LIFE HACK #3
Soy
Nutritious, delicious, and versatile, there is nothing
but goodness in this little bean!
August 2020 | by Dr. Benny Gavi
Soybeans are one of the best sources of plant-based protein. Pour a splash of soymilk
into your morning coffee or enjoy it in other ways.
Snapshot of soy
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Did you know that soybeans are native to Asia and have been a popular vegetable-based protein source for thousands of years?
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Did you know that soybeans are also rich in vitamin C, calcium, iron, fiber, folate, and potassium?
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Did you know that soybeans contain an important organic molecule called isoflavones?
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Can you name the ways people consume soybeans? There are whole soybeans and fermented variations, soy milk, soy sauce, tofu, edamame (green soybeans), miso soup (made from fermented soybeans), natto (fermented soybeans), soy flour, and even soybean oil.
Isoflavones & civilization diseases
Over the years, scientific advances have shed light on the relationship between diet and human health. Natural plant components have nutrients that play an important role in the prevention of many diseases of modern living. The effects of post-industrial revolution living have led to diseases - such as obesity, diabetes, cancer, cardiovascular diseases, hypertension, and osteoporosis - that we call civilization diseases.
You have likely read articles on major oil spills polluting oceans around the world. And you have seen wildfires ravaging communities in recent years. In the United States, mass produced foods and electronics are affordable to most people but high-quality healthcare and education are not. Many factors contribute to civilization diseases: polluted environments, adulterated and unhygienic food, poor nutrition, and stress due to a fast-paced lifestyle.
Soy has gained attention due to its estrogenic and anti-estrogenic effects on the body, but even randomized, double-blind, placebo controlled human studies have not fully clarified whether the effect of soy isoflavones is beneficial. Dr. Marzena Pabich published a literature review in 2019 which takes readers through a concise description of the metabolism of soy, an eye-opening graphic of soy consumption in Eastern and Western countries, and a powerful lens to view the results of soy isoflavone research relating to various diseases.
Since soy consumption is low in Western populations, epidemiological studies are limited to determine the relationship between soybean intake and T2D. Therefore, most clinical trials concern Asian participants.
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Type II Diabetes Mellitus (T2D): Studies have shown that short-term phytoestrogen supplementation reduces insulin resistance and improves glycemic control in postmenopausal women with T2D, while reducing the risk of cardiovascular events by lowering low-density lipoprotein cholesterol. Other studies were neutral, and did not find any interaction between the menopause status, total consumption of soy protein or soy, and risk of T2D.
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Osteoporosis: Studies have shown protective action of isoflavones in maintaining bone density in postmenopausal women. Results suggest that supplementation of 70 mg of isoflavones daily for 12 weeks had a positive effect on bone formation markers: the bone alkaline phosphatase (BALP) alkaline fraction increased by 6.3 ± 4.1% and osteocalcin by 9.3 ± 6.2%. These results are in line with the meta-analysis of randomized controlled trials, which showed that isoflavones significantly increase serum BALP levels (20.3%) when used at a dose of 75 mg/day.
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Hormone-associated cancers: Cancer is one of the biggest challenges of modern medicine, and breast cancer is the leading health issue in women. Studies have linked the relationship between soy and its beneficial effects on breast tumors in postmenopausal women. In addition, studies have shown a negative correlation between the consumption of soy and the risk of breast cancer in pre-and postmenopausal Asian women. This relationship was not observed in women living in Western countries. One explanation for this discrepancy may be the high intake of isoflavones by Asians not only in adulthood, but also from childhood.
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For men, prostate cancer is the 2nd most commonly diagnosed cancer and the 6th most common cause of cancer death worldwide. Studies have shown a statistically significant relationship between soy consumption and decreased prostate cancer risk. In a population-based case–control study on the association between prostate cancer and soy consumption of southern Italians, the authors found that isoflavones were correlated with a reduced risk of prostate cancer. In a Chinese-based study, the authors found that a high blood concentration of genistein was associated with a 70% reduction in prostate cancer in the Chinese population.
