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Research Nut: Walnuts

Long-term consumption of nuts (including peanuts, peanut butter, walnuts, and other nuts) in relation to risk of frailty in older women: evidence from a cohort study.

Wang, R., M.T. Hannan, M. Wang, A.W. Schwartz, E. Lopez-Garcia, F. Grodstein, 2023. Long-term consumption of nuts (including peanuts, peanut butter, walnuts, and other nuts) in relation to risk of frailty in older women: evidence from a cohort study. J Nutr. 153(3):820-7. https://doi.org/10.1016/j.tjnut.2023.01.003

Background: Adherence to a healthy diet is inversely associated with frailty. However, the relationship between nuts, a key food group of Mediterranean diet, and frailty is unclear. Objectives: This study aimed to evaluate the association between nut consumption and frailty in an aging female population. Methods: This population-based observational study included nonfrail women (60 y old) in the NHS from 11 states of the United States. Outcome was incident frailty, defined as having 3 of the FRAIL components (fatigue, lower strength, reduced aerobic capacity, multiple chronic conditions, and significant weight loss) and assessed every 4 y from 1992 to 2016. From 1990 to 2014, FFQs were used to assess the intakes of peanuts, peanut butter, walnuts (added in 1998), and other nuts at 4-y intervals. Exposure was total nut consumption, calculated as the sum of intakes of peanuts, peanut butter, walnuts, and other nuts and categorized into <1 serving/mo, 1–3 servings/mo, 1 serving/wk, 2 4 servings/wk, and  5 servings/wk. The relations of intakes of peanuts, peanut butter, and walnuts with frailty were also investigated separately. Cox proportional hazards models were used to assess the associations between nut consumption and frailty after adjusting for age, smoking, BMI, EI, diet quality, and medication use. Results: Among 71,704 participants, 14,195 incident frailty cases occurred over 1,165,290 person-years. The adjusted HR (95% CI) for consuming 5 servings/wk of nuts was 0.80 (0.73, 0.87), as compared with <1 serving/mo. Higher intakes of peanuts and walnuts, but not peanut butter, were also inversely associated with frailty. Conclusions: This large prospective cohort study showed a strong and consistent inverse association between regular nut consumption and incident frailty. This suggests that nut consumption should be further tested as a convenient public health intervention for the preservation of health and well-being in older adults.

Key Area: Body Weight and Composition

Adding walnuts to the usual diet can improve diet quality in the United States: diet modeling study based on NHANES 2015–2018.

Spence, L.A., B. Henschel, R. Li, C.D. Tekwe, K. Thiagarajah, 2023. Adding walnuts to the usual diet can improve diet quality in the United States: diet modeling study based on NHANES 2015–2018. Nutrients. 15(2):258. https://doi.org/10.3390/nu15020258

Background: The under-consumption of calcium, potassium, fiber, and vitamin D is considered a U.S. public health concern. Shifts in eating patterns that increase the consumption of vegetables, fruits, whole grains, nuts/seeds, and dairy products can help achieve the recommended intakes of these nutrients, leading to healthier diets. Objective: We assessed the impact of adding 1 ounce (28.35 g) of walnuts to usual diets on diet quality and nutrients of concern, including magnesium, fiber, and potassium. Methods: We utilized 24 h dietary recalls obtained from the What We Eat in America, National Health and Nutrition Examination Survey (NHANES) and modeled the addition of 1 ounce (28.35 g) of walnuts to the usual diets of no-nut consumers. No-nut consumers aged ≥4 years (n = 7757) from the 2015–2018 NHANES study were included. Population percentages with intakes below the estimated average requirement (EAR) values for calcium, magnesium, folate, and vitamin E and above the adequate intake (AI) values for potassium and fiber were examined. Diet quality was assessed using the Healthy Eating Index-2015 (HEI-2015). The National Cancer Institute method was used to estimate the usual and modeled intakes. Significant differences between usual (current) and modeled intakes were determined using non-overlapping 95% confidence intervals. All analyses included sample weights to account for the NHANES survey design. Results: Adding 1 ounce (28.35 g) of walnuts to the usual diet resulted in significant reductions in the percentages of adults with intakes below the EAR for magnesium and folate (69.6% vs. 52.0%; 49.2% vs. 40.6%, respectively), and increased the percentage of adults above the AI for potassium (22.8% vs. 26.5%). A similar trend was observed among children (4–18 years). HEI scores improved significantly from 49.1 (95% CI: 48.0–50.4) to 58.5 (95% CI: 57.5–59.6) in children and from 52.4 (95% CI: 51.0–53.8) to 59.2 (95% CI: 58.0–60.5) in adults. Conclusions: Adding 1 ounce (28.35 g) of walnuts to the usual diet of no-nut consumers improved the diet quality and adequacy of some under-consumed nutrients.

