Flavonoids in Edible Plants & Heart Health. Podcast with Nicola Bondonno.

It has become axiomatic that fruits and vegetables are protective against disease. Every single one of us has heard the old adage, “An apple a day keeps the doctor away” (although a recent study found that this particular aphorism, at the most literal level, may not be strictly true).

Humans have intuitively recognized the link between edible plants and health for thousands of years. Of course, our ancient ancestors had to figure it out the hard way – through self-experimentation. It is only very recently in our history as a species that we have been able to identify these benefits through empirical methods. Over the past decades, countless scientific studies have investigated the relationship between consumption of fruits and vegetables and human health and disease, and compelling evidence has emerged.

But why specifically are plant foods so protective? What makes them special?

We know, of course, that fruits and vegetables are good sources of essential nutrients (by that I mean vitamins and minerals). Fruits are particularly rich in vitamin C, for instance, which can fight oxidative stress and prevent DNA damage. And indeed, analyses of large cohort studies have found that dietary intake of antioxidant vitamins is associated with reduced risk of cardiovascular disease.

Understandably, researchers have sought to isolate these essential nutrients and capture their potential benefits in pill form. However, the results on that front have been pretty disappointing. Randomized trials using supplements (as opposed to foods) that contain these vitamins have failed to demonstrate consistently beneficial effects, and in some cases have even shown the opposite. It seems that the health-promoting impact of fruits and veggies probably cannot be fully realized by subbing in a multivitamin. Alas, as with many aspects of health and fitness, sometimes shortcuts just don’t pay off.

Or perhaps scientists were focused on the wrong target.

So, if the protective effects associated with fruits and vegetables are not mainly from essential nutrients like vitamin C and beta-carotene, where do they come from?

We now believe that other biologically active constituents within plants are likely responsible for their disease-fighting power.

And that brings me to our guest.

On this episode of humanOS Radio, we welcome Nicola Bondonno to the show. Nicky has a PhD in nutrition and cardiovascular disease from the University of Western Australia. Her research has been examining the effects of bioactive compounds occurring naturally in plant-based foods and beverages, and how they are connected to the cardiovascular health benefits associated with a plant-rich diet.

In a prior randomized controlled trial, she looked at the effects of apple consumption on endothelial function.

Participants were randomly assigned to consume either

Nicky and her colleagues found that subjects who consumed apples with the skins intact experienced a significant increase in flow-mediated dilation (0.8%) three hours after eating the fruit. Flow-mediated dilation, for those who may be unfamiliar, is a common way to assess vascular function. It refers to the widening of an artery when blood flow increases. Importantly, no such improvement was observed in those eating the apple flesh only.

Flavonoids are a large class of polyphenolic compounds found in fruits and vegetables. They carry out a variety of important functions in plants, and they affect our bodies as well when we eat them, in ways that we are only just now starting to elucidate. Just as one example, flavonoids are thought to enhance bioavailability of nitric oxide, a molecule that regulates vascular tone. Specifically, nitric oxide relaxes the walls of blood vessels, which in turn reduces blood pressure and improves blood flow. With respect to cardiovascular health, you can imagine that this would be a very good thing!

But of course, we can only tell so much about the lasting clinical effects of a given dietary component on health and disease from short term trials like this. This is why Nicky’s recent observational study caught our attention.

She and her team analyzed data from the Danish Diet, Cancer and Health cohort. This study assessed the diets of 53048 middle-aged Danish residents over the course of up to 23 years. Nicky and colleagues estimated the flavonoid content of the foods and beverages that these subjects reported consuming, and compared this dietary intake to the medical outcomes and cause of death (if applicable) of the participants.

From this data, a number of important questions could be addressed:

To hear what they found, and to learn more about dietary flavonoids and their role in health and disease, please check out the interview below!

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Nicola Bondonno - 00:01: Tea is often the highest contributor to total flavonoid intake for most populations. This is followed by apples, oranges and berries, and then other major sources include chocolate and red wine.

Dan Pardi - 00:16: Welcome back, everybody. Today, I have with me Nicola Bondonno. Nicky has a PhD in nutrition and cardiovascular disease from the University of Western Australia. Her research has been examining the effects of bioactive compounds occurring naturally in plant-based foods and beverages and how they are connected to the cardiovascular health benefits associated with a plant-rich diet. It has become axiomatic that fruits and vegetables are good for your health and in turn inadequate intake of them seems to be associated with increased mortality. For instance, one meta-analysis from a couple of years ago found that as many as 7.8 million premature deaths worldwide might be attributed to a fruit and vegetable intake below 800 grams or almost two pounds per day. The reason for this are still being investigated, but a few different factors seem to be at play here.

