#028 Sulforaphane and Its Effects on Cancer, Mortality, Aging, Brain and Behavior, Heart Disease & More

Sulforaphane: Cancer

Smokers who consumed at least four and a half servings of raw cruciferous vegetables a month had a 55% reduction in lung cancer risk compared with those who consume less than two and a half...

"Hello again, boys, girls, distinguished members of the Electron Transport Chain and Extraterrestrials. I'm back, bringing you a fresh edition of the Found My Fitness podcast. This podcast is so fresh your mom, if she heard it, would be telling it not to get fresh with her. I know it feels like it's been a while, but that's just because things move so fast here on the internet. But sometimes you've got to slow down or risk drowning in emojis and flat earth YouTube videos. You've been wondering where I've been, but I've been here all along preparing just me in the dojo with PubMed, putting a stranglehold on the materials and methods, having discussions with the discussion, talking back to those abstracts and telling them they need to be a little bit more concrete. I'm not going to lie to you. Going this deep on a podcast does things to the mind, leaves you asking questions like how my microbiome is feeling about the surrealness of this election cycle? Or whether Bugs Bunny was really a wastly rabbit, or maybe he just had something to say. But don't worry, friends, we are in bat country no longer. Today, I have some great stuff for you. We're going to talk about cruciferous vegetables as a group. In other words, we're going to be talking about broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, turnips, horseradish, radish, mustard, rutabaga, watercress, landcress, gardencress, bok choy, pak choy, daikon, mizuna, maca, tatoy, and wasabi. Yes, wasabi. Who knew? We'll also be talking about broccoli sprouts, so much about broccoli sprouts, and more importantly, sulforaphane. We're going to talk about how sulforaphane is the most potent, naturally occurring dietary activator of a genetic pathway called NRF2 that controls over 200 genes, many of which are antioxidant, anti-inflammatory, and inactivate potentially harmful compounds we are exposed to on a daily basis. We're going to be talking about the cancer preventative properties of sulforaphane. We're going to be talking about the positive effects of sulforaphane on behavior in humans and the potential based on animal research that it may later be shown to have for depression and neurodegenerative diseases like Alzheimer's and Parkinson's disease. How sulforaphane has a positive effect on biomarkers of cardiovascular disease and lowers inflammatory markers in people. We're going to talk about the role of sulforaphane in the aging process in general. How sulforaphane causes people to increase the excretion of carcinogens like benzene and acrylene. We're going to talk about the role of sulforaphane in the aging process in general, how sulforaphane causes people to increase the excretion of carcinogens like benzene and acrylene. We're going to talk about the bioavailability and dose and how I'm able to sustain my 40 to 60 milligram per day sulforaphane habit cheaply through bulk sprouting and so much more. But before we get going, stop what you're doing, hit pause, go to my website at foundmyfitness.com, enter your email in the newsletter subscription box, and click submit. This podcast has been baking in the oven for nearly four months. We're not done here. I need to be able to communicate with you supplementary information that you don't want to miss. And if you're not on my list, I can't get it to you. That address is foundmyfitness, F-O-U-N-D-M-Y-F-I-T-N-E-S-S.com. It's free and it's awesome. And hey, over 50,000 people can't be wrong. When you're done doing that, go to youtube.com forward slash foundmyfitness or just Google foundmyfitness YouTube. Most of my podcasts come out as highly annotated videos that give extra definitions and facilitate better understanding as well as citations. And by subscribing, you're helping me achieve a personal milestone I'm working towards this year for subscribership over there. Finally, if you love this podcast and you just can't get enough, it's able to happen because of the amazing support of over a thousand people pledging to support it for as little as a few bucks a month. You can learn more about that by going to foundmyfitness.com forward slash crowd sponsor. Once again, that's foundmyfitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R crowd sponsor. All right, on to the podcast. Let's start with the basics. And by basics, I mean staying alive. In 2011, a study was published in the American Journal of Clinical Nutrition that showed if we took the population and divided them up by their vegetable consumption, those in the top 20% of the population