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Research Nut: Walnuts

Dietary walnuts protect against obesity-driven intestinal stem cell decline and tumorigenesis.

Guan, F., T. Tabrizian, A. Novaj, M. Nakanishi, D.W. Rosenberg, D. Huffman, 2018. Dietary walnuts protect against obesity-driven intestinal stem cell decline and tumorigenesis. Front. Nutr. doi.org/10.3389/fnut.2018.00037

Obesity can negatively impact intestinal homeostasis, and increase colon cancer risk and related mortality. Thus, given the alarmingly high rates of obesity in the US and globally, it is critical to identify practical strategies that can break the obesity-cancer link. Walnuts have been increasingly recognized to mitigate cancer risk, and contain many bioactive constituents with antioxidant and anti-inflammatory properties that could potentially counteract pathways thought to be initiators of obesity-related cancer. Therefore, the purpose of this study was to determine if walnuts could preserve intestinal homeostasis, and attenuate tumorigenesis and growth in the context of obesity and a high calorie diet. To this end, we studied effects of walnuts on these parameters under different dietary conditions in wildtype mice, two independent Apc models (Apc1638N/+ and ApcΔ14), and in MC38 colon cancer cells in vivo, respectively. Walnuts did not alter the metabolic phenotype or intestinal morphology in normal mice fed either a low-fat diet (LFD), LFD with 6% walnuts (LFD+W), high-fat diet (HFD), or HFD with 7.6% walnuts (HFD+W). However, walnuts did lead to a significant reduction in circulating CCL5 and preserved intestinal stem cell (ISC) function under HFD-fed conditions. Furthermore, walnuts reduced tumor multiplicity in Apc1638N/+ male HFD+W animals, as compared to HFD controls (3.7 ± 0.5 vs. 2.5 ± 0.3; P = 0.015), tended to reduce the number of adenocarcinomas (0.67 ± 0.16 vs. 0.29 ± 0.12; P = 0.07), and preferentially limited tumor growth in ApcΔ14 male mice (P = 0.019) fed a high-calorie western-style diet. In summary, these data demonstrate that walnuts confer significant protection against intestinal tumorigenesis and growth and preserve ISC function in the context of a high-calorie diet and obesity. Thus, these data add to the accumulating evidence connecting walnuts as a potentially effective dietary strategy to break the obesity-colon cancer link.

Effect of distinct lifestyle interventions on mobilization of fat storage pools: The CENTRAL MRI randomized controlled trial.

Gepner, Y., I. Shelef, D. Schwarzfuchs, H. Zelicha, L. Tene, A. Yaskolka Meir, G. Tsaban, N. Cohen, N. Bril, M. Rein, D. Serfaty, S. Kenigsbuch, O. Komy, A. Wolak, Y. Chassidim, R. Golan, H. Avni-Hassid, A. Bilitzky, B. Sarusi, E. Goshen, E. Shemesh, Y. Henkin, M. Stumvoll, M. Blüher, J. Thiery, U. Ceglarek, A. Rudich, M.J. Stampfer, I. Shai, 2018. Effect of distinct lifestyle interventions on mobilization of fat storage pools: The CENTRAL MRI randomized controlled trial. Circulation. 137(11):1143-1157. doi: 10.1161/CirculationAHA.117.030501.