A dietary model of partial meat replacement with walnuts demonstrates changes in the nutrient profile and quality of the United States Population’s Diet.

Spence, L.A., B. Henschel, R. Li, C.D. Tekwe, K. Thiagarajah, 2023. A dietary model of partial meat replacement with walnuts demonstrates changes in the nutrient profile and quality of the United States population’s diet. Nutrients. 15(21):4518. https://doi.org/10.3390/nu15214518

The purpose of the study is to assess the impact of partial meat replacement with walnuts using a dose–escalation approach on nutrient intake and diet quality in the usual US diet. Food modeling was implemented using the nationally representative 2015–2018 National Health and Examination Survey (NHANES), with a focus on non-nut consumers, which included 2707 children and adolescents and 5190 adults. Walnuts replaced meat in a dose-escalating manner (0.5, 1, 1.5, and 2 oz walnuts per day replaced 1, 2, 3, and 4 oz meat, respectively). Diet quality was estimated using the population ratio method of the 2015 Healthy Eating Index. The usual intake of nutrients was estimated using the National Cancer Institute method. Significant differences were determined using non-overlapping 95% confidence intervals. The partial replacement of meat with walnuts demonstrated significant increases in the mean intake of fiber, magnesium, and omega-3 fatty acids and significant decreases in cholesterol and vitamin B12 in the modeled diets for children, adolescents, and adults. Additionally, the partial replacement of meat with walnuts improved overall diet quality. Walnut consumption at 1–2 oz as a replacement for some meat may improve nutrient intake and diet quality across age groups.

Walnut consumption and gut microbial metabolism: Results of an exploratory analysis from a randomized, crossover, controlled-feeding study.

Petersen, K.S., M. Chandra, J.R. Chen See, J. Leister, F. Jafari, A. Tindall, P.M. Kris-Etherton, R. Lamendella, 2023. Walnut consumption and gut microbial metabolism: Results of an exploratory analysis from a randomized, crossover, controlled-feeding study. Clin Nutr. 42(11):2258-2269. https://doi.org/10.1016/j.clnu.2023.09.023

