WALNUTS

Tree nuts such as pecans, almonds and especially walnuts contain health promoting compounds including those proven to reduce cancer risk and progression. Ellagic acid and its metabolite [i.e produced from digestion] urolithin A are well researched examples (see Supplements) and other include plant omega 3 alpha-linlenic acid.  Urolithin A is reaching phase II trials as a supporting treatment to prostate cancer surgery, and has commerical branded products emerging in the anti-aging field.

Analysis of patients dietary consumption of tree nuts in moderate amounts have shown remarkably increased progression free, relative and overall survival in breast, prostate and colorectal cancer. Detailed DNA analysis has shown [pre-surgery] consumption of 2 oz of walnuts per day for about 2 weeks changes gene expression linked to growth and metastasis in human breast cancer. (Highlight 4). Several growth “pathways” including Estrogen Receptor and VEGF were suppressed.

Studes of both population and case controlled patient records report significant relative risk reductions for many systemic inflammatory diseases. There is some limited evidence on anti-metastatic actions. A meta-analysis of clinical studies reports consistent evidence of improved vascular cell adhesion molecule 1 (VCAM-1) levels (see references)

Another indirect factor outcomes is microbiome, e.g increased beneficial gut bacteria inclding clostridium, lachnospira, and roseburia known to be anti-inflammatory so called butyrate producers. Research over two years showed reductions in 6 of 10 markers for inflammation, notably IL-6 and IL-1ß generally associated with cancer progression.

EXAMPLES OF IMPROVED OUTCOMES

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ANALYSIS

PRE-DIAGNOSIS OR PREVENTION

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ANALYSIS

Highlighted Studies

Analyses by amount of nut intake showed a dose-response relationship for both OS [overall survival] and DFS [disease free survival]. Compared with non-consumers, those with nut consumption amounts greater than the median (17.32 g/week) and equal to or less than the median had a respective 52% (HR=0.48) [hazard ratio] and 45% (HR=0.55 ) lower risk of cancer recurrence, metastasis, or breast cancer-specific death, with a linear dose-response relationship.

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After a median follow-up of 6.5 years, compared with [colorectal cancer] patients who abstained from nuts, individuals who consumed two or more servings of nuts per week experienced an adjusted hazard ratio (HR) for disease-free survival of 0.58 ..and for overall survival of 0.43. In subgroup analysis, the apparent benefit was confined to tree nut intake (HR for disease-free survival, 0.54) The association of total nut intake with improved outcomes was maintained across other known or suspect...

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We observed a reasonably large, albeit non-significant, HR of 0.62 [hazard ratio] between post-diagnosis nut consumption and fatal outcome among PCa [prostate cancer] patients. This is consistent with a recent study that found an 18% lower rate of lethal PCa (HR, 0.82) per daily serving increase of nut intake after diagnosis.. In addition, our finding of a significant 34% rate reduction in overall mortality is consistent with other prospective studies

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RNA sequencing expression profiling revealed that expression of 456 identified genes [associated with breast cancer growth] was significantly changed in the tumor due to walnut consumption. Ingenuity Pathway Analysis showed activation of pathways that promote apoptosis and cell adhesion, and inhibition of pathways that promote cell proliferation and migration. These results support the hypothesis that, in humans, walnut consumption could suppress growth and survival of breast cancers.