Background: We aimed to assess whether distinct lifestyle strategies can differentially affect specific body adipose depots. Methods: We performed an eighteen-month randomized controlled trial among 278 sedentary adults with abdominal obesity (75%) or dyslipidemia in an isolated workplace with a monitored provided lunch. Participants were randomized to iso-caloric low-fat (LF) or Mediterranean/low-carbohydrate (MED/LC) diet+28g walnuts/day with/without added moderate physical activity (PA;80% aerobic; supervised/free gym membership). Overall primary outcome was body fat re-distribution, and the main specific endpoint was visceral adipose tissue (VAT). We further followed the dynamics of different fat depots [deep/superficial subcutaneous (D/SSAT), liver, pericardial, muscle, pancreas and renal-sinus] by magnetic-resonance-imaging. Results: Of 278 participants (age=48y; 89%men, body-mass-index=30.8kg/m2), 86% completed the trial, with good adherence. The LF group preferentially decreased reported fat intake (-21.0% vs. -11.5% for the MED/LC; P<0.001), and the MED/LC group decreased reported carbohydrates intake (-39.5%vs. -21.3% for the LF;P<0.001). The PA+ groups significantly increased the metabolic-equivalents (METs)/week vs. the PA- groups (19.0 vs. 2.1;P=0.009). Whereas final moderate weight loss was indifferent, exercise attenuated the waist circumference rebound with the greatest effect in MED/LCPA+ group (P<0.05). VAT (-22%), intra-hepatic (-29%), and Intra-pericardial (-11%) fats declines were higher than pancreatic and femur intermuscular fats (1-2%) loss. Independent of weight loss, PA+ with either diet had a significantly greater effect on decreasing VAT [mean-of-difference=-6.67cm2;95%CI:(-14.8 to -0.45) compared with PA-]. The MED/LC diet was superior to LF in decreasing intra-hepatic, intra-pericardial and pancreatic fats (P<0.05 for all). In contrast, renal-sinus and femoral-intermuscular fats were not differentially altered by lifestyle interventions, but by weight loss per-se. In multivariate models, further adjusted for weight loss, losing VAT or intra-hepatic fat were independently associated with improved lipid profile, losing deep-SAT with improved insulin sensitivity and losing superficial-SAT remained neutral except of association with decreased leptin. Conclusions: Moderate weight loss alone inadequately reflects the significant lifestyle effects on atherogenic and diabetogenic fat depots. The MED/LC diet mobilizes specific ectopic fat depots, and exercise has an independent contribution to VAT loss. Fat depots exhibit diverse responsiveness and are differentially related to cardiometabolic markers. Distinct lifestyle protocols may uniquely induce fat mobilization from specific anatomical sites.

The red blood cell proportion of arachidonic acid relates to shorter leukocyte telomeres in Mediterranean elders: A secondary analysis of a randomized controlled trial.

Freitas-Simoes, T.M., M. Cofán, M.A. Blasco, N. Soberón, M. Foronda, D. Corella, E.M. Asensio, M. Serra-Mir, I. Roth, C. Calvo, C. Valls-Pedret, R.P. Casaroli-Marano, M. Doménech, S. Rajaram, J. Sabaté, E. Ros, A. Sala-Vila, 2018. The red blood cell proportion of arachidonic acid relates to shorter leukocyte telomeres in Mediterranean elders: A secondary analysis of a randomized controlled trial. Clin Nutr. pii: S0261-5614(18)30074-8. doi: 10.1016/j.clnu.2018.02.011. [Epub ahead of print]

BACKGROUND & AIMS: Shortening of leukocyte telomere length (LTL) is a biomarker of aging. Epidemiologic studies of LTL in relation to dietary fatty acids have reported conflicting results. The red blood cell (RBC) fatty acid status is a valid objective biomarker of long-term dietary intake of C18:2n-6, C18:3n-3 and long-chain n-3 polyunsaturated fatty acids (C20:5n-3 and C22:6n-3). In healthy older individuals, we investigated whether LTL relates to the RBC proportions of the main dietary polyunsaturated fatty acids (PUFA), and to the RBC proportion of arachidonic acid (C20:4n-6), a fatty acid that can generate pro-inflammatory lipid mediators once released from cell membranes. DESIGN: Cross-sectional study in 344 subjects (mean age 68.8 y, 68.6% women) who participated in a randomized controlled trial testing whether a diet enriched in walnuts can delay the onset of age-related diseases (https://clinicaltrials.gov/ct2/show/NCT01634841). At baseline, we assessed LTL by high-throughput quantitative fluorescence and determined fatty acids in RBCs by gas chromatography. RESULTS: In multivariate models adjusted for age and gender, the RBC proportions of dietary PUFA were unrelated to LTL. In contrast, the RBC proportion of arachidonic acid inversely related to LTL (regression coefficient [95% confidence interval], -0.10 (-0.19 to -0.01), P = 0.023). CONCLUSION: An increasing proportion of C20:4n-6 in RBCs is associated with shorter telomeres. Further research is needed to investigate the role of this fatty acid and its derived lipid mediators in the aging process.

Walnut consumption for two years and leukocyte telomere attrition in Mediterranean elders: results of a randomized controlled trial.