01:04: For instance, we know that fruits and vegetables are rich in fiber and fiber has a favorable effect on blood lipids, inflammation, blood pressure and other factors. We also know that fruits and vegetables are sources of antioxidants like vitamin C which can fight oxidative stress and prevent DNA damage. They can exert a beneficial effect on the composition of our gut microbiota and its metabolites, and fruit and vegetables also are low in calories relative to their volume and are associated with reduced risk for obesity and weight gain. Finally, eating lots of vegetables and fruits may reduce chronic disease indirectly by displacing junk foods, so fruits and vegetables have a lot going for them. They are rich in a class of phytochemicals, also known as flavonoids, which have been shown to be closely associated with the health benefits we've observed in fruit and vegetable intake. And that's what we're going to discuss today. Nicola, welcome to the show.

Nicola Bondonno - 01:51: Thank you, Dan.

Dan Pardi - 01:52: What got you interested in plant compounds in the first place?

Nicola Bondonno - 01:55: That's a very interesting question. I did my PhD primarily looking at apples and the beneficial compounds found in apples, which are mainly flavonoids. I ran a clinical trial looking at apple consumption, eating apples with the skin or eating apples without the skin and what health benefits you can receive from them. And we found that apples with skin are much more beneficial and this is likely due to the flavonoid compounds found in the skin.

Dan Pardi - 02:21: Very interesting. Now, do the skins, are they a rich source of a lot of the phytochemicals in the plants and fruits that we eat if they have skins?

Nicola Bondonno - 02:28: Yes. Actually, the skin is the greatest source of these protective compounds. For example, with the flavonoids, they're produced by the plant as a defense mechanism against stress such as UV radiation, and it's thought that these flavonoids can have a similar protective effect in animals or humans who consume these plants as food. And as the skin is a barrier for the plant, this can be why the skin has the highest level of these flavonoid compounds.

Dan Pardi - 02:54: Makes sense. Epidemiological research has suggested that fruit and vegetable intake is associated with lower risk of mortality, but as I alluded to in the intro, the reasons why could be fairly complicated since plants contain so many different nutrients, phytochemicals. Broadly speaking, what are some attributes that appear to make fruits and vegetables health-providing?

Nicola Bondonno - 03:12: The fruits and vegetables, like you said before, they're really rich in fiber, which we know can have great effects for our health, particularly through the gut microbiome. Fruits and vegetables also contain other beneficial components, vitamin C. They contain minerals such as potassium and other compounds such as nitrate, flavonoids, carotenoids, and even vitamin K have been shown to be beneficial for our health.

Dan Pardi - 03:40: What are flavonoids then?

Nicola Bondonno - 03:40: Flavonoids are a class of compound. They're found pretty much ubiquitously in any plant-based food or beverage and they're produced, like I said before, as a defense mechanism and potentially can also have beneficial effects in us when we eat these plants as food.

Dan Pardi - 03:55: And are there different subclasses of flavonoids as well?

Nicola Bondonno - 03:58: Flavonoids are classified based on their chemical structure into about six main classes. Interestingly, these classes vary greatly in their properties and their biological activity.

Dan Pardi - 04:09: They're described as antioxidants sometimes, but do we know precisely how they're working in the body? Do we have some ideas of what they're doing?

Nicola Bondonno - 04:16: That's a question that researchers have spent always 70 years trying to answer. One of the original theories was that flavonoids were, like you said, antioxidant compounds, so that is that they acted to counteract pro-oxidant compounds which are circulating in the body. But we now know that this is unlikely to be the main mechanism by which they work as they simply never reach a high enough concentration in our bodies to be able to have a meaningful impact as antioxidants. Flavonoids have been reported to have beneficial effects against the development of many chronic diseases, namely cardiovascular disease, diabetes, cancer, and neurodegenerative disorders.

04:54: Now, there are a really large number of potential mechanisms by which flavonoids may exert these protective effects against this vast array of diseases. For example, flavonoids have been shown to lower inflammation. They can improve how our blood vessels function. They can lower blood pressure and improve our body's response to foods containing glucose.

Dan Pardi - 05:14: Subclasses of the flavonoids then, do they vary in terms of their biological effects or is it more uniform in terms of the effects that they're having?

