When you look at a blueberry, what do you see? When you look at a head of broccoli, what do you see?
Perhaps the most compelling aspect of recent nutrition science is the ability to isolate and examine bioactive components of food, and investigate their potential roles in health and disease. For me, this is the very crux of nutrition; the presence of compounds in foods which are not technically “essential” for life in the manner of vitamins and minerals, but which are essential for maintenance of health and combating disease.
This is also at the crux of the disconnect between nutrition and medicine; if you look at a blueberry and just see a blueberry, then you’re incapable of seeing nutrition as a foundational aspect of health and doomed to overlook the preventative health benefits of diet.
Nutrition is layered. On the macro level, a food can be broken down into its protein, carbohydrate and fat components. Then there are vitamins and minerals, which are essential to life and must be obtained through the diet – vitamins are required in larger amounts than minerals, but deficiencies in either is known to lead to adverse health effects and contribute to the development of disease.
And then there are compounds in food that do not contribute to human nutrition, and as such there are no deficiency states associated with an inadequate intake. These non-nutritive compounds are “secondary plant-metabolites”, meaning they don’t contribute directly to growth and development of the organism. Rather, their production in plants is a protective response by the plant to environmental stressors, for example heat and lack of rain, or to ward off predators.
When consumed in low physiological doses in the diet, these phytochemicals exert multiple actions in the body through a wide range of different pathways. A 2008 paper in the journal Current Opinion in Biotechnology illustrates the role of phytochemicals:
Although phytochemicals might not be essential for growth and development or the maintenance of major body functions, there is increasing knowledge concerning their potential for health maintenance or disease risk reduction throughout adulthood and during aging. This means that they are essential to fulfil the maximum individual lifespan, and so we propose that they are ‘lifespan essential’. This does not necessarily include an increase of the maximum potential lifespan, but rather an increase of the chance of reaching the genetically determined lifespan and an increase in the quality of life during aging by reducing the incidence of chronic, age- related diseases. (Holst & Williamson, 2008).
Cruciferous vegetables – which include broccoli, cauliflower, kale, cabbage and watercress – are one of the most prevalent global food crops (Herr & Büchler, 2010). Populations with the highest intakes of cruciferous vegetables have lower rates of all-cause mortality (Zhang et al., 2011). This protective health effect is believed to result from the activity of a class of phytochemicals known as glucosinolates, which are abundant in cruciferous veg (Dinkova-Kostova & Kostov, 2012).
When chewed, chopped or crushed, an enzyme in cruciferous veg known as myrosinase converts glucosinolates into bioactive phytochemicals known as isothiocyanates (Dinkova-Kostova & Kostov, 2012). The evidence suggests isothiocyanates, in particular the isothiocyanate sulforaphane, may play a protective role in a variety of disease processes (Fahey, Zalcmann & Talalay, 2001).
Epidemiology suggests a dose-response for cruciferous veg intake lowering risk of cardiovascular disease, with the highest level of intake significantly associated with lower risk of CVD (Zhang et al., 2011). There are plausible mechanisms for this effect evident in both animal and human data. In mice, sulforaphane prevents thickening of arteries and protects against arterial oxidative stress and inflammation, all of which are risk factors for atherosclerosis (Miao et al., 2012).
Sulforaphane protects against stroke-inducing effects of high blood pressure in rats (Wu et al., 2004), and prospective studies in humans have associated 1 serving per day (1/2 cup) of cruciferous veg with reduced risk of ischemic stroke (Joshipura et al., 1999). There is evidence that sulforaphane inhibits vascular adhesion proteins (which contribute to arterial plaque development), which are induced in response to secretion of the inflammatory cytokine TNF-α (Hung et al., 2014).
What is interesting about sulforaphane is its ability to act through multiple signalling pathways. Sulforaphane upregulates expression of the Nrf2 pathway, which activates antioxidant and anti-inflammatory genes, and is the most potent dietary inducer of this signalling pathway (Kensler et al., 2017). Sulforaphane also inhibits the the Nf-kB pathway, which inhibits the expression of inflammatory signalling molecules like TNF-α (Hung et al., 2014). In a randomised, placebo-controlled trial in diabetics, sulforaphane reduced TNF-a by 11% and C-reactive protein, an inflammatory marker and risk factor for CVD, by 16% (Mirmiran et al., 2012).