Freitas-Simoes, T.M., M. Cofán, M.A. Blasco, N. Soberón, M. Foronda, M. Serra-Mir, I. Roth, C. Valls-Pedret, M. Doménech, E. Ponferrada-Ariza, C. Calvo, S. Rajaram, J. Sabaté, E. Ros, A. Sala-Vila, 2018. Walnut consumption for two years and leukocyte telomere attrition in Mediterranean elders: results of a randomized controlled trial. Nutrients. 10(12). pii: E1907. doi: 10.3390/nu10121907.

Randomized controlled trials on diet and shortening of leukocyte telomere length (LTL) mostly focus on marine-derived n-3 polyunsaturated fatty acids (PUFA). Walnuts are a sustainable source of n-3 PUFA. We investigated whether inclusion of walnuts (15% of energy) in the diet for 2 years would maintain LTL in cognitively healthy elders (63–79 years old) compared to a control group (habitual diet, abstaining from walnuts). This opportunistic sub-study was conducted within the Walnuts and Healthy Aging study, a dual-centre (Barcelona, Spain and Loma Linda University, California) parallel trial. A sub-set of the Barcelona site participants were randomly assigned to the walnut (n = 80) or control group (n = 69). We assessed LTL at baseline and at 2 years and we conducted repeated-measures ANCOVA with 2 factors: time (baseline, 2 years) and group (control, walnut) and their interaction. Adjusted means (95% confidence interval) of LTL (in kb) in controls were 7.360 (7.084,7.636) at baseline and 7.061 (6.835,7.288) after 2 years; corresponding values in the walnut group were 7.064 (6.807,7.320) and 7.074 (6.864,7.284). The time × intervention interaction was nearly significant (p = 0.079), suggestive of a trend of walnut consumption in preserving LTL. This exploratory research finding should be confirmed in trials with adequate statistical power.

Walnut consumption increases activation of the insula to highly desirable food cues: A randomized, double-blind, placebo-controlled, cross-over fMRI study.

Farr, O.M., D. Tuccinardi, J. Upadhyay, S.M. Oussaada, C.S. Mantzoros, 2018. Walnut consumption increases activation of the insula to highly desirable food cues: A randomized, double-blind, placebo-controlled, cross-over fMRI study. Diabetes Obes Metab. 20(1):173-177. doi: 10.1111/dom.13060.

AIMS: The use of walnuts is recommended for obesity and type 2 diabetes, although the mechanisms through which walnuts may improve appetite and/or glycemic control remain largely unknown. MATERIALS AND METHODS: To determine whether short-term walnut consumption could alter the neural control of appetite using functional magnetic resonance imaging, we performed a randomized, placebo-controlled, double-blind, cross-over trial of 10 patients who received, while living in the controlled environment of a clinical research center, either walnuts or placebo (using a validated smoothie delivery system) for 5 days each, separated by a wash-out period of one month. RESULTS: Walnut consumption decreased feelings of hunger and appetite assessed using visual analog scales and increased the activation of the right insula to highly desirable food cues. CONCLUSIONS: These findings suggest that walnut consumption may increase salience and cognitive control processing of highly desirable food cues, leading to the beneficial metabolic effects observed.

Effects of long-term walnut supplementation on body weight in free-living elderly: results of a randomized controlled trial.

Bitok, E., S. Rajaram, K. Jaceldo-Siegl, K. Oda, A. Sala-Vila, M. Serra-Mir, E. Ros, J. Sabaté, 2018. Effects of long-term walnut supplementation on body weight in free-living elderly: results of a randomized controlled trial. Nutrients. 10(9). pii: E1317. doi: 10.3390/nu10091317.

Abstract: Objective: To assess the effects of chronic walnut consumption on body weight and adiposity in elderly individuals. Methods: The Walnuts and Healthy Aging study is a dual-center (Barcelona, Spain and Loma Linda University (LLU)), 2-year randomized parallel trial. This report concerns only the LLU cohort. Healthy elders (mean age 69 year, 67% women) were randomly assigned to walnut (n = 183) or control diets (n = 173). Subjects in the walnut group received packaged walnuts (28–56 g/day), equivalent to ≈15% of daily energy requirements, to incorporate into their habitual diet, while those in the control group abstained from walnuts. Adiposity was measured periodically, and data were adjusted for in-trial changes in self-reported physical activity. Results: After 2 years, body weight significantly decreased (p = 0.031), while body fat significantly increased (p = 0.0001). However, no significant differences were observed between the control and walnut groups regarding body weight (−0.6 kg and −0.4 kg, respectively, p = 0.67) or body fat (+0.9% and +1.3%, respectively, p = 0.53). Lean body mass, waist circumference, and waist-to-hip ratio remained essentially unchanged. Sensitivity analyses were consistent with the findings of primary analysis. Conclusion: Our findings indicate that walnuts can be incorporated into the daily diet of healthy elders without concern for adverse effects on body weight or body composition.

