Meet Professor Doug Seals. He’s a distinguished professor of Integrative Physiology at the University of Colorado Boulder. Doug is also an award-winning scientist who leads a large body of research, primarily in cardiology and biological aging research. On his recent travels to New Zealand, he was kind enough to stop by the MitoQ office to chat with our Head of Brand and Communications, Liz Hancock. Watch the video below, listen to the podcast on Spotify or keep reading to find out about the research he’s conducted on MitoQ, what he’s learned so far about MitoQ and arterial health, and further research in this area that he’s working on.
Can you tell us about the areas that you specialize in and study? Also, can you tell us a bit about why you’re currently visiting New Zealand?
Yes. I’m visiting New Zealand because I’m on what we call an “academic sabbatical”. I’ve spent a month at The University of Sydney and The University of Melbourne in Australia before coming here. Here, I had a second sabbatical residency at the University of Otago. So, that’s really the main purpose of why I’m in New Zealand at this point.
The focus of our laboratory is actually to create scientific evidence for various kinds of strategies that will promote cardiovascular health throughout the lifespan. We’re very interested in an emerging area of biomedical science – and that’s healthy cardiovascular aging. That’s the primary focus of our research.
It’s very nice that you were in Otago visiting the birthplace of MitoQ! How did you first discover MitoQ and what piqued your interest in studying it?
In the early 2000s, we were very interested in the possibility that antioxidants might be able to help us promote healthy cardiovascular aging. We had tried conventional vitamins such as vitamin C and vitamin E, but those vitamins were shown not to have any effect by us and other laboratories. So, we were searching for an antioxidant that had more promise than those more common antioxidants/over-the-counter antioxidants that had been tried. We heard about this mitochondrial-acting antioxidant – and we had done some work on mitochondrial physiology and knew the importance of mitochondria as producers of reactive oxygen species. If you could position an antioxidant close to the mitochondria that were producing these reactive oxygen species, that made inherent sense to us that this might actually help cardiovascular health.
So, we started with pre-clinical studies on mice. In our initial study, which was in around 2010, we had reached out to Mike Murphy (one of the co-discoverers of MitoQ), and he was performing pre-clinical research at the time, and we formed a collaboration with him. The company supplied us with MitoQ for those initial studies in mice. Basically, what we did was we took groups of old mice and young mice, and half of the young mice and half of the old mice each received MitoQ in their drinking water for three weeks while the other mice did not receive anything in their water – just placebo water, if you will. After three weeks, the old mice that were taking MitoQ completely reversed the cardiovascular dysfunction that they had shown with aging. We were really impressed by that. So that was the original exposure to MitoQ and the original investigation that we undertook. And they were sort of proof-of-concept. So, before you conduct a study in humans, if there’s no evidence to go by, you can usually perform pre-clinical studies and try to design an investigation that provides some kind of proof before you move on to human subjects. That’s how we started.
Amazing! So, moving on to that human clinical trial – could you tell us what you found?
We’re what’s called a “translational physiology lab”. Translational research just means, in most cases, moving from pre-clinical models (so, studying events in cells or making observations in mice). And then, based on that evidence, if it’s promising, move that up to pilot studies (small trials in human subjects) - and then larger and larger trials. That’s the way our laboratory conducts our research. After conducting those mice studies that we just talked about, we felt that the compound showed sufficient promise to try and translate the observations to people. At that time, MitoQ started providing (as a dietary supplement) the current compound which was not available when we were doing the mouse studies. So, the timing was perfect. Just when we wanted to translate the observations to people, the compound became available commercially.
So, we contacted the company and had them provide us with MitoQ and placebo capsules. We were then able to conduct a pilot study. This was a small study – it's what they call a crossover study. So, you randomize volunteers at the very beginning to either 6 weeks of taking MitoQ or 6 weeks of taking the placebo control compound that shouldn’t have any effect. And then, after 6 weeks, they crossover and you take the other treatment, whatever that is. So, we conducted that study and found that the individuals that took MitoQ for 6 weeks, after they took the MitoQ they had a significant improvement in vascular health. Whereas the group that took the placebo did not have any change at all. So, that’s sort of your control condition to make sure that there’s no effect of just being in the study.