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Cardiovascular diseases (CVD): Soy-based foods have attracted attention since 1999, when the FDA approved the health claim that 25 g of soy protein daily, along with a diet low in saturated fat, may reduce the risk of CVD. But, medical research yields mixed results due to the variation in how soy is studied. Some studies point to a 9.3% reduction in total cholesterol, 12.9% in low density lipoprotein (LDL), and 10.5% in triglycerides. In these studies, the average consumption of soy protein was 47 g per day. Another study showed that the consumption of soy isoflavones significantly reduced serum total cholesterol, LDL-cholesterol, and triglyceride, and significantly increased high density lipoprotein (HDL) cholesterol. There were multiple factors affecting the HDL increase, including the level and duration of isoflavone intake, the sex of the research participant, and their initial serum lipid concentrations.
The bottom line is that soy is a nutrient-dense food with possible heath benefits. Further epidemiological studies are needed to understand the protective effect of soy on cardiovascular disease.
Please click here to see Dr. Pablich's full article, "Biological Effect of Soy Isoflavones in the Prevention of Civilization Diseases." Published in 2019 by Nutrients.
Lifehack #3: Consume more plant-based sources of protein
Slowly moving away from a diet based on red meat and refined sugars can add years to your life. There are easy alternatives to red meat such as fish, poultry, beans, nuts, soy, and other plant-based sources of protein which can add variety to your plate.
The Harvard T.H. Chan School of Public Health gives guidelines on how to achieve a healthy diet, including adding vegetable sources of protein via a graphic Healthy Eating Plate. This image is openly available for educational purposes with attribution (below), and is translated into different languages by clicking here to go to the school's webpage.
Word of the day: isoflavones
Click on the arrow to hear the pronunciation.
The Healthy Eating Plate image on this website is owned by Harvard University. It may be downloaded and used
without permission for educational and other non-commercial uses with proper attribution, including the following
copyright notification and credit line: Copyright © 2011, Harvard University. For more information about The Healthy Eating Plate, please see The Nutrition Source, Department of Nutrition, Harvard T.H. Chan School of Public Health, www.thenutritionsource.org, and Harvard Health Publications, www.health.harvard.edu.
Why isoflavones prevent cancer
Soy-based isoflavones have 3 anticancer mechansims. First, it is well known that the isoflavones from soybeans have antioxidant effects. Second, isoflavones demonstrate a hormone-like effect via the binding of estrogen receptors α and β, shown in a 1997 paper published in the journal Endocrinology. And third, isoflavones demonstrate non-hormone-like effects, which can stop cancer cell replication and induces cell death or apoptosis. If cells suffer DNA damage, which predisposes them to become cancerous, then the cell can undergo apoptosis which is an immune process that kills the damaged cell.
In 2019, Dr. Monika Kmetová Sivoňová published an excellent review that takes into account 132 peer-reviewed articles on the anticancer potential of 3 soy isoflavones (genistein, daidzein, and glycitein) as mediated by their effect on angrogen receptors (AR). The author writes, "The AR signaling pathway is essential for maintaining normal prostate growth, differentiation and function, and is an important component in the early pathogenesis of prostate cancer."
An important observation in Dr. Sivoňová's article is worth calling out. She notes that the incidence and mortality of prostate cancer are low in Asian countries, with rates reported at approximately 1/8 of that in Western countries. One possible explanation for this phenomenon is the high consumption of soy foods by Asian men as part of their regular diet.
This article offers an up-to-date and nuanced discussion of isoflavones in prostate cancer prevention. Isoflavones are assumed to exert multiple mechanisms to affect AR, leading to apoptosis and the inhibition of cancer cell growth. There are an overwhelming number of animal models, in vitro studies, epidemiological studies, and case-control studies indicating that soy isoflavones have the potential to reduce prostate cancer risk.
Please click here to see Dr. Sivoňová's article, "Androgen receptor and soy isoflavones in prostate cancer (Review)." Published in 2019 by Molecular and Clinical Oncology.
"Induction of Apoptosis in Low to Moderate-Grade Human Prostate Carcinoma by Red Clover-derived Dietary Isoflavones"
Dietary isoflavones induce apoptosis
Scientists hypothesize that diet plays a significant role in prostate cancer progression. In epidemiological studies, there is evidence that Western and Asian men have identical rates of microfocal cancer (<1mm on needle biopsy or <1mm on radical prostatectomy), but the progression to clinical prostate cancer happens more frequently in men from Western countries. This is a key point that factors lead to the progression of cancer in America and other Western countries. The hypothesis is validated by a study that highlights the effect of Western lifestyle on Asian males: within 2 generations, Asian male migrants who relocated to the US had the same mortality rate from prostate cancer as American-born men.