eating the most vegetables had a 16% reduction in what is known as all-cause mortality. What this means is that for that period of time studied, they were 16% less likely to die from all non-accidental deaths compared to others in their age group, regardless of many other health factors like exercise. Hey, that's pretty good, right? But if instead of just looking at vegetable consumption, we look at the top 20% of cruciferous vegetable consumers, the effect on all cause mortality is even more substantial. The top 20% of consumers of cruciferous vegetables reduce their all cause mortality by 22%. Well, that alone is actually almost enough to make me start a broccoli farm. There's been a lot of research on the profound associations between cruciferous vegetable consumption and risk of cancer. For example, one study found that men that ate between three to five servings of cruciferous vegetables a week had a 40% decrease in prostate cancer risk compared to men that ate less than one serving per week. Another study found that men who ate two or more half cup servings of broccoli per week had a 44% lower incidence of bladder cancer compared to men who ate less than one serving each week. Smokers who consumed at least four and a half servings of raw cruciferous vegetables a month had a 55% reduction in lung cancer risk compared with those who consume less than two and a half servings per month. Multiple studies have shown that women who consume cruciferous vegetables at least once a week had between a 17% to 50% decrease in breast cancer risk. The variation between these studies likely has to do with the preparation of the cruciferous vegetables and whether they were fresh or frozen, all of which actually affect the bioavailability of the active compounds, which we'll talk about in a minute. But what if you already had cancer? People with bladder cancer that had just four servings of raw broccoli per month had a 57% reduction in bladder cancer mortality and a 43% reduction in all-cause mortality compared to those that just had one serving per month. Something is obviously going on here that's important. These are some pretty powerful associations. But before we begin to establish causality, we have to establish a plausible mechanism. Our most likely candidate, isothiocynates. Isothiocynates are produced from compounds known as glucosinolates by an enzyme called myrosinase, which becomes activated when the cruciferous plant is chopped, crushed, or chewed, but deactivated when subjected to prolonged high temperatures, such as sustained boiling. One isothiocyanate, sulforaphane, stands out from all the rest because of its potency and the sheer amount of scientific scrutiny it's been subjected to. Remember how we said isothiocyanates are made from glucosinolates? Sulforaphane is no exception. The glucosinolate sulforaphane is made from is known as glucoraphanin, but it's often simply referred to as sulforaphane glucosinolate. The single best source of glucoraphanin and thus sulforaphane are most likely broccoli sprouts, which contain up to a hundred times more glucoraphanin than their mature counterpart, broccoli. Moreover, broccoli sprouts are something that anyone can very, very cheaply produce at home in bulk. All it takes is around six glass jars, sprouting seeds in continuous rotation to yield about eight ounces every single day. This is something truly accessible to absolutely everyone since around 20 bucks will buy you a couple pounds of seeds, which is enough to sustain production for months. There are several different mechanisms by which isothiocinates, particularly sulforaphane, reduce cancer risk and kill cancer cells. And this involves many different molecular pathways, including inactivating a family of enzymes called phase one biotransformation enzymes, which are responsible for converting potential pro carcinogens into carcinogens. This is one way that sulforaphane prevents the formation of DNA adducts, which is a type of DNA damage that forms after exposure to a carcinogen and has been shown to lead to cancer. Tobacco smoke has many carcinogens that form DNA adducts once they're inside the cell, which is why it's really nasty stuff that significantly increases the risk for several types of cancer, including lung cancer and bladder cancer, which may help explain the really strong association between just a few extra servings of cruciferous vegetables and a 55% reduction in lung cancer risk in smokers mentioned just a little while ago. But what about the study on bladder cancer? Here too, we've got pretty good cause to believe that it's the isothiocyanates. In a study where rats were given a chemical compound that causes bladder cancer, almost 96% of those animals went on to develop large tumors. By comparison, only 38% of the animals that were given a very