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TABLE OF REFERENCES

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https://pmc.ncbi.nlm.nih.gov/articles/PMC8678210/5Human study - adjunctAt 5-year post dietary assessment (ie, 10-year postdiagnosis), regular nut consumers had higher OS (93.7% vs 89.0%) and DFS (94.1% vs 86.2%) rates. After multivariable adjustment, nut consumption was positively associated with OS (Ptrend = .022) and DFS (Ptrend = .003) following a dose-response pattern, with hazard ratios (95% confidence interval) of 0.72 (0.52-1.05) for OS and 0.48 (0.31-0.73) for DFS, for participants with greater than median nut intake compared with nonconsumers Compared with non-consumers, those with nut consumption amounts greater than the median (17.32 g/week) and equal to or less than the median had a respective 52% (HR=0.48, 95% CI: 0.31, 0.73) and 45% (HR=0.55 95% CI: 0.37, 0.81) lower risk of cancer recurrence, metastasis, or breast cancer-specific death, with a linear dose-response relationship. Point estimates for OS, however, did not reach statistical significance. Similar association patterns were observed for consumption of peanuts, walnuts, and other nuts. The sensitivity analysis using age at diagnosis as the entry time showed very similar results
https://pmc.ncbi.nlm.nih.gov/articles/PMC5891130/5Human study - adjunctAfter a median follow-up of 6.5 years, compared with patients who abstained from nuts, individuals who consumed two or more servings of nuts per week experienced an adjusted hazard ratio (HR) for disease-free survival of 0.58 (95% CI, 0.37 to 0.92; Ptrend = .03) and an HR for overall survival of 0.43 (95% CI, 0.25 to 0.74; Ptrend = .01). In subgroup analysis, the apparent benefit was confined to tree nut intake (HR for disease-free survival, 0.54; 95% CI, 0.34 to 0.85; Ptrend = .04; and HR for overall survival, 0.47; 95% CI, 0.27 to 0.82; Ptrend = .04). The association of total nut intake with improved outcomes was maintained across other known or suspected risk factors for cancer recurrence and mortality.In this prospective cohort of patients with stage III colon cancer who received adjuvant chemotherapy, a diet with increased total nut intake was associated with a significant improvement in cancer recurrence or mortality (DFS) and all-cause mortality (OS). Moreover, these associations seemed to be independent of other predictors of patient outcome, diet, and lifestyle factors, and the effect of total nut consumption was maintained across other known or suspected risk factors of cancer recurrence
https://pmc.ncbi.nlm.nih.gov/articles/PMC4973153/5Human study - adjunctThere were no statistically significant associations between nut consumption after diagnosis and development of lethal or fatal PCa (Table 2). But patients who consumed nuts five or more times per week had a 34% lower rate of overall mortality compared with those who consumed less than once per month (HR: 0.66) [hazard ratio]. We also observed a statistically significant difference in overall survival across nut-intake categoriesOur study suggests that nuts, although not associated with being diagnosed with PCa, may still improve the overall survival of PCa patients. Among PCa patients in the HPFS, cardiovascular disease was the leading cause of death, accounting for nearly one-third of the deaths (Richman et al, 2013; Kenfield et al, 2014). Large cohort studies have consistently shown that increased nut consumption was associated with reduced cardiovascular disease incidence and mortality (Hu, 2003; Kelly and Sabaté, 2007; Kris-Etherton et al, 2008). Nuts are dense in nutrients and bioactive compounds that may confer cardio-protective, anti-inflammatory, and antioxidant properties
https://www.sciencedirect.com/science/article/pii/S02715317183119044Human study - adjunct...phosphatidylinositol 3-kinase/ serine/threonine kinase 1 (PI3K/Akt) is significantly suppressed by walnut consumption. PI3K/Akt has been reported to promote breast cancer cell survival and resistance to chemotherapy [37]. Because PI3K and Akt were suppressed in the cancers of patients who consumed walnuts, it would be expected that apoptosis in residual tumor cells might increase and that these patients might also respond better to chemotherapy following surgeryAt surgery, about 2 weeks after biopsy, additional specimens were taken from the breast cancers. Changes in gene expression in the surgical specimen compared to baseline were determined in each individual woman in walnut-consuming (n = 5) and control (n = 5) groups. RNA sequencing expression profiling revealed that expression of 456 identified genes was significantly changed in the tumor due to walnut consumption. Ingenuity Pathway Analysis showed activation of pathways that promote apoptosis and cell adhesion, and inhibition of pathways that promote cell proliferation and migration. These results support the hypothesis that, in humans, walnut consumption could suppress growth and survival of breast cancers.