Nicola Bondonno - 05:21: They do vary greatly in their biological effects, but interestingly, when you eat a flavonoid compound, it's rapidly changed by your body pretty much as soon as you eat them. Importantly, the bacteria found in the gut microbiome metabolizes these compounds or breaks them down into a group of smaller compounds, and these smaller compounds can be the same between different flavonoid subclasses. So because flavonoids have a very similar chemical structure, when they're broken down into smaller compounds, these smaller compounds can be the same or at least very similar among the subclasses. We know now that these smaller compounds are also having a beneficial effect on our heart health, so maybe flavonoids from different subclasses aren't as different as we originally thought.

Dan Pardi - 06:05: Well, let's talk about your study. Looking at the Danish Diet, Cancer and Health Cohort, what was the aim of the study and what population were you looking at and why did you choose this particular group?

Nicola Bondonno - 06:16: For this study, we wanted to look at whether people who eat plenty of foods rich in flavonoids are less likely to die of heart disease or cancer. We chose this particular group of people as we had information on what foods they tended to eat and also what happened to them over 23 years of followup. So in Denmark, citizens are provided a unique and personal identification number, which means that you can link information on them to a number of large registries which contain information on whether the person is alive, whether they went to hospital, what they went to hospital for, what information can be linked, which means that we can get a really good idea of what happened to these people during follow up. They were roughly between the ages of 50 and 60 when they completed the dietary questionnaire, so they were really at a stage of their life where the impact of diet on their health could really be seen.

Dan Pardi - 07:08: How many people were included in the study?

Nicola Bondonno - 07:11: We had information on just over 56,000 people.

Dan Pardi - 07:15: The information was collected on them between ages 50 to 65 as you said. Do they have to be healthy? Tell us about the period of time where they were evaluated.

Nicola Bondonno - 07:25: They were originally recruited for a study looking at the effect of diet on cancer. They were recruited between 1992 and 1994 and they were asked to fill out a very detailed questionnaire about what foods they normally consume. We then followed them for the next 23 years, which takes us up to about 2017.

Dan Pardi - 07:45: Were there follow followup assessments of their diet in that time or was it just a one-time assessment and then looking at health outcomes later?

Nicola Bondonno - 07:53: It was just a one-time assessment looking at outcomes later.

Dan Pardi - 07:56: Tell us a little bit more about the dietary survey used in that study.

Nicola Bondonno - 08:00: It was a very detailed questionnaire. For example, a question would be how often do you eat apples, and then the participant would tick the box that best applied to them, ranging from I never eat apples to I eat apples more than four times per day. And questions were asked on every component of the diet.

Dan Pardi - 08:16: So there's 192 items on that questionnaire, so that probably took a while for them to fill out. From there, how did you determine the flavonoids that were in the diet?

Nicola Bondonno - 08:25: There's a large online database of the flavonoid contents of foods and this is called Phenol-Explorer. Each food in the dietary questionnaire was matched up to Phenol-Explorer and the amount of each flavonoid compound reported to be found in that food was obtained. We could then add up the flavonoid content of each food to obtain an estimate of total flavonoid intake for each person.

Dan Pardi - 08:50: What did you find when you analyzed the data on total flavonoid intake in mortality?

Nicola Bondonno - 08:50: We found that participants who tended to eat more flavonoid-rich foods were less likely to die. And when we looked at specific causes of death, we saw that they were less likely to die of heart disease and less likely to die of cancer.

Dan Pardi - 09:03: Were there any interesting differences when you looked at associations for flavonoid subclasses?

Nicola Bondonno - 09:09: We found that most of the flavonoid subclasses seem to show the same pattern. That is people with high intakes were less likely to die of both heart disease and cancer. Interestingly, for some subclasses, the risk of dying actually increased again for people with very high intakes. This is very unlikely to be due to the actual flavonoid compounds, but it may be due to other components of foods that these compounds are found in.

Dan Pardi - 09:33: Interesting. The thinking is, just to repeat that, it's not that these compounds become harmful after a certain dose, but it might be the co-occurrence of other compounds in those foods that might be causing the reduction in the benefits seen at higher levels.

Nicola Bondonno - 09:47: Exactly.

Dan Pardi - 09:48: Got it. You also observed some differences in the association between flavonoid intake, specifically in smokers, regular drinkers and subjects who were obese. Why do you think there were differences in these lifestyle factors?