Background & aims: The effect of walnut-related modulation of gut microbiota composition on microbiota functionality is unknown. The aim was to characterize the effect of a walnut-enriched diet (WD), compared to a fatty acid-matched diet devoid of walnuts (WFMD) and a diet where oleic acid replaces alpha-linolenic acid (ORAD), on bacterial gene expression. Methods: A 3-period, randomized, crossover, controlled-feeding study was conducted. Participants were provided a 2-week run-in standard western diet (SWD; 50% kcal carbohydrate, 16% protein, 34% fat, 12% SFA). Following the SWD in random sequence order, participants were provided the WD, WFMD, and ORAD (48% carbohydrate; 17% protein; fat 35%; 7% SFA). The WD contained 18% of energy from walnuts (57 g/d/2100 kcal). The WFMD and ORAD were devoid of walnuts; liquid non-tropical plant oils were included in these diets. Metatranscriptomic analyses were performed as an exploratory outcome. Results: The analytical sample included 35 participants (40% female) with a mean ± SD age of 43 ± 10 y and BMI of 30.3 ± 4.9 kg/m2. The ⍺-diversity of taxa actively expressing genes, assessed by observed species (p = 0.27) and Pielou’s Evenness (p = 0.09), did not differ among the diets. The ⍺-diversity of actively expressed genes was greater following the WD compared to the WFMD and ORAD as assessed by the observed genes and Pielou’s Evenness metrics (p < 0.05). β-Diversity of the actively expressed genes differed following the WD compared to the WFMD (p = 0.001) and ORAD (p = 0.001); β-diversity did not differ between the WFMD and ORAD. Active composition analyses showed increased Gordonibacter (p < 0.001) activity following the WD vs. the ORAD. Greater expression of many genes was observed following the WD compared to the WFMD and ORAD. Following the WD, greater expression of metabolism-related genes encoding glycine amidinotransferase (GATM; K00613) and arginine deiminase (K01478) was observed compared to the WFMD. Greater expression of glycine amidinotransferase (GATM; K00613) by Gordonibacter was also observed following the WD vs. the WFMD and ORAD. Conclusion: Our results suggest walnut intake may increase endogenous production of homoarginine through gut microbiota-mediated upregulation of GATM, which is a novel mechanism by which walnuts may lower cardiovascular disease risk. However, given the exploratory nature replication is needed.

Effect of walnut consumption on neuropsychological development in healthy adolescents: a multi-school randomised controlled trial.

Pinar-Martí, A., F. Gignac, S. Fernández-Barrés, D. Romaguera, A. Sala-Vila, I. Lázaro, O.T. Ranzani, C. Persavento, A. Delgado, A. Carol, J. Torrent, J. Gonzalez, E. Roso, J. Barrera-Gómez, M. López-Vicente, O. Boucher, M. Nieuwenhuijsen, M.C. Turner, M. Burgaleta, J. Canals, V. Arija, X. Basagaña, E. Ros, J. Salas-Salvadó, J. Sunyer, J. Julvez, 2023. Effect of walnut consumption on neuropsychological development in healthy adolescents: a multi-school randomised controlled trial. eClinicalMedicine. 59:101954. https://doi.org/10.1016/j.tjnut.2023.01.003

Background: Omega-3 fatty acids are critical for neuropsychological functioning. Adolescence is increasingly believed to entail brain vulnerability to dietary intake. The potential benefit on adolescent neurodevelopment of consuming walnuts, a source of omega-3 alpha-linolenic acid (ALA), remains unclear. Methods: We conducted a 6-month multi-school-based randomised controlled nutrition intervention trial to assess whether walnut consumption has beneficial effects on the neuropsychological and behavioural development of adolescents. The study took place between 04/01/2016 and 06/30/2017 in twelve different high schools in Barcelona, Spain (ClinicalTrials.gov Identifier: NCT02590848). A total of 771 healthy teenagers aged 11–16 years were randomised into two equal groups (intervention or control). The intervention group received 30 g/day of raw walnut kernels to be incorporated into their diet for 6 months. Multiple primary endpoints concerning neuropsychological (working memory, attention, fluid intelligence, and executive function) and behavioural (socioemotional and attention deficit hyperactivity disorder [ADHD] symptoms) development were assessed at baseline and after intervention. Red blood cell (RBC) ALA status was determined at baseline and 6 months as a measure of compliance. Main analyses were based on intention-to-treat using a linear mixed-effects model. A per-protocol effect of the intervention was analysed using inverse-probability weighting to account for post-randomisation prognostic factors (including adherence) using generalised estimating equations. Findings: In intention-to-treat analyses, at 6 months there were no statistically significant changes between the intervention and control groups for all primary endpoints. RBC ALA (%) significantly increased only in the intervention group, coefficient = 0.04 (95% Confidence Interval (CI) = 0.03, 0.06; p < 0.0001). The per-protocol (adherence-adjusted) effect on improvement in attention score (hit reaction time variability) was −11.26 ms (95% CI = −19.92, −2.60; p = 0.011) for the intervention group as compared to the control group, improvement in fluid intelligence score was 1.78 (95% CI = 0.90, 2.67; p < 0.0001), and reduction of ADHD symptom score was −2.18 (95% CI = −3.70, −0.67; p = 0.0050). Interpretation: Our study suggested that being prescribed eating walnuts for 6 months did not improve the neuropsychological function of healthy adolescents. However, improved sustained attention, fluid intelligence, and ADHD symptoms were observed in participants who better complied with the walnut intervention. This study provides a foundation for further clinical and epidemiological research on the effect of walnuts and ALA on neurodevelopment in adolescents.