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7346045/3.5Meta-analysisCompared with no nut intake, nut intake was associated with a lower cancer risk (Relative Risk=0.90; 95% confidence interval, 0.86–0.94). Inverse associations were observed with colorectal cancer, gastric cancer, pancreatic cancer, and lung cancer in subgroup analyses. Tree nut consumption was found to reduce cancer risk (Relative Risk=0.88; 95% confidence interval, 0.79–0.99). Dose-response curves suggested that protective benefits against cancer increased with increased nut intake (P=0.005, P-nonlinearity=0.0414). An inverse correlation with cancer-specific mortality (Odd Ratio=0.90; 95% confidence interval, 0.88–0.92) was observed. In conclusion, nut consumption is inversely associated with the risks of cancer incidence and mortality; a higher intake is significantly associated with a lower cancer risk.We also conducted a subgroup analysis of the specific types of cancer. Inconsistent with a similar meta-analysis in 2015 [4], inverse associations were observed between nut intake and the risk of gastric, lung, colorectal, and pancreatic cancers. A statistically significant association was found between nut intake and a lower risk of endometrial cancer after pooling of the estimates from two included studies on endometrial cancer. Our study included only one study on endometrial cancer; another study was excluded because it examined nut intake combined with the intake of other foods. Therefore, given the limited evidence, we did not find an association indicating a reduced risk of endometrial cancer. We identified a significant inverse association between a reduced cancer risk and the consumption of tree nuts but not with the consumption of peanuts or peanut butter
https://www.sciencedirect.com/science/article/pii/S2161831322001156?via%3Dihub3.5Meta-analysisThe summary effect size (ES) for risk of cancer, comparing the highest with lowest intakes of total nuts, was 0.86 (95% CI: 0.81, 0.92, P < 0.001, I2 = 58.1%; P < 0.01), indicating a significant inverse association. Such a significant inverse association was also seen for tree nut intake (pooled ES: 0.87, 95% CI: 0.78–0.96, P < 0.01, I2 = 15.8%; P = 0.28). Based on the dose-response analysis, a 5-g/d increase in total nut intake was associated with 3%, 6%, and 25% lower risks of overall, pancreatic, and colon cancers, respectively. In terms of cancer mortality, we found 13%, 18%, and 8% risk reductions with higher intakes of total nuts, tree nuts, and peanuts, respectively. In addition, a 5-g/d increase in total nut intake was associated with a 4% lower risk of cancer mortality. In conclusion, our findings support the protective association between total nut and tree nut intake and the risk of cancer and its mortality.We found 14% and 13% risk reductions in overall cancer with higher intakes of total nuts and tree nuts, respectively. These risk reductions were also seen for specific cancers including colon, pancreatic, and lung cancers in relation to total nut intake. In the dose-response analysis, each 5-g/d increase of total nut intake was associated with a 3% lower risk of overall cancer. There was evidence of a nonlinear association in which the overall cancer risk decreased when the consumption of total nuts increased from very low levels to higher amounts with a steeper decrease from 0 to 3 g/d. The meta-analysis of cancer mortality risk and consumption of total nuts and tree nuts revealed, respectively, 13% and 8% risk reductions. To the best of our knowledge, this study is among the first comprehensive meta-analyses to summarize prior publications on the association of total and individual nut intake with overall and specific cancer risk and also cancer mortality. Moreover, 3 earlier meta-analyses of cancer risk (61, 62, 66) had several limitations that make their findings misleading; and 3 meta-analyses of cancer mortality (59, 67, 83) needed to be updated.