Sulforaphane also improves cholesterol profiles. In a trial in humans, broccoli sprouts (the highest food source of sulforaphane) reduced LDL and total cholesterol while significantly increasing HDL, and reduced oxidative stress biomarkers (Murashima et al., 2004). The lipid-modulating and antioxidant effect of broccoli sprouts have been confirmed in a recent controlled trial which found the ratio of oxidised-LDL to LDL reduced by 14%, an 18% decrease in triglycerides and an overall 52% reduction in atherogenic index (Bahadoran et al., 2012).
Cumulatively these data suggest a cardioprotective role for sulforaphane, through improved lipid metabolism and modulation of vascular inflammation and oxidative stress (Miao et al., 2012; Murashima et al., 2004; Bahadoran et al., 2012).
Systemic inflammation is a hallmark of disease processes, and isothiocyanates exert anti-inflammatory effects through both Nf-kB and Nrf2 pathways (Negi, Kumar & Sharma, 2011). Sulforaphane reduces systemic inflammation and expression of multiple inflammatory biomarkers in humans (Jiang et al., 2014; Navarro et al., 2014).
Sulforaphane may thus benefit chronic inflammatory conditions. In asthmatics, sulforaphane has been shown to inhibit airway inflammation, through activation of Nrf2 and induction of anti-inflammatory enzymes in the respiratory tract (Brown et al., 2015). This is consistent with evidence from mice induced with asthma, in which the Nrf2 pathway mediates chronic inflammation (Rangasamy et al., 2005).
In a review of epidemiological studies looking at cruciferous veg intake and multiple cancers, 67% of studies found an inverse relationship [i.e. the higher the intake, the lower the risk] (Verhoeven et al., 1996). Diets high in cruciferous veg tend be high in vegetables generally, which mean that it is hard to find a true association with an isolated food or family. However, after controlling for other vegetable intake, >3 servings/week of cruciferous veg was associated with a 41% reduction in risk for prostate cancer (Cohen, Kristal & Stanford, 2000).
4.5 servings per month of raw cruciferous veg was associated with a 55% reduced risk of lung cancer in smokers; >3 servings/month significantly decreased risk of bladder cancer (Tang et al., 2010; Tang et al., 2008). The carcinogenic detoxification capacities of isothiocyanates may also modulate the progression of cancer; >4 servings/month raw broccoli decreased bladder cancer mortality by 57% (Tang et al., 2010b). This reflects animal model data. After inducing rats with a carcinogen, 38% of rats supplemented with broccoli isothiocyanates developed cancer compared with 95% of controls (Munday et al., 2008).
The protective effect of cruciferous veg against cancer is likely due to their potent induction of anti-carcinogenic phase-II detoxification (Prochaska, Santamaria & Talalay, 1992). [Note on detoxification: phase-I converts compounds into more readily excreted, but often more potent/active/toxic molecules, while phase-II is where they are modified for elimination]. Isothiocyanates from cruciferous veg selectively induce phase-II detoxification without inducing the conversion of carcinogenic compounds through phase-I (Talalay, 1989).
In response to phase-II induction by sulforaphane, cellular antioxidant defence systems are stimulated, leading to increased tissue levels of glutathione-S-transferases [GST] (Fahey & Talalay, 1999). After 12-weeks of consuming a glucoraphanin and sulforaphane-rich beverage, subjects in China exhibited a 61% increase in excretion of the airborne carcinogen benzene, through induced GST levels (Enger et al., 2014). Upregulated antioxidant action from sulforaphane has reduced oxidative damage to skin cells in culture (Benedict, Knatko & Dinkova-Kostova, 2012), an anti-carcinogenic effect which has been replicated in mice from glucoraphanin-rich broccoli extract (Dinkova-Kostova et al., 2010).