Dietary walnuts preserve aspects of health span and alter the hippocampal lipidome in aged high-fat diet-fed mice.

Novaj, A., M.G. Engel, R. Wang, K. Mao, X. Xue, Y. Amir, G. Atzmon, D.M. Huffman, 2023. Dietary walnuts preserve aspects of health span and alter the hippocampal lipidome in aged high-fat diet-fed mice. International Journal of Molecular Sciences. 24(3):2314. https://doi.org/10.3390/ijms24032314

Evidence continues to accrue that aging and its diseases can be delayed by pharmacologic and dietary strategies that target the underlying hallmarks of the aging process. However, identifying simple, safe, and effective dietary strategies involving the incorporation of whole foods that may confer some protection against the aging process is also needed. Recent observational studies have suggested that nut consumption can reduce mortality risk in humans. Among these, walnuts are particularly intriguing, given their high content of n-3 fatty acids, fiber, and antioxidant and anti-inflammatory compounds. To this end, 12-month-old male CB6F1 mice were provided either a defined control low-fat diet (LFD), a control high-fat diet (HFD), or an isocaloric HFD containing 7.67% walnuts by weight (HFD + W), and measures of health span and related biochemical markers (n = 10-19 per group) as well as survival (n = 20 per group) were monitored. Mice provided the HFD or HFD + W demonstrated marked weight gain, but walnuts lowered baseline glucose (p < 0.05) and tended to temper the effects of HFD on liver weight gain (p < 0.05) and insulin tolerance (p = 0.1). Additional assays suggested a beneficial effect on some indicators of health with walnut supplementation, including preservation of exercise capacity and improved short-term working memory, as determined by Y maze (p = 0.02). However, no effect was observed via any diet on inflammatory markers, antioxidant capacity, or survival (p = 0.2). Ingenuity Pathway Analysis of the hippocampal transcriptome identified two processes predicted to be affected by walnuts and potentially linked to cognitive function, including estrogen signaling and lipid metabolism, with changes in the latter confirmed by lipidomic analysis. In summary, while walnuts did not significantly improve survival on a HFD, they tended to preserve features of health span in the context of a metabolic stressor with aging.

Key Area: Cognitive Health

Effect of nuts on gastrointestinal health.

Mandalari, G., T. Gervasi, D.W. Rosenberg, K.G. Lapsley, D.J. Baer, 2023. Effect of nuts on gastrointestinal health. Nutrients. 15(7):1733. https://doi.org/10.3390%2Fnu15071733

Abstract: Nuts are high nutrient-dense foods containing healthy lipids, dietary fiber, and bioactive phytochemicals, including vitamins and minerals. Although the beneficial effect of nut consumption on different chronic diseases has been well documented, especially in relation to their cardiometabolic benefits, less scientific evidence is available on their possible beneficial effects on gastrointestinal health. In this narrative review, we summarize the most important findings and new research perspectives in relation to the importance of nut consumption on gastrointestinal health. The integrity of the cell wall structure, cell size and particle size after mastication are known to play a crucial role in energy, nutrient and bioactive release from nuts during digestion, therefore affecting bioaccessibility. Other mechanisms, such as cell wall composition, thickness and porosity, as well as stability of the membranes surrounding the oil bodies within the cell, are also important for energy extraction. As the undigested nutrients and phytochemicals are delivered to the colon, effects on gut microbiota composition are predicted. Although the overall effect of nut consumption on microbial alpha- and beta-diversity has been inconsistent, some scientific evidence suggests an increase in fecal butyrate after almond consumption, and a beneficial role of walnuts on the prevention of ulcerative colitis and protection against the development of gastric mucosal lesions.