So those were very promising results – and the improvement in vascular health was just one of the results we found. The primary outcomes measure, which is sort of clinical trials jargon for “the main result” is something called “vascular endothelial function”. That’s a fancy term to describe the health of the lining of our arteries. So, all of our arteries - at the interface of the inner layer of the artery and where blood flows in what we call the lumen of the artery - there’s a single layer of cells called endothelial cells. They’re very important to promote the health of the artery because they manufacture and release important bioactive molecules into the artery. You can measure the health of that lining by stimulating the artery to dilate – which basically just means to widen. In the conditions that we’re talking about, the greater the induced dilation, the more healthy that endothelial lining is because the stimulus actually causes the endothelial cells to release the molecules that eventually cause the artery to widen. So, an endothelial lining that isn’t healthy won’t produce enough of the molecules to dilate the artery as much.
So, our main measure was simply how much the artery would dilate when we stimulated these endothelial cells to produce the molecules that they should produce – and that was impressively improved with the 6 weeks of MitoQ.
We also measured another important assessment of arterial health – and that’s the stiffness of the arteries. For example, as we age, our arteries tend to stiffen. That drives up our blood pressure and causes a lot of other problems. We found that MitoQ reduced a standard reference measure of arterial stiffness. So, we consider that endothelial function, the dilation capacity and arterial stiffness, to be the two most important changes that occur to our arteries with aging – and both of those were improved.
So, presumably, that also has a positive knock-on beneficial effect on heart health? Are we talking about any other parts of the body or mostly heart health?
Yes, well, mostly heart health. It turns out that the heart does undergo changes with aging, and many of those changes are adverse, but they’re all primarily driven by changes to arteries. The idea is that, if you can promote arterial health, by whatever strategy, then you’re also going to have an impact on the heart. It’s also possible, because the arteries are the blood vessels that provide blood from the heart and the heart pumps blood out into the circulation, the arteries are the vessels that carry that oxygenated blood with all their nutrients and delivers that blood to all of your tissues and organs and cells.
So, it’s possible that, by improving arterial health, you can improve a variety of other functions in the body. Your muscles need blood flow when you’re active and you need to move around, very fundamental processes throughout the body require this oxygenated, rich nutrient blood. So, even though it hasn’t been investigated yet, it’s still the early parts of investigations in this area, it is possible that we’ll find many other positive health benefits because we have improved arterial health as a primary event. And brain health would be part of that. The health of the brain is very importantly influenced by the health of the arteries.
I guess there are a lot of people out there who don’t understand what a clinical trial is and how it’s funded. Could you talk a little bit about that?
What they call a “randomized clinical trial” - you’ll see it abbreviated “RCT” - that’s considered the gold standard of investigations on human research that involves treatments. And those treatments could be prescription drugs, they could be various types of dietary supplements, they could be healthy lifestyle behaviors such as exercise or dietary restrictions, eating a different diet...whatever the case. But whatever the treatment is, the randomized clinical trial is designed to show the potential benefits of a treatment by isolating the effects of that treatment verse other effects. What I mean by that is, if someone is given a drug or some type of dietary supplement or they’re asked to do some type of physical activity or eat a certain type of diet – then they might feel that something has improved and, in fact, if you measure something, some function of the body, you may actually find that it has improved. The problem is that if the measurement is subjective, the person may respond that they feel better because they think that they have taken something that should make them feel better. If it’s the case where something is actually being measured, you don’t know if the measurement is stable. So, if you’ve given them something that should have no effect at all but they still show an improvement in that measurement, that’s called a time control. So, measurements can change over time.
Basically, what a clinical trial does is it takes a group of individuals and it randomly assigns them to either a treatment or a placebo control condition. Then, they are put on those respective treatment conditions for some period of time. They’re measured again at the end of it. Now you have a situation where the effects of the treatment can be compared to whatever affects you see in the control group. A promising study, the type of study results that you would like to have if you believe in a treatment and it’s going to be successful, would be that the individuals put on the treatment condition the experimental condition where they’re receiving an actual active compound or whatever the treatment is that you think is going to produce benefits. If they show an improvement, in a health outcome for example, and the other group that’s been on the placebo does not, now you have a very clear picture and compelling evidence that the treatment may indeed be effective. But it’s always compared to any changes that occur in the control condition.
