.3	671.8
Pecan	8.6–9.0	60.0–62.2	10.0–13.0	13.0–13.4	28.7	1284.0
Macadamias	7.9–8.4	66.2–75.8	8.6	1.4–13.8	122.3	126.0
Brazil nut	14.1–18.6	64.9–67.2	8.0–8.5	6.3–7.6	152.8	244.0
Pine nut	13.1–13.7	61.7–68.4	3.7	1.8–13.1	229.5	58.2

Note: Data from Rusu et al. (2018) and Polmann et al. (2022).

Nuts have an optimal fatty acid content, mainly composed of polyunsaturated and monounsaturated fatty acids. Oleic acid is present in most nuts, followed by linoleic and alpha-linolenic acids. Previous studies reported that supplementation with nut oil has improved memory disorders (Islam et al., 2020; Liao et al., 2020). Nuts also contain other fat-soluble compounds, such as tocopherols, chlorophylls, carotenoids, phytosterols, and sphingolipids, which have strong biological activities (Alasalvar et al., 2020). Nuts are optimal sources of proteins containing all the essential amino acids required for human well-being. Arginine is found in high amounts in nuts; in the human body, it is metabolized into nitric oxide, a major contributor to the cardiovascular health, and can ameliorate insulin sensitivity in patients with T2DM. Moreover, bioactive peptides from nuts have exhibited multiple biological activities in specific diseases, such as neuroprotective activity, antidiabetic activity, antioxidant, and anticancer activities (Acevedo-Juárez et al., 2022). Additionally, nuts contain multifunctional phenolic compounds, such as proanthocyanidins, resveratrol, quercetin, and epigallocatechin gallate, which significantly reduce inflammatory responses and regulate different signaling pathways to maintain brain health. Nuts are available sources of trace elements and minerals, such as phosphorus, iron, calcium, and magnesium, necessary for human health. Based on this composition, nuts are a viable option for sustaining healthy physical conditions.

The main phytochemicals in nuts include polyphenols, vitamin E, and unsaturated fat acids, which can reduce age-related oxidative stress and neuroinflammation. However, the neurological benefits is associated with the synergistic interaction of different bioactive compounds. According to the data from United States Department of Agriculture (USDA) (USDA, 2013), walnuts, pistachios, and pecans contain higher contents of total polyphenols; almonds, pecans, and pistachios contain higher contents of vitamin E, while macadamias, pecans, and walnuts contain higher contents of unsaturated fat acids.

ASSOCIATION BETWEEN NUT CONSUMPTION AND COGNITIVE DISORDERS

In recent years, dietary walnut intake has gained increasing attention as it is associated with a lower risk of cognitive impairment and other age-related diseases (Rabassa et al., 2020; Theodore et al., 2021). However, these results are obtained from various epidemiological investigations, and clinical data on these effects are lacking.

Recent epidemiological studies on elderly individuals established almond consumption significantly improves memory and learning and reduces cognitive impairment risk (Mustra Rakic et al., 2022; Rabassa et al., 2020). An observational study evaluated the relationship between whole-walnut intake and cognition in older adults and observed higher cognitive scores in individuals who consumed walnuts (Bishop & Zuniga, 2021). However, in a randomized trial including older overweight adults, almond consumption did not induce effective changes in mood or cognitive performance (Coates et al., 2020). Another randomized control trial revealed no significant cognition improvement in healthy elderly individuals after a 2-year daily consumption of walnuts. However, further analysis indicated that walnut intake positively affected higher risk subgroups (Sala-Vila et al., 2020). The results of human studies are inconsistent possibly owing to the interindividual differences of the volunteers included, to inconsistent research methods, as well as to interference from multiple factors. However, several animal studies consistently revealed that nut consumption provides neuroprotection and improves cognitive function (Esselun et al., 2021; Nuzzo et al., 2020), suggesting that further human trials with controlled independent variables are required. An overview of recent observational studies assessing the associations between nut intake and cognitive performance is presented in Table 2.

TABLE 2 Observational studies assessing the association between nut intake and cognitive performance.