Walnut inclusion in a palm oil-based atherogenic diet promotes traits predicting stable atheroma plaque in Apoe-deficient mice.

Lázaro. I., J. Bobi, M. Cofán, G. Kapravelou, A.J. Amor, J. Surra, C. Gómez-Guerrero, E. Ortega, J. Osada, A.P. Dantas, A. Sala-Vila, 2023. Walnut inclusion in a palm oil-based atherogenic diet promotes traits predicting stable atheroma plaque in Apoe-deficient mice. Front. Nutr. 10:1079407. https://doi.org/10.3389/fnut.2023.1079407

INTRODUCTION: The lower rates of cardiovascular disease in Southern Europe could be partially explained by the low prevalence of lipid-rich atheroma plaques. Consumption of certain foods affects the progression and severity of atherosclerosis. We investigated whether the isocaloric inclusion of walnuts within an atherogenic diet prevents phenotypes predicting unstable atheroma plaque in a mouse model of accelerated atherosclerosis. METHODS: Apolipoprotein E-deficient male mice (10-week-old) were randomized to receive a control diet (9.6% of energy as fat, n = 14), a palm oil-based high-fat diet (43% of energy as fat, n = 15), or an isocaloric diet in which part of palm oil was replaced by walnuts in a dose equivalent to 30 g/day in humans (n = 14). All diets contained 0.2% cholesterol. RESULTS: After 15 weeks of intervention, there were no differences in size and extension in aortic atherosclerosis among groups. Compared to control diet, palm oil-diet induced features predicting unstable atheroma plaque (higher lipid content, necrosis, and calcification), and more advanced lesions (Stary score). Walnut inclusion attenuated these features. Palm oil-based diet also boosted inflammatory aortic storm (increased expression of chemokines, cytokines, inflammasome components, and M1 macrophage phenotype markers) and promoted defective efferocytosis. Such response was not observed in the walnut group. The walnut group’s differential activation of nuclear factor kappa B (NF-KB; downregulated) and Nrf2 (upregulated) in the atherosclerotic lesion could explain these findings. CONCLUSION: The isocaloric inclusion of walnuts in an unhealthy high-fat diet promotes traits predicting stable advanced atheroma plaque in mid-life mice. This contributes novel evidence for the benefits of walnuts, even in an unhealthy dietary environment.

Key Area: Heart Health

A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial.

Hoffmann, A., A.Y. Meir, T. Hagemann, P. Czechowski, L. Müller, B. Engelmann, S.B. Haange, U. Rolle-Kampczyk, G. Tsaban, H. Zelicha, E. Rinott, A. Kaplan, I. Shelef, M. Stumvoll, M. Blüher, L. Liang, U. Ceglarek, B. Isermann, M. von Bergen, P. Kovacs, M. Keller, I. Shai, 2023. A polyphenol-rich green Mediterranean diet enhances epigenetic regulatory potential: the DIRECT PLUS randomized controlled trial. Metab.: Clin. Exp. 145, 155594. https://doi.org/10.1016/j.metabol.2023.155594