A walnut-enriched diet affects gut microbiome in healthy Caucasian subjects: A randomized, controlled trial.

Bamberger, C., A. Rossmeier, K. Lechner, L. Wu, E. Waldmann, S. Fischer, R.G. Stark, J. Altenhofer, K. Henze, K.G. Parhofer, 2018. A walnut-enriched diet affects gut microbiome in healthy Caucasian subjects: A randomized, controlled trial. Nutrients. 10(2). pii: E244. doi: 10.3390/nu10020244.

Regular walnut consumption is associated with better health. We have previously shown that eight weeks of walnut consumption (43 g/day) significantly improves lipids in healthy subjects. In the same study, gut microbiome was evaluated. We included 194 healthy subjects (134 females, 63 ± 7 years, BMI 25.1 ± 4.0 kg/m²) in a randomized, controlled, prospective, cross-over study. Following a nut-free run-in period, subjects were randomized to two diet phases (eight weeks each); 96 subjects first followed a walnut-enriched diet (43 g/day) and then switched to a nut-free diet, while 98 subjects followed the diets in reverse order. While consuming the walnut-enriched diet, subjects were advised to either reduce fat or carbohydrates or both to account for the additional calories. Fecal samples were collected from 135 subjects at the end of the walnut-diet and the control-diet period for microbiome analyses. The 16S rRNA gene sequencing data was clustered with a 97% similarity into Operational Taxonomic Units (OTUs). UniFrac distances were used to determine diversity between groups. Differential abundance was evaluated using the Kruskal-Wallis rank sum test. All analyses were performed using Rhea. Generalized UniFrac distance shows that walnut consumption significantly affects microbiome composition and diversity. Multidimensional scaling (metric and non-metric) indicates dissimilarities of approximately 5% between walnut and control (p = 0.02). The abundance of Ruminococcaceae and Bifidobacteria increased significantly (p < 0.02) while Clostridium sp. cluster XIVa species (Blautia; Anaerostipes) decreased significantly (p < 0.05) during walnut consumption. The effect of walnut consumption on the microbiome only marginally depended on whether subjects replaced fat, carbohydrates or both while on walnuts. Daily intake of 43 g walnuts over eight weeks significantly affects the gut microbiome by enhancing probiotic- and butyric acid-producing species in healthy individuals. Further evaluation is required to establish whether these changes are preserved during longer walnut consumption and how these are linked to the observed changes in lipid metabolism.

Insulin resistance improves more in women than in men in association with a weight loss intervention.

Badri, N.W., S.W. Flatt, H.S. Barkai, B. Pakiz, D.D. Heath, C.L. Rock, 2018. Insulin resistance improves more in women than in men in association with a weight loss intervention. J Obes Weight Loss Ther. 8(1). pii: 365. doi: 10.4172/2165-7904.1000365.

Background: Fasting glucose and homeostatic model assessment-insulin resistance (HOMA-IR) are important measures of the risk for metabolic syndrome and diabetes. Weight loss interventions are considered part of the first line of therapy for those who develop disease states associated with insulin resistance, such as pre-diabetes, diabetes, or metabolic syndrome. Sex differences in insulin resistance have been extensively reported, but sex differences in the ability to improve insulin sensitivity are not well-established. This study sought to identify factors that predict change in HOMA-IR in response to weight loss. Methods: Non-diabetic subjects who were overweight/obese (n=100) were randomly assigned to a walnut-enriched reduced-energy diet or a standard reduced-energy-density diet in a 6-month weight loss intervention. There were no significant differences in weight change, glucose, insulin, or HOMA-IR between the two diet groups. These subjects were combined into a single cohort and analyzed with multivariate analysis. Results: The combined groups lost an average of 8.7 kg (p<0.0001), decreased serum glucose by an average 0.2 mmol/L (p<0.001), and decreased HOMA-IR by an average of 1.4 (p<0.0001). Change in HOMA-IR (R2=0.69) was positively associated with weight change (p<0.0001) and male sex (p<0.01), and negatively associated with baseline HOMA-IR (p<0.0001). Conclusion: Findings from this study suggest that men may have a more difficult time improving insulin sensitivity as compared with women with an equivalent weight loss and baseline HOMA-IR. One hypothesis to explain the differences across sexes may be due to sex differences in visceral adipose fat (VAT). This may mean that insulin resistant men require more aggressive intervention than women to prevent progression to metabolic syndrome or diabetes.