Nicola Bondonno - 10:00: One of the main findings of this study was that people who smoke, or like you said drink too much alcohol, they tended to be the ones who benefited the most from flavonoid intake. So smokers and high alcohol consumers are at a higher risk of both heart disease and cancer. They have higher levels of inflammation and oxidative stress. It may be that the flavonoids are counteracting at least in part these higher levels of inflammation and oxidative stress, and so their beneficial effects aren't really apparent in this group. In terms of the people who are overweight, actually we saw that people who were obese tended to receive less of a benefit compared to people who were normal or overweight, and this may be due to the gut microbiome. So the gut microbiome is crucial for the breakdown of these flavonoid compounds. And we know that people who are obese have a different microbiota profile. So it may be that they're not breaking these flavonoid compounds down into their active components and may not be receiving as much of a beneficial effect as people who are normal or just slightly overweight.

Dan Pardi - 11:05: Wow, that's very interesting. What were the biggest sources of flavonoids in this population? Are they pretty similar in other populations that have been studied in similar studies as well?

Nicola Bondonno - 11:13: Tea is often the highest contributor to total flavonoid intake for most populations. This is followed by apples, oranges and berries. And then other major sources include chocolate and red wine. There are other foods which are higher in flavonoid content, but they're often less consumed and so don't end up contributing to the overall flavonoid intake of the population as much as these food sources.

Dan Pardi - 11:36: The threshold for maximum benefit in terms of flavonoid intake for all-cause mortality and cardiovascular disease mortality was around 500 milligrams per day and cancer mortality was around 1,000 milligrams per day. That's a pretty achievable level. Can you describe roughly what that might look like in a day for people that don't know exactly what those levels mean in terms of the foods they consume?

Nicola Bondonno - 11:57: Absolutely. 500 milligrams of flavonoids could be achieved by having say a cup of tea, maybe one apple, one orange, 100 grams of blueberries and 100 grams of broccoli. That would provide you with over 500 milligrams of flavonoids and it pretty much covers all of the flavonoid subclasses as well. Of course, other fruits and vegetables that we eat and other foods would raise that. Even eating 1,000 milligrams isn't unachievable.

Dan Pardi - 12:24: About 500 milligrams is about a cup of tea or an apple or an orange, 100 grams of blueberries, 100 grams of broccoli. That's achievable levels. That's exciting to know that you don't have to consume such extraordinary amounts to get these benefits that we're talking about.

Nicola Bondonno - 12:38: No, and in fact in the study, we saw the threshold effect, so even consuming higher levels didn't seem to give you any added benefit.

Dan Pardi - 12:46: I've seen it in a few epidemiological studies that examine intake of flavonoids or polyphenols in general, and it seems like the biggest sources tend to be beverages like coffee, tea and fruit juices. Are there meaningful differences between getting flavonoids from juices instead of in the whole food form with the food matrix, like oranges versus orange juice for instance?

Nicola Bondonno - 13:06: Like I said before, I did my PhD on apples, so one of the studies that I looked at was apples as a whole food versus apples as a juice. And it seemed that eating apples as a whole food was associated with much greater beneficial health effect. And this may be due to the protective effect of, for example, fiber, which is found in the whole food. So there's evidence that fiber and flavonoids can work together and that when you consume flavonoids with fiber, their health benefits are actually greater. Another thing is that in the juice form, there's a high level of sugar. Fiber can help improve your body's response to this sugar. So if you're not having it in a whole food source, if you're just having it as a juice, you don't have that protective fiber component and you can actually get a spike in glucose. It doesn't seem to be as beneficial.

Dan Pardi - 13:56: As of this moment in time, the last podcast I published with Professor Pankaj Kapahi from the Buck Institute, and we talked about hyperglycemic states being one of the main sources of methylglyoxal, which is a precursor for age formation and that they believe that it's not necessarily the hyperglycemia per se that's causing a lot of the diabetic complications that we see in people with diabetes, but it's rather the formation of these compounds that then embed themselves into certain tissues throughout the body and in parafunction. Other interesting aspects too is that these phytochemicals that we're talking about, hesperidin, resveratrols, they seem to inhibit the formation of those reactive compounds also, so another mechanism here which might be associated with some of the mortality benefits that you saw. Are there potentially unique benefits associated with consuming plant compounds in their whole form? We talked about orange juice versus orange. What about isolates? Do you think that the smarter strategy was to get the whole plant versus identifying the most active ingredient in it?