In vitro [i.e. in cell cultures] and animal models have elucidated further anti-cancer mechanisms of sulforaphane beyond detoxification and antioxidant upregulation, including induction of apoptosis [programmed cell death], cell-cycle arrest, and protection against DNA damage (Juge, Mithen & Traka, 2007). These effects may explain in vivo [living] results. In a randomized controlled trial in men with at risk for prostate cancer, sulforaphane increased doubling time of prostate-specific antigen levels by 86% (Cipolla et al., 2015). Sulforaphane has been shown to accumulate in mammary tissue and induce expression of the cytoprotective enzyme NQO1 in breast tissue (Cornblatt et al., 2007).
Another cruciferous phytochemical, 3,3′-diindolylmethane [DIM], has demonstrated strong protective effects against breast cancer in pre-clinical and clinical data through modulation of estrogen metabolism, while inducing apoptosis and cell-cycle arrest (Thomson, Ho & Strom, 2016). In otherwise healthy male smokers, 250g per day of broccoli significantly reduced DNA-damage, a characteristic feature of cancer resulting from cigarette smoke (Riso et al., 2010).
A randomised controlled trial in humans found a 20% reduction in fasting blood glucose from sulforaphane in type-2 diabetics (Bahadoran et al., 2012). In vitro evidence suggests isothiocyanates may reduce expression of gluconeogenic genes, an effect mediated through the Nrf2 pathway (Guzmán-Pérez et al., 2016). Thus, emerging data suggests a potential benefit to metabolic diseases, but this is a recent development and more data is needed.
Inflammation is gaining recognition as a cause of depression (Martín-de-Saavedra et al., 2013). In a mouse model of depression, sulforaphane attenuates symptoms through anti-inflammatory action via the Nrf2 pathway (Ibid.), and has demonstrated similar efficacy to fluoxetine as an anti-depressant agent, effects which corresponded with reduced inflammatory and stress hormone biomarkers (Wu et al., 2016). Sulforaphane has reduced symptoms of diabetic neuropathy in a mouse model (Negi, Kumar & Sharma, 2010). Sulforaphane has demonstrated neuroprotective effects in rodent models against ischemic injury, haemorrhage, spinal cord and brain traumatic injury, and Parkinson’s Disease (Dinkova-Kostova & Kostov, 2012).
A recent randomised controlled trial in children with autism found both statistical and clinically significant improvements across several behavioural measures from 9-25mg per day of sulforaphane (Singh & Zimmerman, 2016). Mice models of Alzheimer’s Disease have demonstrated that sulforaphane ameliorates cognitive deficits and protects against amyloid-β aggregation and oxidative damage (Kim et al., 2012; Zhang et al., 2014). Sulforaphane may protect against future neurodegeneration, as a glucoraphanin-rich diet in young and adolescent mice prevented induced cognitive deficits in adulthood and protected against oxidative stress, an effect potentially mediated through Nrf2 activation (Shirai et al., 2015).
To date, however, the evidence in relation to most neurological disorders is confined to animal models, and yet to be confirmed in human trials.
Cruciferous phytochemicals, in particular sulforaphane and DIM, confer a wide array of health benefits at physiologically relevant concentrations that are easily obtainable through diet. Public health recommendations continue to be mundane, unspecific and inexplicit – for example “5-a-Day.” There is enough evidence for cruciferous vegetables through in vitro, pre-clinical, clinical and epidemiological data to develop portion-based recommendations for this food group specifically. Public health recommendations should specifically emphasise consumption of CV in line with evidence for their preventative health properties. How about “2-servings a day of cruciferous vegetables”, isn’t that more actionable, more directive?
In the meantime, how much do you need? You can easily obtain the levels of isothiocyanates from consuming broccoli, kale, cauliflower and other cruciferous veg on a daily basis – aim for 1-2 cups chopped veg daily.
If you want to get really technical and geeky, then you want something in the region of 20-40mg sulforaphane. Order your seeds, and some sprouting jars, then follow this simple guide to home sprout your own. This is minimal effort. Broccoli sprouts are highest in sulforaphane content at 2-3 days old. Toss them in salads, or throw them in the blender as part of a shake.
Research into phytochemicals will continue to expand our understanding of the protective roles of these compounds in health and disease. Sulforaphane and other isothiocyanate compounds do appear to have particular benefit, and the evidence to substantiate an emphasis on them in your diet.