Design	Study participants and settings	Exposure	Outcome measures	Main findings	Reference
CS	500 men and 500 women aged ≧20 years (mean age = 35.8 years).	Nuts intake from FFQ based on the Qatar Biobank Study.	MRT	Nut intake was inversely associated with MRT (p = 0.024), specifically among those aged > 50 years.	(Nafea et al., 2021)
PS	16,737 participants in a population-based cohort; two major Chinese dialect groups, the Hokkiens and the Cantonese.	165-item semi-quantitative FFQ at baseline; nuts intake included a combination of peanuts and tree nuts.	SM-MMSE	The mean adjusted SM-MMSE scores were significantly higher for those who consumed 1-3 servings/month, 1 serving/week, and ≥2 servings/week than for participants who consumed < 1 serving/month of nuts (all p values < 0.01).	(Jiang et al., 2021)
CS	2454 adults aged between 60 and 80 years (mean age = 69.4) who had two 24-h dietary recalls, cognitive function tests, and education level and with no history of stroke.	P/PB and TN consumption was measured based on 2011-2014 NHANES data.	CERAD W-L, AFT, DSST	Participants who did not consume P/PB were prone to have poor CERAD W-L outcomes (adjusted OR [aOR] = 1.56, 95% CI 1.24–1.97; p < 0.05), AFT (aOR = 1.29, 95% CI 1.03–1.61; p < 0.05), and DSST (aOR = 1.43, 95% CI 1.12–1.82; p < 0.05) compared to those who did consume P/PB.	(Katzman & Nielsen, 2021)
PS	33,931 nurses in the Nurses’ Health Study from 1998 to 2002; USA.	Nuts intake from the FFQ.	Age-adjusted models	A significant association was observed between total nut intake and higher odds of healthy aging for analyses including and excluding peanut butter and in age-adjusted models (trend  <  0.0001 for both).	(Freitas-Simoes et al., 2020)
CS	1848 older adults (≥ 60 years) from the NHANES 2011–2012 and 2013–2014 cohorts.	Nut intake; tree and ground nuts were estimated from both 24-h dietary recalls.	CERAD, DSST, animal fluency	CERAD total, animal fluency, and DSST scores were significantly higher from nonconsumers (lowest scores) to low and moderate (highest scores) intake group, but not the met recommendation group (all p <  0.05).	(Tan, Georgousopoulou, et al., 2021)
CS	536 older adults (≥ 65 years) from NAHSIT between 2014 and 2016; Taiwan, China.	79-item FFQ to investigate the dietary information.	MMSE	Significantly decreasing trends (all p < 0.001) and protective effects in MCI occurrence were observed with an increased intake frequency of nuts and seeds (four or more times per week: aOR = 0.27, p < 0.001; one to three times per week: aOR = 0.57, p < 0.001).	(Fan et al., 2022)
CS	9028 participants (≥ 60 years) from Zhejiang Ageing and Health Cohort Study; Zhejiang province, China.	Frequency of nut intake and daily amount of nut intake in the consuming nuts days.	The log-binomial regression models; the GEE method	Compared with nonconsumers or less-than-weekly consumers, participants consuming nuts of ≥ 70 g/week had a 17%-lower risk of cognitive impairment (RR = 0.83, 95% CI 0.75–0.91).	(F. Li, Jiang et al., 2022)
PS	1037 community-dwelling nondemented participants aged 70 to 90 years; Sydney, Australia.	The dietary intake of participants was assessed at baseline via completion of the Dietary Questionnaire for Epidemiological Studies Version 2.	Neuropsychological tests	Higher intake of legumes and nuts was related to better overall performance in global cognition (β = 0.091; 95% CI: 0.035–0.146; p = 0.001), multiple cognitive domains, and less decline in global cognition (β = −.016; 95% CI: −0.032 to −0.001; p = 0.032).	(Chen et al., 2022)

Abbreviations: AFT, animal fluency test; CERAD W-L, Word Learning subtest; CERAD, Consortium to Establish a Registry for Alzheimer's Disease; CS, cross-sectional study; DSST, digit symbol substitution test; FFQ, food frequency questionnaire; GEE, generalized estimating equation; MCI, mild cognitive impairment; MMSE, mini-mental state examination; MRT, mean reaction time; NAHSIT, Nutrition and Health Survey in Taiwan; NHANES, National Health and Nutrition Examination Surveys; P/PB, peanut and peanut butter; PS, prospective study; SM-MMSE, Singapore modified version of the Mini-Mental State Examination; TN, tree nuts.

EFFECT OF NUT INTAKE ON COGNITIVE IMPAIRMENT CAUSED BY OXIDATIVE STRESS

Oxidative stress is characterized by an imbalance between the production of reactive oxygen species (ROS) and the ability of antioxidant systems to counteract them. The excess of ROS induces negative effects such as neuronal injury (Izzo et al., 2021), dysregulating synaptic plasticity, and ultimately causing memory impairment. The consensus is that oxidative stress is associated with age-related cognitive decline (Dröge & Schipper, 2007). Dietary antioxidant intervention has become a feasible strategy to delay age-related dysfunctions (Shanmugam et al., 2022). An antioxidant-rich dietary pattern and aliments rich in polyunsaturated fatty acids may be effective against ROS-induced cognitive impairment and may delay aging (Parilli-Moser et al., 2021). Through their chemical constituents, nuts exert antioxidant effects (Figure 2) preventing lipid peroxidation, activating DNA repair mechanisms, and modulating age-related signaling pathways (Lorenzon dos Santos et al., 2020).