Let's look at what human and animal models show us. In human studies, the effects of isoflavones such as genistein, daidzein, and biochanin A on prostate cancer cell lines (PC3, LNCaP, and DU145) include inhibition of cell proliferation and induction of apoptosis. There is a case report describing the effect of an isoflavone supplement (160 mg) derived from red clover taken daily for 7 days before radical prostatectomy after diagnosis of moderately high-grade adenocarcinoma. The resected specimen showed degenerative changes and increased apoptosis in the malignant tissue, whereas the surrounding nonmalignant tissue was unaffected.
In several animal studies, such as transgenic TRAMP mice, isoflavones also inhibited the growth of prostate cancer xenografts. In young mice, soy consumption prevented estrogen-induced premalignant changes to the prostate gland. Collectively, the data suggest that dietary isoflavones are contributory in regulating cell proliferation and inducing apoptosis in prostate cancer cells.
Materials and Methods
In 2002, Dr. Renea Jarred Taylor published an intervention study to determine the short-term effects of red clover-derived isoflavones in men with prostate cancer in the time between diagnosis and radical prostatectomy. Dr. Jarred's study was based on 20 men from Melbourne, Australia who were diagnosed with clinically significant prostate cancer. Unlike the other studies reviewed here, this was a nonrandomized, nonblind intervention study meaning that the diganoses and treatment courses were known to researchers as they intervened with red-clover isoflavone. The patients had nonmetastatic prostate cancer and a Gleason score of ≥5 based on pathological assessment from biopsy specimens.
Each patient in the treated group consumed 160 mg of isoflavones daily consisting of 4 tablets/day of Trinovin containing 40 mg of standardized red clover-derived isoflavones, including predominantly formononetin and biochanin A with smaller amounts of genistein and daidzein. Click here to see Figure 1 delineating the treatment protocol.
Samples were collected by a single pathologist (Dr. John Pedersen, Monash University) and 4-μm sections were cut and mounted on Superfrost Plus slides for detection of apoptosis. Please click here and scroll down to the Detection of Apoptosis section for a full description of the sample staining, mounting, and detection process. Judges who scored the level of apoptosis were blinded to the treatment status of the patient, and slides were independently code numbered by the personnel who prepared the slides. The blind scorer then identified apoptosis.
The 3 panels below show radical prostatectomy specimens from patients after dietary isoflavone consumption. In panel A, there are nuclear stains and apoptotic cells indicated by arrows. In panel B, there are low- to moderate-grade cancer. And panel C shows high-grade cancer. The bar in the lower right corner of panel A = 25 μm. This image is licensed from the copyright clearance center on behalf of the American Association for Cancer Research.
Results
In the entire tissue, including all pathological grades and cell types, there was a significant difference in the incidence of apoptosis in the treatment group with a mean percentage of 0.9% compared with the control group at 0.25%. Patients who consumed the dietary isoflavones showed a significantly higher percentage of apoptosis in epithelial cells throughout the prostate, where the median percentage apoptosis was 1.14% compared with the control group at 0.24%.
Interestingly, apoptotic cells were identified in nonmalignant, low- to moderate-grade cancer, and high-grade cancer tissue in radical prostatectomy specimens. When the incidence of apoptosis was analyzed by pathological grade, neither the nonmalignant tissue nor the high-grade cancer tissue, showed any statistical differences between control and treated groups. But, low- to moderate-grade cancer tissue displayed a significant difference where the median percentage apoptosis was 1.48% in the treatment group compared to 0.25% in the control group.
The Takeaway
This Australian study demonstrates that isoflavones can slow or stop the progression of prostate cancer. In the future, a randomized, double-blinded, clinical trial using multiple doses of isoflavones with extensive follow-up would fully determine the effects of dietary isoflavones on the progression of prostate cancer.