Bahadoran, Z., Mirmiran, P., Hosseinpanah, F., Rajab, A., Asghari, G. and Azizi, F. (2012). Broccoli sprouts powder could improve serum triglyceride and oxidized LDL/LDL-cholesterol ratio in type 2 diabetic patients: A randomized double-blind placebo-controlled clinical trial. Diabetes Research and Clinical Practice, 96(3), pp.348-354.
Benedict, A., Knatko, E. and Dinkova-Kostova, A. (2012). The indirect antioxidant sulforaphane protects against thiopurine-mediated photooxidative stress. Carcinogenesis, 33(12), pp.2457-2466.
Brown, R., Reynolds, C., Brooker, A., Talalay, P. and Fahey, J. (2015). Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2-mediated gene pathways. Respiratory Research, 16(1).
Cipolla, B., Mandron, E., Lefort, J., Coadou, Y., Della Negra, E., Corbel, L., Le Scodan, R., Azzouzi, A. and Mottet, N. (2015). Effect of Sulforaphane in Men with Biochemical Recurrence after Radical Prostatectomy. Cancer Prevention Research, 8(8), pp.712-719.
Cohen, J., Kristal, A. and Stanford, J. (2000). Fruit and Vegetable Intakes and Prostate Cancer Risk. JNCI Journal of the National Cancer Institute, 92(1), pp.61-68.
Cornblatt, B., Ye, L., Dinkova-Kostova, A., Erb, M., Fahey, J., Singh, N., Chen, M., Stierer, T., Garrett-Mayer, E., Argani, P., Davidson, N., Talalay, P., Kensler, T. and Visvanathan, K. (2007). Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis, 28(7), pp.1485-1490.
Dinkova-Kostova, A. and Kostov, R. (2012). Glucosinolates and isothiocyanates in health and disease. Trends in Molecular Medicine, 18(6), pp.337-347.
Dinkova-Kostova, A., Fahey, J., Benedict, A., Jenkins, S., Ye, L., Wehage, S. and Talalay, P. (2010). Dietary glucoraphanin-rich broccoli sprout extracts protect against UV radiation-induced skin carcinogenesis in SKH-1 hairless mice. Photochemical & Photobiological Sciences, 9(4), p.597.
Egner, P., Chen, J., Zarth, A., Ng, D., Wang, J., Kensler, K., Jacobson, L., Munoz, A., Johnson, J., Groopman, J., Fahey, J., Talalay, P., Zhu, J., Chen, T., Qian, G., Carmella, S., Hecht, S. and Kensler, T. (2014). Rapid and Sustainable Detoxication of Airborne Pollutants by Broccoli Sprout Beverage: Results of a Randomized Clinical Trial in China. Cancer Prevention Research, 7(8), pp.813-823.
Fahey, J. and Talalay, P. (1999). Antioxidant Functions of Sulforaphane: a Potent Inducer of Phase II Detoxication Enzymes. Food and Chemical Toxicology, 37(9-10), pp.973-979.
Fahey, J., Zalcmann, A. and Talalay, P. (2001). The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry, 56(1), pp.5-51.
Guzmán-Pérez, V., Bumke-Vogt, C., Schreiner, M., Mewis, I., Borchert, A. and Pfeiffer, A. (2016). Benzylglucosinolate Derived Isothiocyanate from Tropaeolum majus Reduces Gluconeogenic Gene and Protein Expression in Human Cells. PLOS ONE, 11(9), p.e0162397.
Herr, I. and Büchler, M. (2010). Dietary constituents of broccoli and other cruciferous vegetables: Implications for prevention and therapy of cancer. Cancer Treatment Reviews, 36(5), pp.377-383.
Holst, B. and Williamson, G. (2008). Nutrients and phytochemicals: from bioavailability to bioefficacy beyond antioxidants. Current Opinion in Biotechnology, 19(2), pp.73-82.
Hung, C., Huang, H., Wang, C., Liu, K. and Lii, C. (2014). Sulforaphane Inhibits TNF-Î±-Induced Adhesion Molecule Expression Through the Rho A/ROCK/NF-ÎºB Signaling Pathway. Journal of Medicinal Food, 17(10), pp.1095-1102.