FIGURE 2. Three mechanisms underlying the effect of nut consumption on neurons. IL, interleukin; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α.

Cellular antioxidant activity study revealed that polyphenols in pecan kernel have strong antioxidant activity (Kellett et al., 2019), and dietary polyphenols have been proven to reduce oxidative stress and improve hippocampal connectivity (W. Yang et al., 2021). Brazil nuts with high content of selenium and polyphenols inhibited lipid peroxidation and scavenged free radicals, suggesting their alleviating cognitive impairment effects (Godos et al., 2022). Walnut kernel and septum extracts exerted significant neuroprotective activity and decreased ROS in young and older Wistar rats (Rusu et al., 2020). Nut-derived bioactive peptides play an important role in reducing cognitive disorders. Using a scopolamine-induced memory impairment model in mice, antioxidant peptides from pine nuts were found to improve memory by enhancing synaptic plasticity and reducing neuronal oxidative damage. These effects resulted from the activation of the extracellular-signal-regulated kinase/cAMP response element-binding protein (ERK/CREB) pathway (Lu et al., 2021). Recent studies have shown that walnut-derived peptides can effectively reduce oxidative stress in vitro (Wang et al., 2020; J. Yang et al., 2022; Zhao et al., 2020).

NUT INTAKE REDUCES THE INFLAMMATORY ASSOCIATED COGNITIVE IMPAIRMENT

Cognitive disorders are characterized by an increased level of inflammatory markers, such as tumor necrosis factor-alpha, interleukin-1 and −6, which are found in most tissues and regulate various physiopathological processes (Fang et al., 2022). A persistent increase in inflammation impairs neurogenesis, triggering chronic diseases in the peripheral and central nervous system.

Nuts are foods with anti-inflammatory effects (Figure 2). These effects have been demonstrated for both vegetal products and individual active components in various animal models. For example, in vivo studies have demonstrated that cashew nuts reduce inflammation in multiple types of animal models, such as dinitrobenzene sulfonic acid–induced colitis, monosodium iodoacetate–induced osteoarthritis, and carrageenan-induced paw edema (Cordaro et al., 2020; Fusco et al., 2020; Siracusa et al., 2020). Glansreginin A, a characteristic walnut component, exerts neuroprotective effects by reducing inflammation generated by LPS-induced abnormal behavior (Haramiishi et al., 2020). Walnut oil exhibits anti-inflammatory properties in inflammatory bowel disease by inhibiting TLR4/NF-κB signaling pathway (Bartoszek et al., 2020; Miao, Shan, Shah et al., 2021). Proanthocyanidins and quercetin also exert anti-inflammatory effects resulting in the improvement of cognitive performance by inhibiting Aβ aggregation, pTau level, and NLRP3 inflammasome activation (Li et al., 2021; Ruan et al., 2021).

Walnuts are the most studied nuts in terms of nuts—inflammation relationship. According to a randomized clinical trial, dietary walnut intake ameliorates lipid profile (triglyceride, total cholesterol, and low-density lipoprotein cholesterol concentrations) and some inflammatory markers, such as interferon-γ, interleukin-6, interleukin-1β, and tumor necrosis factor-α (Mateș et al., 2022). Regular walnut intake (15 g/day for 6 weeks) alleviated inflammation in aged men in a 6-week trial (Kamoun et al., 2021). Preliminary data from a single study revealed that long-term (2-year) walnut intake reduced certain inflammatory factors (Cofán et al., 2020). However, several observational studies have reported that walnut consumption alone does not significantly affect inflammation, similar to the results observed for pistachios (Asbaghi et al., 2021). Therefore, further large-scale trials are required to confirm the effect of nuts on inflammation and identify the confounding factors.