high dose of isothiocyanates at the same time went on to develop cancer. And those that did develop cancer, the tumors were much smaller in size. Many other animal studies have also mechanistically shown that isothiocyanates reduce cancer incidence when challenged with a tumor initiator. And what about the study on prostate cancer? Yep, probably the isothiocinates too. There have been a couple of clinical trials, both involving prostate cancer, investigating the effects of the active compound sulforaphane from broccoli sprouts on cancer treatment. Men with prostate cancer that were given 60 milligrams of sulforaphane per day, an amount in about 140 grams of fresh broccoli sprouts, resulted in the slowing of the doubling rate of a cancer biomarker known as prostate-specific antigen, or PSA, by 86% compared to placebo. First of all, think about that for a second. Slowing the rate at which a tumor marker is increased in a clinical trial by 86%. That's pretty gigantic. It appears as though this robust effect of sulforaphane on slowing the growth of prostate cancer may be dose dependent. In another study, when 35 milligrams of sulforaphane was used instead of 60 milligrams, and while it theoretically still slowed the growth of prostate cancer, it only increased the average PSA doubling time by 57%, which, while impressive, isn't quite as jaw-dropping as the 86% from the previous study. And breast cancer? Again, interesting things going back to the sulforaphane. In this case, bioaccumulation of the isothiocyanate. In 2007, a pilot study found that after receiving broccoli sprout extract containing about 37 milligrams of sulforaphane, or the amount you might get from consuming about 85 grams of fresh broccoli sprouts, the accumulation of sulforaphane was detected in actual human breast tissue, around 1.45 picomole per milligram for the right breast and two picomole per milligram for the left. Don't bother looking up what a pico is. It's extremely small. This is however interesting in the sense that we're seeing the molecule itself actually making its way to the breasts. Additionally, breast tissue also displayed increased levels of a gene called NQ01. This gene makes an enzyme that has many protective functions, including detoxification of certain compounds, preventing them from damaging cells, and even more interestingly, protecting a very important tumor suppressor gene called p53 from being degraded. All of this is happening within one hour after consuming broccoli sprout extract. p53 is itself so important to cancer biology that over 50% of all adult cancers have a mutated or broken P53 gene. Keeping our P53 working well is very important. We've also seen a bit more directly that in mice, sulforaphane is able to inhibit the growth of breast cancer stem cells. Look, I know I'm trying to blow your freaking mind here. I'm trying to suck you into my world and get you interested in isothiocyanates, but this stuff isn't cutting edge. I'm not the first person to rant and rave about this stuff. In fact, if we rewind a couple thousand years, an ancient Roman statesman, Cato the Elder, had this to say about a prominent member of the cruciferous family of vegetables. That cabbage eaten crude with vinegar or cooked with oil or fat banishes and cures all from crapulence after exceeding too much wine or all the way up to serious diseases like cancer. Crapulence. Now that's a fun and totally legitimate word to throw around at parties. Okay, we already talked a little bit about how isothiocyanates can play a role at preventing the formation of carcinogens by inactivating phase one biotransformation enzymes. But what if in addition to inactivating carcinogens, we got better at just getting rid of them? I'm talking about excretion, removing them from the body. This relies on a whole different set of enzymes for which isothiocyanates are known to activate the phase two detoxification enzymes. This effect happens via the NRF2 pathway for which sulforaphane is the most potent naturally occurring inducer of. NRF2 is a very important pathway because it controls literally hundreds of genes by a short sequence of DNA within these genes known as the antioxidant response element, which Nrf2 is able to bind to and thereby initiate or suppress the transcription of the gene. Phase 2 detoxification enzymes like glutathione S-transferase are important because they are able to inactivate procarcinogenic agents by transforming them into water-soluble compounds known as conjugates that are usually less reactive and are able to be excreted in urine or bile. Additionally, these enzymes are able to decrease DNA damage by reducing inflammation and reactive oxygen species. So it's a good thing that an increase in glutathioneus transferase is exactly what we see when people start bumping up their