Jiang, Y., Wu, S., Shu, X., Xiang, Y., Ji, B., Milne, G., Cai, Q., Zhang, X., Gao, Y., Zheng, W. and Yang, G. (2014). Cruciferous Vegetable Intake Is Inversely Correlated with Circulating Levels of Proinflammatory Markers in Women. Journal of the Academy of Nutrition and Dietetics, 114(5), pp.700-708.e2.
Joshipura, K. (1999). Fruit and Vegetable Intake in Relation to Risk of Ischemic Stroke. JAMA, 282(13), p.1233.
Juge, N., Mithen, R. and Traka, M. (2007). Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cellular and Molecular Life Sciences, 64(9), pp.1105-1127.
Kensler, T., Egner, P., Agyeman, A., Visvanatha, K., Groopman, J., Chen, J., Fahey, J. and Talalay, P. (2017). Keap1-Nrf2 Signaling: A Target for Cancer Prevention by Sulforaphane. Top Curr Chem, 2013(329), pp.162-77.
Kim, H., Kim, H., Ehrlich, H., Choi, S., Kim, D. and Kim, Y. (2012). Amelioration of Alzheimer’s disease by neuroprotective effect of sulforaphane in animal model. Amyloid, 20(1), pp.7-12.
Martín-de-Saavedra, M., Budni, J., Cunha, M., GÃ³mez-Rangel, V., Lorrio, S., del Barrio, L., Lastres-Becker, I., Parada, E., Tordera, R., Rodrigues, A., Cuadrado, A. and Lopez, M. (2013). Nrf2 participates in depressive disorders through an anti-inflammatory mechanism. Psychoneuroendocrinology, 38(10), pp.2010-2022.
Miao, X., Bai, Y., Sun, W., Cui, W., Xin, Y., Wang, Y., Tan, Y., Miao, L., Fu, Y., Su, G. and Cai, L. (2012). Sulforaphane prevention of diabetes-induced aortic damage was associated with the up-regulation of Nrf2 and its down-stream antioxidants. Nutrition & Metabolism, 9(1), p.84.
Mirmiran, P., Bahadoran, Z., Hosseinpanah, F., Keyzad, A. and Azizi, F. (2012). Effects of broccoli sprout with high sulforaphane concentration on inflammatory markers in type 2 diabetic patients: A randomized double-blind placebo-controlled clinical trial. Journal of Functional Foods, 4(4), pp.837-841.
Munday, R., Mhawech-Fauceglia, P., Munday, C., Paonessa, J., Tang, L., Munday, J., Lister, C., Wilson, P., Fahey, J., Davis, W. and Zhang, Y. (2008). Inhibition of Urinary Bladder Carcinogenesis by Broccoli Sprouts. Cancer Research, 68(5), pp.1593-1600.
Murashima, M., Watanabe, S., Zhuo, X., Uehara, M. and Kurashige, A. (2004). Phase 1 study of multiple biomarkers for metabolism and oxidative stress after one-week intake of broccoli sprouts. BioFactors, 22(1-4), pp.271-275.
Navarro, S., Schwarz, Y., Song, X., Wang, C., Chen, C., Trudo, S., Kristal, A., Kratz, M., Eaton, D. and Lampe, J. (2014). Cruciferous Vegetables Have Variable Effects on Biomarkers of Systemic Inflammation in a Randomized Controlled Trial in Healthy Young Adults. Journal of Nutrition, 144(11), pp.1850-1857.
Negi G., Kumar, A., Sharma, SS. (2011). Nrf2 and NF-κB modulation by sulforaphane counteracts multiple manifestations of diabetic neuropathy in rats and high glucose-induced changes. Current Neurovascular Research, 8(4), p.294.
Prochaska, H., Santamaria, A. and Talalay, P. (1992). Rapid detection of inducers of enzymes that protect against carcinogens. Proceedings of the National Academy of Sciences, 89(6), pp.2394-2398.