Background: The capacity of a polyphenol-enriched diet to modulate the epigenome in vivo is partly unknown. Given the beneficial metabolic effects of a Mediterranean (MED) diet enriched in polyphenols and reduced in red/processed meat (green-MED), as previously been proven by the 18-month DIRECT PLUS randomized controlled trial, we analyzed the effects of the green-MED diet on methylome and transcriptome levels to highlight molecular mechanisms underlying the observed metabolic improvements. Methods: Our study included 260 participants (baseline BMI = 31.2 kg/m2, age = 5 years) of the DIRECT PLUS trial, initially randomized to one of the intervention arms: A. healthy dietary guidelines (HDG), B. MED (440 mg polyphenols additionally provided by walnuts), C. green-MED (1240 mg polyphenols additionally provided by walnuts, green tea, and Mankai: green duckweed shake). Blood methylome and transcriptome of all study subjects were analyzed at baseline and after completing the 18-month intervention using Illumina EPIC and RNA sequencing technologies. Results: A total of 1573 differentially methylated regions (DMRs; false discovery rate (FDR) < 5 %) were found in the green-MED compared to the MED (177) and HDG (377) diet participants. This corresponded to 1753 differentially expressed genes (DEGs; FDR < 5 %) in the green-MED intervention compared to MED (7) and HDG (738). Consistently, the highest number (6 %) of epigenetic modulating genes was transcriptionally changed in subjects participating in the green-MED intervention. Weighted cluster network analysis relating transcriptional and phenotype changes among participants subjected to the green-MED intervention identified candidate genes associated with serum-folic acid change (all P < 1 × 10-3) and highlighted one module including the KIR3DS1 locus, being negatively associated with the polyphenol changes (e.g. P < 1 × 10-4), but positively associated with the MRI-assessed superficial subcutaneous adipose area-, weight- and waist circumference- 18-month change (all P < 0.05). Among others, this module included the DMR gene Cystathionine Beta-Synthase, playing a major role in homocysteine reduction. Conclusions: The green-MED high polyphenol diet, rich in green tea and Mankai, renders a high capacity to regulate an individual’s epigenome. Our findings suggest epigenetic key drivers such as folate and green diet marker to mediate this capacity and indicate a direct effect of dietary polyphenols on the one‑carbon metabolism.

Antioxidant and anti-inflammatory properties of walnut constituents: focus on personalized cancer prevention and the microbiome.

Fan, N., J.L. Fusco, D.W. Rosenberg, 2023. Antioxidant and anti-inflammatory properties of walnut constituents: focus on personalized cancer prevention and the microbiome. Antioxidants. 12(5):982. https://doi.org/10.3390/antiox12050982

Walnuts have been lauded as a ‘superfood’, containing a remarkable array of natural constituents that may have additive and/or synergistic properties that contribute to reduced cancer risk. Walnuts are a rich source of polyunsaturated fatty acids (PUFAs: alpha-linolenic acid, ALA), tocopherols, antioxidant polyphenols (including ellagitannins), and prebiotics, including fiber (2 g/oz). There is a growing body of evidence that walnuts may contribute in a positive way to the gut microbiome, having a prebiotic potential that promotes the growth of beneficial bacteria. Studies supporting this microbiome-modifying potential include both preclinical cancer models as well as several promising human clinical trials. Mediated both directly and indirectly via its actions on the microbiome, many of the beneficial properties of walnuts are related to a range of anti-inflammatory properties, including powerful effects on the immune system. Among the most potent constituents of walnuts are the ellagitannins, primarily pedunculagin. After ingestion, the ellagitannins are hydrolyzed at low pH to release ellagic acid (EA), a non-flavonoid polyphenolic that is subsequently metabolized by the microbiota to the bioactive urolithins (hydroxydibenzo[b,d]pyran-6-ones). Several urolithins, including urolithin A, reportedly have potent anti-inflammatory properties. These properties of walnuts provide the rationale for including this tree nut as part of a healthy diet for reducing overall disease risk, including colorectal cancer. This review considers the latest information regarding the potential anti-cancer and antioxidant properties of walnuts and how they may be incorporated into the diet to provide additional health benefits.

Key Area: Cancer