cruciferous vegetable consumption. In one study where participants were asked to eat 300 grams of Brussels sprouts per day, which is one of the cruciferous vegetables higher in isothiocyanate precursors, increased glutathione S transferase circulating in their blood plasma by about 1.4 fold, while overall oxidative DNA damage went down by about 28%. Drops in DNA damage are a very good thing since these are ultimately what initiate cancer and are fundamental to the process of aging itself. But when it comes to showing off the ability of sulforaphane to help trigger systems that boost the excretion of carcinogens, there's really one study that stands out. This study demonstrated that sulforaphane and its precursor glucoraphanin can actually significantly increase the excretion of benzene. Participants that were given a daily broccoli sprout beverage containing around 262.5 milligrams of glucoraphanin and about 7.1 milligrams of sulforaphane, which is about probably an effective dose of something like 135 grams of fresh broccoli sprouts per day, increased the rate of excretion of benzene by 61% beginning on the first day of consuming the drink and continuing throughout the entire 12-week period of the trial. For those of you that don't know, benzene is a nasty carcinogen that is known to cause cancer in humans and animals, particularly leukemia. Some of the major sources of benzene that people are exposed to are from automobile exhaust fumes and air pollution in general, and cigarette smoke, even secondhand. Air pollution is the major benzene source for non-smokers, and cigarette smoke really is the big culprit for smokers. In the U.S., cigarette smoke accounts for about half of the population's high exposure to benzene, with the typical cigarette smoker inhaling around 10 times as much benzene per day as a non-smoker, or around 2 milligrams of benzene compared to 200 micrograms for a non-smoker. This starts to make a pretty interesting case for tobacco smokers, right? Here's the facts we've got so far. Tobacco smokers that eat more cruciferous vegetables have a lower risk of lung cancer than smokers who don't. Smoking loads us up with a carcinogen called benzene, and interestingly, a supercharged broccoli sprout drink increases our excretion of benzene. But even if you're not a smoker, which I really hope you're not, we still have plenty of other places we can get benzene from. Air pollution is another place we get it. That's because air pollution in the United States primarily comes from automobile exhaust, which is a source of benzene. High dose benzene exposure from air pollution has been shown to increase oxidative DNA damage in a dose dependent manner in people, while even low dose exposure to benzene from air exposure and gasoline exposure has been shown to epigenetically change genes that are involved in suppressing leukemia. If we wish to concern ourselves with air pollution, however, we should look to a study published in 2008 on the use of a broccoli sprout homogenate. This study found that broccoli sprouts, when administered as a homogenate, had a direct effect on increasing the expression of phase two detoxification enzymes in the upper airway. In other words, right where it counts. The doses they gave to individuals ranged from 25 grams of broccoli sprout homogenate all the way up to 200 grams with a clear dose response relationship where the largest dose had the most potent effect, strongly increasing the production of various glutathione related enzymes such as glutathione S-transferases, heme oxygenase 1, and NQO1, which is an enzyme we talked about earlier when we discussed breast cancer. Benzene isn't the only airborne carcinogen the anti-benzene broccoli sprout drink worked some magic on. Over the 12-week trial, excretion of the carcinogen acrolein rapidly increased by 23%. Acrolein is found in most of the major sources already mentioned for benzene, including air pollution, but it differs in that it can also be formed when carbohydrates, proteins, and fats are heated. Another study found that consumption of a broccoli sprout beverage containing 27 milligrams of sulforaphane led to a 50% increase in excretion of acrolein, crotonaldehyde, ethylene oxide, and benzene. Finally, yet another study showed that a tobacco-specific lung carcinogen called NNK can be detoxified through the action of an isothiocyanate that is found in watercress. In other words, different isothiocyanate in different cruciferous vegetable, but again, an effect on carcinogen excretion. In this study, 57 grams of watercress was given to smokers to eat with each meal for three days while they continue to smoke. Those dirty rascals. This led to a 35% increase in excretion for biomarkers indicating the inactivation of the carcinogen NNK. The bottom line is that consumption of cruciferous