Rangasamy, T., Guo, J., Mitzner, W., Roman, J., Singh, A., Fryer, A., Yamamoto, M., Kensler, T., Tuder, R., Georas, S. and Biswal, S. (2005). Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. The Journal of Experimental Medicine, 202(1), pp.47-59.
Riso, P., Martini, D., Moller, P., Loft, S., Bonacina, G., Moro, M. and Porrini, M. (2010). DNA damage and repair activity after broccoli intake in young healthy smokers. Mutagenesis, 25(6), pp.595-602.
Shirai, Y., Fujita, Y., Hashimoto, R., Ohi, K., Yamamori, H., Yasuda, Y., Ishima, T., Suganuma, H., Ushida, Y., Takeda, M. and Hashimoto, K. (2015). Dietary Intake of Sulforaphane-Rich Broccoli Sprout Extracts during Juvenile and Adolescence Can Prevent Phencyclidine-Induced Cognitive Deficits at Adulthood. PLOS ONE, 10(6), p.e0127244.
Singh, K. and W. Zimmerman, A. (2016). Sulforaphane Treatment of Young Men with Autism Spectrum Disorder. CNS & Neurological Disorders – Drug Targets, 15(5), pp.597-601.
Talalay, P. (1989). Mechanisms of induction of enzymes that protect against chemical carcinogenesis. Advances in Enzyme Regulation, 28, pp.237-250.
Tang, L., Zirpoli, G., Guru, K., Moysich, K., Zhang, Y., Ambrosone, C. and McCann, S. (2008). Consumption of Raw Cruciferous Vegetables is Inversely Associated with Bladder Cancer Risk. Cancer Epidemiology Biomarkers & Prevention, 17(4), pp.938-944.
Tang, L., Zirpoli, G., Jayaprakash, V., Reid, M., McCann, S., Nwogu, C., Zhang, Y., Ambrosone, C. and Moysich, K. (2010). Cruciferous vegetable intake is inversely associated with lung cancer risk among smokers: a case-control study. BMC Cancer, 10(1).
Tang, L., Zirpoli, G., Guru, K., Moysich, K., Zhang, Y., Ambrosone, C. and McCann, S. (2010). Intake of Cruciferous Vegetables Modifies Bladder Cancer Survival. Cancer Epidemiology Biomarkers & Prevention, 19(7), pp.1806-1811.
Thomson, C., Ho, E. and Strom, M. (2016). Chemopreventive properties of 3,3-diindolylmethane in breast cancer: evidence from experimental and human studies. Nutrition Reviews, 74(7), pp.432-443.
Verhoeven, D., Goldbohm, R., van Poppel, G., Verhagen, H. and van den Brandt, P. (1996). Epidemiological studies on brassica vegetables and cancer risk. Cancer Epidemiol Biomarkers Prev., Sep;5(9), pp.733-48.
Wu, L., Noyan Ashraf, M., Facci, M., Wang, R., Paterson, P., Ferrie, A. and Juurlink, B. (2004). Dietary approach to attenuate oxidative stress, hypertension, and inflammation in the cardiovascular system. Proceedings of the National Academy of Sciences, 101(18), pp.7094-7099.
Wu, S., Gao, Q., Zhao, P., Gao, Y., Xi, Y., Wang, X., Liang, Y., Shi, H. and Ma, Y. (2016). Sulforaphane produces antidepressant- and anxiolytic-like effects in adult mice. Behavioural Brain Research, 301, pp.55-62.
Zhang, R., Miao, Q., Zhu, C., Zhao, Y., Liu, L., Yang, J. and An, L. (2014). Sulforaphane Ameliorates Neurobehavioral Deficits and Protects the Brain From Amyloid-b Deposits and Peroxidation in Mice With Alzheimer-Like Lesions. American Journal of Alzheimer’s Disease and Other Dementias, 30(2), pp.183-191.
Zhang, X., Shu, X., Xiang, Y., Yang, G., Li, H., Gao, J., Cai, H., Gao, Y. and Zheng, W. (2011). Cruciferous vegetable consumption is associated with a reduced risk of total and cardiovascular disease mortality. American Journal of Clinical Nutrition, 94(1), pp.240-246.