THE EFFECT OF NUTS AND GUT MICROBIOTA ON COGNITIVE DISORDERS

Gut microbiota mediates communication between the central nervous and immune systems through the gut-brain axis, exerting beneficial effects on neurodegenerative diseases. Specifically, gut microbiota can influence the neuronal brain circuits, synaptic connections, and neuroimmune function. Moreover, gut microbiota can modulate the accumulation of amyloid-β peptides and regulate the function of hippocampal and amygdala (Gao et al., 2020). However, the mutual interactions between the gut microbiome and neurons are not well understood. Intestinal microflora of healthy people differ from those of patients with memory impairment, the latter having more intestinal pro-inflammatory bacteria and less microbial diversity than the former (Hur & Park, 2022). Among plant-based foods, nuts have complex matrices of nutrients, comprising polyphenols and carbohydrates, which act as substrates for microbial fermentation, inducing changes in the intestinal microbial community and their metabolites including secondary bile acids and short-chain fatty acids (SCFAs; Figure 2) (Song et al., 2022). Animal studies revealed that, owing to the high percentage of lipid content, nuts can effectively shape the gut microbiome by increasing probiotic bacteria (Bifidobacterium, Akkermansia, Lactobacillus, and Faecalibaculum) and decreasing pathogenic bacteria (Staphylococcus, Streptococcus, and Bacteroides) (R. Liu et al., 2021; Miao, Shan, Ma et al., 2021). These results were generally consistent across animal studies, demonstrating that nut consumption benefits the gut microbiota, as they increase the abundance of healthy bacteria and improve the gut barrier function (X. Li, Wang et al., 2022; Prapa et al., 2022; Terzo et al., 2020; Yanni et al., 2020).

However, population studies investigating the same effect produced discrepant results. A randomized study including patients with HIV-1 indicated that a Mediterranean diet containing walnuts and extra virgin olive oil improved gut microbiota diversity and lipid profile (Pastor-Ibáñez et al., 2021). Meta-analysis reported that almond-based diets significantly promoted the growth of SCFAs-producing bacteria in humans with type 2 diabetes (Ojo et al., 2021). However, compared to the Mediterranean diet, diet intervention with nuts alone exerted significantly less changes in the gut microbiome (Galié, García-Gavilán, Camacho-Barcía et al., 2021; Galié, García-Gavilán, Papandreou et al., 2021). These discrepancies may be attributed to experimental design, methodology, and individual variation.

Nuts may protect the nervous system by exerting prebiotic effects (Fitzgerald et al., 2021) owing to the presence of nondigestible carbohydrates in their composition. These stimulate the growth of beneficial gut microbiota, such as Bifidobacterium and Lactobacillus, and contribute to SCFAs production. SCFAs have been reported to enhance natural killer (NK) cells activity (Pujari & Banerjee, 2021). Gut-derived NK and immunoglobulin A⁺ (IgA⁺) plasma cells translocate to the brain through the gut-brain axis to reduce neuroinflammation, which is regulated by the gut microbiome (Agirman et al., 2021). Therefore, dietary nut intake elicits advantageous microbiota changes, lowering the risk of chronic diseases (Dreher, 2021; Ren et al., 2020). The possible mechanisms underlying the interaction between nut consumption, gut microbiota, and brain function are summarized in Figure 3.

FIGURE 3. The effect of the interaction between nut consumption and gut microbiota on the brain function. BBB, blood–brain barrier; FFAR2, free fatty acid receptor 2; IFN-1, interferon 1; IgA, immunoglobulin A; IL, interleukin; ILC3, group 3 innate lymphoid cells; LAMP1, lysosomal-associated membrane protein 1; LPS, lipopolysaccharide; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NK, natural killer; PSA, polysaccharide A; SCFAs, short-chain fatty acids; TGF-β, transforming growth factor-β; TRAIL, TNF-related apoptosis-inducing ligand; Treg, regulatory T cells.

CONCLUSION

In this review, we mainly summarized the effects of nut consumptions on cognitive improvement regarding the anti-oxidative stress, inflammatory response, and gut microbiota. A consensus exists that nut consumption has numerous benefits because of the contained nutrients. Nuts are functional foods essential in attenuating oxidative stress and modifying inflammatory responses and the gut microbiota. Epidemiological investigations have suggested that nut consumption is associated with a lower incidence of cognitive disorders; this may be the result of a synergism of action between all nutrient constituents, such as unsaturated fatty acids, bioactive peptides, and polyphenols. However, clinical data on the effects of nut consumption on cognitive function remain limited, and the results have been inconsistent. These discrepancies may be the results of differences in the experimental design, study methodology, and between individuals. The beneficial effects associated with nut consumption are potentiated by an overall healthy diet. Therefore, further large-scale clinical randomized trials are still required to confirm the association between nut consumption and cognitive disorders.

AUTHOR CONTRIBUTIONS

Weijie Wu: Conceptualization; validation; writing—original draft. Ben Niu: Conceptualization; validation; writing—original draft. Qi Chen: Conceptualization; validation; writing—original draft. Huizhi Chen: Conceptualization; validation; writing—original draft. Hangjun Chen: Writing—review and editing. Wei Xia: Writing—review and editing. Long Jin: Writing—review and editing. Liang Peng: Validation; writing—original draft. Jesus Simal-Gandara: Writing—review and editing; supervision. Haiyan Gao: Conceptualization; writing—review and editing; supervision.

ACKNOWLEDGMENTS

This work was supported by the Agricultural Research Outstanding Talents Training Program from the Ministry of Agriculture and Rural Affairs of China.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.