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0730-33Meta-analysisTwenty studies (29 publications) were included in the meta-analysis. The summary RRs per 28 grams/day increase in nut intake was for coronary heart disease, stroke, cardiovascular disease, total cancer [8 studies averaged to 15% lower risk] , all-cause mortality, 0.78 [22% lower relative risk], and for mortality from diabetes, neurodegenerative disease and kidney disease. The results were similar for tree nuts and peanuts. If the associations are causal, an estimated 4.4 million premature deaths in the America, Europe, Southeast Asia, and Western Pacific would be attributable to a nut intake below 20 grams per day in 2013.In this meta-analysis there was a 24%, 11%, 19%, 18%, and 19% reduction in the relative risk of coronary heart disease, stroke, cardiovascular disease, total cancer, and all-cause mortality with a higher nut intake, respectively. In the dose–response analysis there was a 29%, 7%, 21%, 15%, and 22% reduction in the relative risk for a one serving per day increase in nut intake (one serving = 28 grams), respectively, although the association for stroke was not statistically significant in the linear dose–response analysis. There was evidence of a nonlinear association between nut intake and coronary heart disease, stroke, cardiovascular disease, total cancer, and all-cause mortality, with most of the reduction in risk observed up to an intake of approximately 15–20 grams per day or 5–6 servings per week for most of the outcomes.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6853029/3Meta-analysisTwenty studies were included in the meta-analysis. The summary Risk Reductions per 28 grams/day increase in nut intake was for coronary heart disease, stroke, cardiovascular disease, total cancer, 0.85 [15% lower], all-cause mortality, and for mortality from respiratory disease, and kidney disease, 0.27 (95% CI: 0.04–1.91, I2 = 61%, n = 2).If the associations are causal, an estimated 4.4 million premature deaths in the America, Europe, Southeast Asia, and Western Pacific would be attributable to a nut intake below 20 grams per day in 2013In this meta-analysis there was a 24%, 11%, 19%, 18%, and 19% reduction in the relative risk of coronary heart disease, stroke, cardiovascular disease, total cancer, and all-cause mortality with a higher nut intake, respectively. In the dose–response analysis there was a 29%, 7%, 21%, 15%, and 22% reduction in the relative risk for a one serving per day increase in nut intake (one serving = 28 grams), respectively, although the association for stroke was not statistically significant in the linear dose–response analysis. There was evidence of a nonlinear association between nut intake and coronary heart disease, stroke, cardiovascular disease, total cancer, and all-cause mortality, with most of the reduction in risk observed up to an intake of approximately 15–20 grams per day or 5–6 servings per week for most of the outcomes.
https://pmc.ncbi.nlm.nih.gov/articles/PMC2696995/2.5Meta-analysisMarkers of endothelial function included monocyte chemoattractant protein 1, interleukin-6, tumor necrosis factor-α, intracellular adhesion molecule 1, vascular cell adhesion molecule 1 (VCAM-1), hyperemic flow, and vasodilation of the brachial artery (15, 19, 24). VCAM-1 concentrations were consistently significantly lowered for participants during the walnut diets compared with the control diets across the 3 studiesEndothelium-dependent vasodilation of the brachial artery significantly improved under the walnut diet compared with the control diet during the one study that evaluated this intermediate endpoint (24). Overall, evidence of decreasing VCAM-1 and increasing endothelium-dependent vasodilation suggests that walnut-rich diets may have benefits for vascular endothelial function,
https://pmc.ncbi.nlm.nih.gov/articles/PMC7468923/2.5Meta-analysis Eight studies reporting nine RCTs were included, investigating almonds (n = 5), walnuts (n = 3) and pistachios (n = 1). Nut consumption significantly increased Clostridium (SMD: 0.40), Dialister (SMD: 0.44), Lachnospira (SMD: 0.33) and Roseburia (SMD: 0.36, and significantly decreased Parabacteroides (SMD: −0.31).Nut consumption increased the relative abundances of the genera Clostridium, Lachnospira and Roseburia, all of which are known butyrate producers [36,37,38]. Butyrate is vital for gastrointestinal health, both as an energy source for intestinal colonocytes and in the maintenance of the intestinal epithelium [12]. As such, the enrichment of butyrate producers supports the hypothesis of the prebiotic effect of nut consumption. Dietary lipids have been shown to influence the composition of the gut microbiota [39]. Sensitivity analyses revealed that the effect of nut consumption on Roseburia was explained by studies involving walnuts