Association between walnut consumption and diabetes risk in NHANES.

Arab, L., S.K. Dhaliwal, C.J. Martin, A.D. Larios, N.J. Jackson, D. Elashoff , 2018. Association between walnut consumption and diabetes risk in NHANES. Diabetes Metab Res Rev. Oct; 34(7):e3031. doi: 10.1002/dmrr.3031. Epub 2018 Jul 11.

BACKGROUND: Dietary interventions and cohort studies relating tree nut consumption to blood glucose levels suggest a possible effect of walnuts. OBJECTIVE: To examine the associations between walnut consumption and diabetes risk using data from the National Health and Nutrition Examination Survey (NHANES). METHODS: NHANES survey data on adults conducting 24-hour dietary recall was pooled across the years 1999 through 2014. Diabetes status or risk was based on self-report, medication use, fasting plasma (FPG) glucose levels and hemoglobin A1c (HbA1c) levels. Individuals were characterized based on reported consumption of walnuts, mixed-nuts, or no nuts. RESULTS: After adjustment for covariates, walnut consumers showed lower risk for diabetes compared to non-nut consumers based on self-report (odds ratio of 0.47 95% confidence interval 0.31-0.72) as well as fasting blood glucose (RRR 0.32 CI 0.17-0.58) and HbA1c (RRR 0.51 CI 0.27-0.99). For each standard deviation of increase in walnut intake, prevalence of diabetes dropped 47%. The gender by walnut interaction suggests the effect may be more potent among women than men (dose response p=0.061). CONCLUSIONS: Both among individuals with known diabetes and those diagnosed based on elevated diabetes blood markers, the prevalence of individuals with diabetes was significantly lower among the walnut consumers. A possible gender specific effect invites further attention.

Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts.

Estruch, R., E. Ros, J. Salas-Salvadó, M.-I. Covas, D. Corella, F. Arós, E. Gómez-Gracia, V. Ruiz-Gutiérrez, M. Fiol, J. Lapetra, R.M. Lamuela-Raventos, L. Serra-Majem, X. Pintó, J. Basora, M.A. Muñoz, J.V. Sorlí, J.A. Martínez, M. Fitó, A. Gea, M.A. Hernán, M.A. Martínez-González, PREDIMED Study Investigators, 2018. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl J Med.  378(25):e34. doi: 10.1056/NEJMoa1800389. Epub 2018 Jun 13.

Background: Observational cohort studies and a secondary prevention trial have shown inverse associations between adherence to the Mediterranean diet and cardiovascular risk. Methods: In a multicenter trial in Spain, we assigned 7447 participants (55 to 80 years of age, 57% women) who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was a major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes). After a median follow-up of 4.8 years, the trial was stopped on the basis of a prespecified interim analysis. In 2013, we reported the results for the primary end point in the Journal. We subsequently identified protocol deviations, including enrollment of household members without randomization, assignment to a study group without randomization of some participants at 1 of 11 study sites, and apparent inconsistent use of randomization tables at another site. We have withdrawn our previously published report and now report revised effect estimates based on analyses that do not rely exclusively on the assumption that all the participants were randomly assigned. Results: A primary end-point event occurred in 288 participants; there were 96 events in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%). In the intention-to-treat analysis including all the participants and adjusting for baseline characteristics and propensity scores, the hazard ratio was 0.69 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.72 (95% CI, 0.54 to 0.95) for a Mediterranean diet with nuts, as compared with the control diet. Results were similar after the omission of 1588 participants whose study-group assignments were known or suspected to have departed from the protocol. Conclusions: In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet. (Funded by Instituto de Salud Carlos III, Spanish Ministry of Health, and others; Current Controlled Trials number, ISRCTN35739639 .).