So if your measurement – we call it in science “measurement drift” - if your measurement indicates it improves in the control group, you’re always comparing the response in the treatment group directly against the control group. This is a way that we can cut out a lot of these biases that are inherent to certain kinds of research. What you always want to see is medical studies, more than one whenever possible, that show what we just talked about. That the treatment has a significant effect in improving a health outcome compared with the placebo control. So that’s called a randomized control study because you’re controlling all the other factors, except for the effects of your treatment.
MitoQ currently has *15 clinical trials that have been published on it. How common is that for a dietary supplement?
I think it’s relatively uncommon, in our experience. We’ve studied both healthy lifestyle strategies and pharmacological strategies. The pharmacological strategies are usually within the range of dietary supplements, including MitoQ. So, we’re pretty experienced in what goes on in that world and the great majority of dietary supplements that are commercially available have no evidence whatsoever from any kind of research, much less a randomized clinical trial – which is considered the gold standard for producing evidence of a health benefit.
Most dietary supplements, if you walk into the grocer or the vitamin cottage or whatever it is, you’ll see hundreds – perhaps thousands – of dietary supplements. Relatively few have had any research done on them. The rarest of that would be to have a clinical trial. Even more rare would be several clinical trials on a particular compound or dietary supplement, showing benefit. But that’s really what you should look for – some type of research that’s been well-controlled, that shows benefit. Ideally, that research would then include a pilot clinical trial and then, eventually, larger clinical trials that meet these standards for rigor. Then you have confidence.
But, like I said, the great majority do not have any research at all. So, I think it’s very unusual.
*18 as of February 2023
So, you spoke to us about a larger clinical trial. Could you talk to us about that?
Yes. And I’ll just mention, as part of the response, you cannot perform research without grant funding. Clinical research, especially, is very expensive. So, if I can take a half-step back to tackle your question, when we first started out with the mouse work, that was largely unfunded. We, essentially, funded that internally from other laboratory sources. Once we had the promising data from the mice, we took those data and we applied to the national institutes of health – which is a huge biomedical funding organization in the United States. They fund 90-something percent of all biomedical research that occurs in the United States – that's a lot of research. So, you know, tens of billions of dollars.
What we did was we applied for a pilot grant to study MitoQ in humans – that was the pilot study we were talking about. We received a two-year pilot grant from the National Institutes of Health. Then we conducted that study. Then we obtained promising results from that pilot trial. Then we took those data from the pilot trial, those promising results, and we used them as preliminary data to try to fund a larger trial. We wrote an application, and the data from the pilot study were key promissory notes showing that we do believe the compound works and that it improves these aspects of cardiovascular health. And that was funded. So that’s a five-year, approximately $2-2.5 million dollar grant that is currently supporting what we cause a phase 2 – which is the next step up – investigation, a randomized clinical trial of MitoQ verse placebo control. Instead of people crossing over for those 6-week periods, we’re having people stay on MitoQ for 12 weeks. So, the randomization is that you either go into the MitoQ treatment group or to the placebo control group for three months and you’re measured before and after in terms of cardiovascular health markers. We’re in the second year of that five-year study now.
So, you can see how the research has grown from what we call pre-clinical research in animal models, to a small human investigation and now we’re at that next step. Then the next step might be to try to obtain funding for a multi-center trial. That means that, instead of a single institution/laboratory like mine performing the trial, there will be 2 or more different sites at other universities and they would all be following the same protocol. That is really the ultimate hallmark of randomized clinical trial-based evidence: when you put all of the evidence together from all of the sites, you are now showing a treatment effect. Because it means it could not have been due to some kind of odd effect of having the study done at the single site – if everybody is showing the same thing. So, that’s how we like to see the progression. We’re probably one step from that with our current trial.
I think a lot of people don’t understand that the clinical trials are independently funded and that they have nothing to do with MitoQ, apart from us providing you with the free product. We have no influence on the outcomes.