vegetables, including watercress, but perhaps especially broccoli sprouts, since they are so rich in sulforaphane, is a powerful way to deactivate and excrete harmful compounds that we are exposed to on a daily basis, but even more so if you're a smoker. While some of this carcinogen excretion stuff is somewhat new, the general anti-cancer properties of glucosinolates and their metabolites, isothiocinates, are pretty well established, which is one reason why many studies looking into the effects of cruciferous vegetables specifically look at cancer incidents. What's interesting, however, is the effect cruciferous vegetables have on cardiovascular risk factors. Remember that study I mentioned earlier that showed a 22% reduction in all-cause mortality for the highest quintile of cruciferous vegetable consumption? It turns out the reduced risk of death was mostly associated with reduction in death from cardiovascular disease, which is still the number one killer in the United States, which may be surprising since we spent so much time talking about the number of cancer studies floating around out there. In fact, multiple studies have found that people that eat a higher quantity of cruciferous vegetables have a lower risk of cardiovascular disease, heart attack, and stroke compared to those with a lower intake. But better still is actually measuring the strength of this effect. One study in people with type 2 diabetes showed that it's possible to actually drive real changes in biomarkers that are predictive of future heart disease. Supplementing with 10 grams of broccoli sprout powder per day, which comes out to about 40 milligrams of sulforaphane and is probably comparable to around 100 grams fresh weight for four weeks, lowered their serum triglyceride by 18.7% and lowered oxidized LDL ratio by 13.5%. Overall, this reduced trial participants' atherogenic index by just over 50%, which is a measure of cardiovascular disease that incorporates a wide variety of factors. Not to mention, they also had a nearly 20% drop in fasting blood sugar, which is a pretty darn good thing if you're a type 2 diabetic. Other studies using fresh sprouts, but with a similar effective dose of sulforaphane, have also demonstrated anti-atherogenic effects. There are likely multiple mechanisms by which sulforaphane and cruciferous vegetables in general positively affect cardiovascular health. One of the most important ones goes back to the genetic pathway we mentioned earlier, the same one responsible for activating those phase 2 detoxification enzymes, which is NRF2. And that is because NRF2 activates antioxidant genes. It activates anti-inflammatory genes. It deactivates inflammatory genes, which all affect cardiovascular health. Sulforaphane has been shown in rat studies to increase antioxidant activity and glutathione expression in endothelial cells that line the blood vessels. It also relaxes smooth muscle cells. Additionally, sulforaphane appears to be able to reduce adhesive molecules that are part of the atherogenic state that drives heart disease, such as E-selectin, which is a cell adhesion molecule expressed only in endothelial cells and activated by inflammatory cytokines. Studies like these ultimately help give us some insights into what might be happening at a mechanistic level to drive these larger associations at a population level that are being seen between reductions in heart disease risk and consumption of cruciferous vegetables. So far, we have talked about how sulforaphane has been shown to prevent cancer, cardiovascular disease, and soon we'll be talking about neurodegenerative diseases, all of which are diseases of age. We've also talked about how associative studies like the one mentioned at the beginning of the video show reductions in all-cause mortality for the top 20% of cruciferous vegetable consumers. The question remains, however, does sulforaphane slow the aging process itself? One way to answer this question would be to see if sulfurophane has a direct effect on lifespan. Unfortunately, this hasn't, to my knowledge, been done in animals. I'd love to see that happen. I did, however, run across a bit of a tease, a study looking at the effect of broccoli extract on a type of beetle known as red flower beetles that were given a diet supplemented with 1% broccoli extract. It increased their mean lifespan by 15% under normal physiological conditions and under conditions of higher oxidative stress, increased their mean lifespan by 30%. The lifespan extension from the broccoli extract depended on the activation of Nrf2 and the FOXO pathway that is homologous to humans FOXO3 longevity pathway. Finding out the benefits in these little critters are derived from the same genetic pathway that is conserved in humans is promising if we're to have any hope that the