https://academic.oup.com/nutritionreviews/article/81/1/26/66519422.5Meta-analysisConsuming walnuts at least once per week (0 vs ≥ 1 serving/wk; 1 serving = 28 g) was associated with a [19%]lower risk of total CVD (myocardial infarction, stroke or fatal CVD [fatal stroke, fatal myocardial infarction, and cardiovascular death], multivariate HR 0.81, and CHD (fatal and nonfatal myocardial infarction, multivariate HR 0.79 compared with those who never or almost never consumed walnuts. Walnut intake of 1 or more times per week was associated with a 17% lower risk of stroke. Hazard ratios for CVD, CHD, and stroke per 28 g increase were 0.71 , 0.63, and 0.83This review summarizes recent evidence investigating the link between walnut consumption and health or risk markers for health outcomes, including data from 33 articles describing results from 8 cohorts and 13 RCTs published from 2017 onwards. There was sufficient, suitable evidence for results to be synthesized for body weight and composition, blood lipids, cardiovascular function, glucose metabolism, and inflammation and hemostatic factors, employing the vote counting based on the direction of effect method. Smaller numbers of studies were identified reporting results related to total mortality, CVD (hard end points), MetS, cancer, aging, appetite, gut microbiota, and mental health
https://www.mdpi.com/2072-6643/15/6/14432Human study - adjunctNuts in the diet may also have arole in tertiary prevention in cancer survivors where a higher nut intake was consistentlyrelated to better survival of cancers of the colorectum, breast, and prostate. Considering theobservation that nut consumption appears to be more consistently associated with reducedtotal cancer mortality than total cancer incidence, it is also possible that an associationwith cancer is driven more so by improvements in survival after a cancer diagnosis thanreductions in cancer incidence,vidence from multiple lines of research encompassing cell line studies, animal mod-els, observational studies, interventional studies, and meta-analyses is suggestive that ahigher consumption of nuts is inversely associated with the risk of certain cancers and ofdying from cancer. Among the 12 cancer sites investigated in the literature (i.e., esoph-agus, stomach, colorectum, liver, pancreas, lung, breast, ovary, endometrium, leukemia,prostate, and lymphomas), inverse associations were most consistent across studies forthe incidence of colorectal cancer and, more specifically, with colon cancer.
https://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866-024-03626-52Human studyFecal microbial composition was found to be significantly different between pre- and post-walnut intervention (beta diversity, FDR-p = 0.018; alpha diversity, p = 0.018). Roseburia, Rothia, Parasutterella, Lachnospiraceae UCG-004, Butyricicoccus, Bilophila, Eubacterium eligens, Lachnospiraceae UCG-001, Gordonibacter, Paraprevotella, Lachnospira, Ruminococcus torques, and Sutterella were identified as the 13 most significantly enriched genera after daily intake of walnuts. Incorporating polyphenol-rich foods, such as walnut, can modulate gut microbiota by increasing the abundance of beneficial bacteria like Phascolarctobacterium, Coprococcus, and Anaerostipes [32]. These bacteria contribute to the production of short-chain fatty acids, such as acetate and propionate, which are important for gut health and have anti-inflammatory and metabolic benefits [33, 34]. This modulation of the gut microbiome through polyphenol intake supports overall health by promoting a more diverse and balanced microbial community.
https://www.jacc.org/doi/10.1016/j.jacc.2020.07.0711.5Human studyA recent meta-analysis of 25 RCTs concluded that nuts had no effect on inflammation (3), but most studies had small sample sizes and a short follow-up, whereas the WAHA study is the largest and longest nut trial to date. Concurring with prior meta-analytical data from walnuts (2) and total nuts (3), we found no effect on hs-CRP. However, we observed a beneficial impact on other relevant inflammatory molecules, including interleukin-1β, a cytokine for which inactivation with the human monoclonal antibody canakinumab resulted in prevention of recurrent coronary artery disease in a landmark RCT (5). The anti-inflammatory effect of long-term consumption of walnuts demonstrated in this study provides novel mechanistic insight for the benefit of walnut consumption on CVD risk beyond that of lipid lowering.In this substudy, 634 participants had complete data (90% retention). Participants’ clinical characteristics were similar to those of the parent cohort (4). Mean age was 69 years, 66% were women, and 32% were treated with statins. Compliance with the walnut diet was good, and there were no changes in body weight, as reported (4). Baseline and 2-year changes in inflammatory markers by group allocation are depicted in Table 1. Compared with the control diet, the walnut diet significantly reduced concentrations of 6 of 10 biomarkers examined. In-trial changes in main food groups were unrelated to changes of inflammatory molecules.

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