One takeway from the study is that the results support the hypothesis that dietary isoflavones may contribute to the lower prevalence of clinical prostate cancer between Asian and Western populations. Remember that subclinical prostate cancer is the same in Asia and Western countries, yet something slows or stops the progression of prostate cancer in Asia.
Please click here to see Dr. Jarred's full article, "Induction of Apoptosis in Low to Moderate-Grade Human Prostate Carcinoma by Red Clover-derived Dietary Isoflavones." Published in 2002 by Cancer Epidemiology, Biomarkers & Prevention.
Apoptosis plays a role in cancer prevention
Life at a cellular level is a delicate balance from the development process to cell death via apoptosis. Dr. Christopher P. Austin writes that apoptosis "is a funny way of committing suicide [because] there's a whole scripted choreography of pathways and proteins within a cell that get activated to actually kill the cell and without making too much of a mess." But, he also makes an analogy that illustrates how apoptosis is a normal part of human development. As fetuses, our hands look like a duck paddle foot with webs between our fingers. The cells apoptose, giving us our discrete fingers.
Thanks to apoptosis, our bodies can replace damaged cells with new young cells. It is such an essential balancing act in human health that the absence of apoptosis can lead to cancer. The opposite is true too. Too much apoptosis can lead to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Lou Gehrig's disease because cells die when they aren't supposed to die.
The illustration of apoptosis (below) comes to us courtesy of the National Genome Research Institute, where you can explore their wonderful collection of educational materials on genomics and various genetic conditions.
Population study in Japan
Shining a spotlight on the Asian population could help unlock the etiology of prostate cancer. We found a population-based study that examines men of Japanese nationality and excludes men living in Japan who are not of Japanese nationality. The first author, Dr. Norie Kurahashi of the National Cancer Research Center in Tokyo, Japan, notes that prostate cancer rates are much lower in Asia than in the West. Maybe environmental factors - such as diet and food sources - have a large role in causing prostate cancer.
Dr. Kurahashi conducted a population-based prospective study of 43,509 Japanese men ages 45 to 74 years who generally have a high intake of isoflavones and low incidence of prostate cancer. Research participants responded to a questionnaire including lifestyle factors, medical, and smoking histories as well as 147 food items.
During the followup period from 1995 - 2004, 307 men were newly diagnosed with prostate cancer (74 cases were advanced, 220 cases were organ localized, and 13 cases were of an undetermined stage). Consumtion of genistein, daidzein, miso soup, and soy-based food were not associated with total prostate cancer. But, dietary isoflavones decreased the risk of localized prostate cancer.
In contrast, positive associations were seen between isoflavones and advanced prostate cancer. In men >60 years, dietary isoflavones were associated with a dose-dependent decrease in the risk of localized cancer. The author concludes that the research team found isoflavone consuption to be associated with a decreased risk of localized prostate cancer.
Please click here to see Dr. Kurahashi's full article, "Soy Product and Isoflavone Consumption in Relation to Prostate Cancer in Japanese Men." Published in 2007 by Cancer Epidemiology, Biomarkers & Prevention.
Chinese-American versus Chinese rates of prostate cancer
We found a case-control study that opens with the astonishing statistic that the rate of prostate cancer is 15x higher for Chinese men in the United States compared with those living in Shanghai and Tianjin. The study's author, Dr. Marion M. Lee from UCSF reflects that "prostate cancer is the second most commonly diagnosed cancer among Chinese-American males, contributing to 16% of the overall cancer burden in this population."
This study examined the association between soy consumption and the risk of prostate cancer focusing on cases from 12 cities in China. Dr. Lee recruited 133 prostate cancer subjects and 265 age- and community-matched controls between 50 - 89 years old. The research subjects were interviewed in person. Usual consumption of soy foods and isoflavones was assessed using a food frequency questionnaire.
Researchers found that a reduced risk of prostate cancer is associated with consumption of soy foods and isoflavones. Study participants with the highest soy consumption displayed a 49% decreased risk of prostate cancer compared with participants with the lowest consumption. Another wonderful finding from this study is that participants who consumed the highest quantity of isoflavones had a 44 - 47% reduction in prostate cancer risk.