results might replicate in a species a bit closer to us. Discovering that the FOXO genetic pathway is also involved, which is so closely linked with human longevity, and I've talked about in numerous other videos and podcasts, is just the cherry on top. In humans, for example, certain polymorphisms, which are genetic variations associated with increased activity of FOXO3A are associated with a 2.7 fold increased likelihood that a given person will live to be a centenarian. The chances of actually becoming a Thank you. FOXO3A are associated with a 2.7 fold increased likelihood that a given person will live to be a centenarian. The chances of actually becoming a centenarian, however, seem to depend a lot on keeping inflammation at bay. And it is now believed that suppression of inflammation is the single most important driver of successful longevity, and that this actually increases importance with advancing age. And we're not just talking about survival either, but also a strong association with capability in terms of being able to more adequately perform activities of daily living, as well as cognition in all major age groups, including elderly, centenarians, semi-supercentenarians, which are 105 to 109 years old, and supercentenarians, which are 110 years old and older. In fact, inflammation has been shown to be the single most important predictor of cognitive ability surpassed in its predictive ability only by a person's chronological age itself. And this relationship isn't surprising. We know that if we take mice, for example, and induce chronic low-level activation of a master regulator of the pro-inflammatory response known as NF-kappa B, it can actually accelerate aging by 30% in mice. Again, suggesting that chronic enhancement of pro-inflammatory mediators really is not just a bystander, but an actual driver of aging. Sulforaphane has been shown in mice to inhibit NF-kappa B through the activation of NRF2. NF-kappa B activates a multitude of inflammatory pathways and induces cytokines that regulate the immune response. One such example is IL-6, which is often activated downstream of NF-kappa B. Higher circulating levels of IL-6 are associated with increased risk for cancers and other age-related diseases. Here we see a benefit in humans. Healthy individuals given 14 grams of cruciferous vegetables per kilogram body weight daily decreased their circulating levels of IL-6 by 20%. Another study showed that a broccoli sprout powder containing approximately 40 milligrams of sulforaphane, an amount you might get from around 100 grams of fresh broccoli sprouts, reduced TNF alpha, a marker of inflammation, by 11%, and lowered C-reactive protein, another marker of inflammation, by 16% in people with type 2 diabetes. Associative studies in humans show a similar effect on inflammation. When comparing the top 20% consumers of cruciferous vegetables with the bottom 20%, they had, on average, a reduction of circulating IL-6 by 25%, and a similar decrease for other important inflammatory cytokines like TNF-alpha, which was lowered by 12.6%. If we accept the premise that sulforaphane from cruciferous vegetables is driving some of these reductions in inflammation by way of Nrf2, we have to ask ourselves, what is happening to Nrf2, and what does this mean for other processes in the body? Under normal conditions, NRF2 is briefly activated every 129 minutes or so. But when stimulated by sulforaphane, NRF2's pattern of activation changes. It becomes activated every 80 minutes, which is a 61% increase."

Liver Support Discussion

This gene makes an enzyme that has many protective functions, including detoxification of certain compounds, preventing them from damaging cells, and even more interestingly, protecting a very important tumor suppressor gene called p53 from being...

"This gene makes an enzyme that has many protective functions, including detoxification of certain compounds, preventing them from damaging cells, and even more interestingly, protecting a very..."

Blood Brain Barrier Discussion

This increase in NRF2's activity is important because NRF2 regulates over 200 genes, many of which affect cellular aging. It protects from cancer, which is an age-related disease by inactivating carcinogens and increasing their excretion.

"It deactivates inflammatory gene and activates antioxidant genes, which also protect DNA from damage that can lead to cancer, but also slow cellular aging in general. It does this by lowering the amount of damage that accumulates within cells."

Thyroid Health: Diet

This enzyme, which is released when the plant matter is crushed or chewed, unfortunately is heat sensitive. This is where a lot of people get into trouble.

"Most evidence indicates that this may only be a problem under conditions of severe iodine deficiency, which is not common."