Nicola Bondonno - 14:52: There seem more than 5,000 flavonoid compounds discovered. If there's one that's having the greatest effect, how do we know which one? It's much more likely to be a combination of flavonoid compounds rather than an isolated compound. And another interesting thing is that the form in which the flavonoid compound is found can have a huge impact on your body's ability to absorb it. For example, flavonoids found in an apple generally have a glucose molecule attached to them and this can greatly help with absorption. When those same flavonoid compounds are given as a supplement, they are generally in their pure form and they don't have that glucose molecule attached. Your body cannot absorb them anywhere near as well, and therefore the beneficial effect on health is greatly reduced. Of course, as we spoke about before, there's evidence for a synergistic interaction between flavonoids and fiber and there's a great number of different beneficial components found in whole foods. I recommend definitely sticking for the whole foods, trying to get as many of different compounds in there as possible because really we don't know which one is having the beneficial effect if there even is one.

Dan Pardi - 16:00: It's very much a drug development model that tries to view whole plants as how do we find the one thing that's having the effect versus looking at that term that's been used as the entourage effect or how they all work together in the form that they come in, in the form that had been eaten for millennia of human evolution. That's always going to be the safer bet is my take after looking at a lot of this research myself.

Nicola Bondonno - 16:24: Yes, absolutely.

Dan Pardi - 16:28: What sort of research are you doing currently that is looking at these compounds in other areas?

Nicola Bondonno - 16:34: Following on from this research in the same population of people, we're now trying to have a look at specifically which type of cardiovascular diseases the flavonoids seem to be most protective against. We're also looking at other outcomes such as dementia and diabetes in these cohorts, so that's some papers that I'm currently working on at the moment. I'm also working on a clinical trial looking at the health benefits of blueberries. So blueberries are very rich in compounds called anthocyanins. That's one of the subclasses of flavonoids. Interestingly, studies have shown that some people benefit greatly from eating blueberries, whereas other people don't seem to show those same health benefits. Our theory is this is due to how they metabolize those flavonoid compounds. So we're trying to have a look at differences in how people metabolize these flavonoid compounds and if that can explain why some people benefit from eating flavonoid-rich foods, whereas other people don't really seem to show those same benefits. We're trying to tease apart that and answer some questions there.

Dan Pardi - 17:34: What is your personal strategy now in terms of extrapolating your work, looking into these specific compounds to your diet? What do you practice personally in terms of how you eat and how this information has informed your practice of good health and good diet?

Nicola Bondonno - 17:49: My main strategy is to try and vary my diet as much as possible. Eat predominantly a plant-based diet. Try and mix it up a lot, not eat the same foods every day, which can be challenging. I also try to make sure I have a lot of fiber in my diet as I know that that can greatly improve my gut microbiome and improve how I break down these flavonoid compounds so that I can really obtain the greatest benefit from them.

Dan Pardi - 18:13: Do you have a strategy in terms of across the day, always try to get some phytochemicals in the morning or mid-afternoon? Do you go that far or just try to make sure that you're getting enough on a daily basis?

Nicola Bondonno - 18:23: I generally didn't use to eat fruit, for example. Fruit consumption was quite low, so I've tried to make sure that I have fruit every morning. And then I know, "Okay, I've got my fruit." That's the main source of flavonoids in my diet and if I get that done first thing in the morning, it's kind of a tick for the rest of the day. And then lunch and dinner, I mainly focus on vegetables and whole grains I would say.

Dan Pardi - 18:48: I've seen you've done some work looking at atrial fibrillation and looking at these compounds and their effects there. What have you found in that area?

Nicola Bondonno - 18:56: Interestingly, we found that flavonoids weren't as protective against atrial fibrillation as they are against other types of cardiovascular disease that are more atherosclerotic in etiology. We did see that the flavonoid compounds did protect against atrial fibrillation in smokers and high alcohol consumers. But in the population overall, we didn't see those same beneficial effects.

Dan Pardi - 19:20: Have you identified any other food factors that do seem to be beneficial in atrial fibrillation?

Nicola Bondonno - 19:26: No. The evidence linking diet to atrial fibrillation, there's not a lot and they really haven't identified any dietary components that are protective against atrial fibrillation. It may be that diet doesn't play as big a role in atrial fibrillation as it does in other types of cardiovascular disease.

Dan Pardi - 19:44: Right. Thank you. Really appreciate you coming on to talk about your work here. It's very interesting. It has some pretty clear takeaways. Fruit and vegetable consumption is good for you and the quantities that are needed don't seem to be astronomical and rather they are very attainable. It's nice to reinforce that message and we really appreciate your time.

Nicola Bondonno - 20:03: Thank you, Dan.