Some clinical trials, in general, are funded by pharmaceutical companies. These are prescription medications that are often funded by pharmaceutical companies. But in the case of dietary supplements like this, and in the case of our laboratory, we have always obtained National Institutes of Health (NIH) grants to do this work. It’s a quite rigorous process. Folks may not know that, in general, what you do is you write an application and you submit it to this grant-funding organization and then they identify what they call “Pure Reviewers”: scientists like me with expertise in my area and they receive my grant application and 3-4 of those scientists are assigned to review my grant application. In that system, only one out of ten grants get approved. So, it’s highly competitive. It’s a very rigorous review process. The same process goes on in New Zealand, in Australia, in Europe – so this is an international standard for how countries use the tax dollars of their citizens to disperse for biomedical research. They have these expert review teams that rigorously review the applications. And then they score those applications and only the very best applications are funded.
Jumping back to the 2018 trial, I believe that found that MitoQ significantly fights oxidative stress. Could you talk a bit about why that is important for cardiovascular health?
Oxidative stress, if you wanted to try to define it, is an excessive production of what we call reactive oxygen species. Sometimes, in the popular press, they’re called free radicals. These are derivatives of molecular oxygen that happen to be chemically changed in a way that they damage other molecules and they disrupt the healthy function of your cells and your tissues and your organs. We think oxidative stress, and there’s good evidence suggesting this, that the development of oxidative stress with aging is really what’s driving the loss of cardiovascular health with advancing age. It can stimulate inflammation, which is sort of its culprit in crime, and it becomes a vicious cycle. That leads to cardiovascular dysfunction and a loss of cardiovascular health.
So, oxidative stress is a setting in which we’re producing too many of these reactive oxygen species – an excessive number. There’s a proper number, and that actually is important for physiological signaling and health and function. But when you produce an excessive amount compared to your antioxidant defenses (so your body does have defenses to neutralize these reactive oxygen species) but, in some cases – and aging is one of them – the body just produces too much and the antioxidant defenses can’t keep up. So, there becomes an imbalance. So, then the state that is developed is called oxidative stress. Because you have these reactive oxygen species in such abundance that they’re damaging your cells, your tissues and your organs. And that leads to a loss of proper function and a loss of health.
How did MitoQ compare to what you would normally expect to see with diet improvements, exercise improvements, things like that?
Before we started studying any dietary supplements we performed investigations for decades on healthy lifestyle behaviors like aerobic exercise, low sodium diets, dietary restrictions and weight loss. We really had a good reference point with how those healthy lifestyle strategies improved arterial function, including the capacity of the arteries to dilate. So we had a good foundation of points of reference there.
When we performed the pilot investigation with MitoQ – the first study – we found that the improvements in dilater capacity were very much in keeping with what we see with healthy lifestyle behaviors: including aerobic exercise, sodium restriction and going on a diet with accompanying weight loss. So we were really surprised because that was the first time that we had ever studied a dietary supplement that had the same kind of impact that we could invoke with those healthy lifestyle behaviors. So, I think that’s one of the things that stand out with our MitoQ pilot study and what we’re hoping to be able to recapitulate with the current larger clinical trial.
Amazing. Obviously, at MitoQ we advocate for a varied approach to health – our hope is that adding MitoQ just gives you that next level. Obviously, there are people who perhaps can’t exercise as much as they should, so I guess this also helps those people too?
That’s really why we started performing research on dietary supplements. Even though we had shown, at a certain point, that all of these healthy lifestyle behaviors are very powerful strategies to improve cardiovascular health with aging, the unfortunate truth is that, if you look at the number of people that follow guidelines that are promoted by medical organizations or the government on how much to exercise, how to control your diet, how to eat a healthy diet – the number of people that actually follow those guidelines, especially in mid-life and older age, are well under 50%. So when I would present our data on the healthy lifestyle strategy, a lot of physicians would come up to me afterward and say, “that’s great, but my patients won’t do that. What else do you have for me?”. That’s kind of an anecdotal story but it’s the truth. After hearing that for many years after my presentations on exercise and healthy diet practice, I finally decided that there were tens of millions – perhaps hundreds of millions – of people that, for whatever reason, either couldn’t engage in those behaviors or wouldn’t engage in those behaviors. And there are a lot of reasons why people don’t do that – sometimes they simply can’t because they can’t afford healthy food or they don’t have access to healthy food or they have some kind of disability in terms of exercise.