Please click here to see Dr. Lee's full article, "Soy and Isoflavone Consumption in Relation to Prostate Cancer Risk in China." Published in 2003 by Cancer Epidemiology, Biomarkers & Prevention.
Does traditional Japanese cuisine reduce the risk of prostate cancer?
Traditional Japanese cuisine & cancer risk
The traditional Japanese diet is rich in fish and soybean-based foods, yet low in added sugars and saturated fat. Small portions of minimally processed, seasonal, whole foods are eaten with chopsticks. Add to this a warm pot of green tea which infuses polyphenols and epigallocatechin-3-gallates (EGCGs) - both compounds are natural antioxidants - into the meal.
In 2004, Dr. Tomoko Sonoda at Sapporo University published a case-control study based on men from the Ibaraki and Hokkaido prefectures in Japan. Dr. Sonoda hypothesized that the traditional Japanese diet may be protective against prostate cancer, because soybean products and fish were found to be associated with reduced risk.
The research team recruited 140 prostate cancer subjects and 140 age-matched controls from the same hospital. Each person completed a diet survey on their consumption of rice, meat, fish, eggs, milk, dairy products, all vegetables, green-yellow vegetables, fruits, all soybean products, alcohol, coffee, black tea, and green tea.
Will you be surprised at the results? The consumption of fish, all soybean products, tofu, and natto was associated with decreased risk. The consumption of meat was significantly associated with increased risk. Eggs did not show a significant association with increased risk. Interestingly, in this study milk, fruits, all vegetables, green-yellow vegetables, and tomatoes showed no association.
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Men who consumed the most soybean-based foods enjoyed a 47% reduction in prostate cancer risk compared to those who consumed the least.
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Tofu and natto (fermented soybean) consumption were heavy hitters in reducing the risk of cancer.
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Men who consumed the most tofu enjoyed a 53% reduction in prostate cancer risk.
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Men who consumed the most natto enjoyed a 75% reduction in prostate cancer risk.
The author also notes that a recent experimental study showed a direct inhibitory effect of low concentrations of antioxidant wine polyphenols on the proliferation of human prostate cancer cells. This suggests a beneficial effect of wine, but he could not examine this effect in Japan because too few subjects (9.7%) drank wine.
Please click here to see Dr. Sonoda's full article, "A case-control study of diet and prostate cancer in Japan: possible protective effect of traditional Japanese diet." Published in 2004 by Cancer Science.
Variations in clinical studies
Medical research continues to shed light on nutrition and cancer, giving us a more nuanced understanding of the subject. Studies may lead to conflicting conclusions partly because there are variations in how soy is studied. We just reviewed the work of 3 research teams based in Australia, Japan, and China. Variations also arise due to the type of study, ethnicity of the participants, their hormone levels, and even the type of soy (whole soybeans, fermented soy, soy-based protein powder, even plant-based veggie burgers).
"As the area of light increases, so does the circumference of darkness."
-- Albert Einstein
Research shows that soy decreases prostate cancer risk
Additional research teams have found that soy, soy-based foods, and isoflavones can decrease the risk of prostate cancer and have a mitigating effect on low- or moderate-grade cancer. Here are a few papers that reflect these findings:
Please click here to see the full article: Wu, Y., Zhang, L., Na, R., Xu, J., Xiong, Z., Zhang, N., Dai, W., Jiang, H., & Ding, Q. (2015) "Plasma genistein and risk of prostate cancer in Chinese population." International Urology and Nephrology, 47(6): 965–970. DOI: 10.1007/s11255-015-0981-5.
Please click here to see an abstract: Nagata, Y., Sugiyama, Y., Fukuta, F., Takayanagi, A., Masumori, N., Tsukamoto, T., Akasaka, H., et al. (2016). "Relationship of serum levels and dietary intake of isoflavone, and the novel bacterium Slackia sp. strain NATTS with the risk of prostate cancer: A case-control study among Japanese men." International Urology and Nephrology, 48(9): 1453–1460. DOI: 10.1007/s11255-016-1335-7.
Please click here to see an abstract: Jacobsen, B.K., Knutsen, S.F., & Fraser, G.E. (1998). "Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States)." Cancer Causes & Control, 9(6): 553–557. DOI: 10.1023/a:1008819500080.