The point is, I felt we needed to create evidence-based alternative approaches. And that is really what led to our research on dietary supplements which now includes over a decade of investigation with MitoQ.
Is this something that only “old people” need to be thinking about? At what sort of age should people be prioritizing these sorts of things?
One of the things I mentioned at the very beginning was our interest in promoting cardiovascular health throughout the lifespan – really, I should narrow that to say throughout the adult lifespan, because you’re sort of protected until you become an adult. We’re not exactly sure why, but that’s the time when your health is very strong and resistant. The process by which the cardiovascular system becomes dysfunctional and loses that healthy profile actually occurs over decades. It probably starts within the 20s or 30s, it could even happen in the late teens. There’s evidence that soldiers that were killed in the Korean war had plaques in many of their arteries – and these were late teens, early twenties. So, there’s good evidence from a cardiovascular standpoint that the threat to maintaining cardiovascular health starts in young adulthood and then, as time goes on (probably because of issues like developing more oxidative stress) it becomes more and more difficult to maintain cardiovascular health. But it does not start at a specific age.
Some people will be protected because of their genetic profile or their lifestyle behaviors or whatever, but that process is occurring in everyone. At some point, even if you live a healthy lifestyle and engage in healthy practices, there is some consequence of the aging process. Your arteries, for example, will begin to stiffen – even in those folks that exercise regularly and eat healthy.
So, I think maintaining cardiovascular health throughout the adult lifespan – that's how folks should consider (if they want to be healthy when they’re in their older age) that needs to start early. You can’t spend the first three or four decades of adulthood engaging in unhealthy behaviors and then say, “I'll get to it." Because some of the damage has already been done and some of it is irreversible.
What are the measures that people should be taking early on (to take care of their cardiovascular health)?
I’ve given a couple of public lectures, one in Australia and one in New Zealand, on this recently. If I could give any health advice based on evidence/what the research literature says:
- Regular aerobic exercise probably would be the first thing that I mention – simply because that has the most evidence that it has promising cardiovascular health benefits.
- Healthy diet: that can be viewed as how much you eat or what you eat, or both. So, making sure that you don’t eat too much and that you have good weight management. We tend to gain a pound or two every year or two throughout the adult lifespan, so making sure you do whatever you can to prevent or minimize that age-related weight gain, I think is also helpful. We also know a lot about what a healthy diet composition is. So, independent of how much you eat, there is, of course, what you eat. We know a lot about that now. We know about the kinds of foods that are healthy, we read about these things. I think, just eating healthy foods, not being too subjective or reactive to fad diets – I think that’s a real problem that has spawned internationally, people grabbing onto fad diets. And exercise is also a very important part of dietary health because they’ve shown that people who exercise have a much easier time managing their weight. If they have to lose weight, it’s a key determinant of whether they keep the weight off vs. regain the weight. So, I think a healthy diet and exercise work hand-in-hand.
- If you’re unable to do those types of healthy lifestyle behaviors, then I think some of the dietary supplements that we’ve been studying, at some point, can certainly be considered. If they talk to their doctor and suggest that they want to maintain their cardiovascular health and have those conversations with them. The work that we’re doing with dietary supplements is meant to provide alternatives to the individuals in the community and to general practice doctors.
We have clinical trials on MitoQ in energy production, recovery from exercise, etc. Our hope is that, for people who are struggling with exercise, that it becomes a tool to help them continue exercising regularly and to maybe get more out of it because they don’t feel as bad afterward.
And there are people who really do not respond well to exercise that find it very unpleasant. We're finding out now that, like with everything else, there’s a biology to that. I think it’s important to consider different demographics and characteristics of people when we try to help them, for example, maintain cardiovascular health throughout the aging process. We need to be mindful of the limitations.
Absolutely. I’m going to put you on the spot now: talk us through your healthy living routine.
Mine is based on what we just talked about. Regular exercise and also eating a healthy diet. I perform a combination of aerobic and resistance exercises throughout the week, and then try to maintain a healthy diet in both the amount of food that I eat and then make sure that I’m eating, primarily, healthy foods. That combination works for me. I think each individual is biologically different. Their lifestyle is different and so are their demands, from a family perspective. But, for me, that’s a combination that really works. That’s my foundation of health, my foundational strategy.