The Supplement That Reversed Aging in Human Trials, with Dr. Anurag Singh

Summary

Podcast Summary: The Supplement That Reversed Aging in Human Trials, with Dr. Anurag Singh

Introduction In this enlightening episode of The Dr. Hyman Show, host Dr. Mark Hyman welcomes leading immunologist and mitochondrial researcher Dr. Anurag Singh. The discussion delves deep into the pivotal role of mitochondria in health and aging, exploring groundbreaking research on a supplement called urolithin A (commercially known as Mitopure) that has shown promise in reversing some aspects of aging in human trials.

Understanding Mitochondria and Their Importance Dr. Hyman initiates the conversation by highlighting the fundamental role of mitochondria—the "powerhouses of the cell"—in producing energy and maintaining overall cellular health. He emphasizes that despite their importance, mitochondria are often overlooked in traditional healthcare.

Dr. Singh elaborates, stating, “Mitochondrial dysfunction and the lack of energy and fatigue as we age, is the root cause of the central hallmark of aging” ([06:25]). He compares mitochondria to a cell phone battery, explaining how their decline affects our energy levels and overall vitality.

The Role of Mitochondria in Aging and Disease Both experts agree that mitochondrial health is intrinsically linked to various age-related diseases, including heart disease, Alzheimer’s, Parkinson’s, diabetes, cancer, and mental health disorders. Dr. Hyman notes, “Most of these conditions at the end of the day come down to problems with mitochondria and inflammation, which are linked” ([09:35]).

Dr. Singh discusses how mitochondrial dysfunction not only leads to reduced energy production but also contributes to increased inflammation, creating a vicious cycle that exacerbates aging and disease ([16:35]).

Urolithin A (Mitopure) as a Mitochondrial Supplement A significant portion of the episode focuses on urolithin A, a compound derived from gut microbiome metabolism of polyphenols found in foods like pomegranates. Dr. Singh shares the discovery journey of urolithin A, explaining its limited natural production in the population due to factors like antibiotic use affecting gut bacteria.

He states, “Urolithin A is actually a very potent gut metabolite produced by the gut microbiome that has these immense rejuvenation effects in mitochondria” ([46:26]). Dr. Hyman is particularly fascinated by the supplement’s ability to mimic the effects of exercise, noting that Dr. Singh and his team observed a “10-12% improvement in strength and a 10% improvement in VO2 levels” in clinical trials ([47:55]).

Clinical Studies and Benefits Dr. Singh presents compelling evidence from randomized, placebo-controlled trials demonstrating that urolithin A supplementation leads to significant improvements in mitochondrial health, muscle strength, cardiovascular fitness, and reduced inflammation. Notably, he mentions that after two months of supplementation, participants began to show physiological improvements, culminating in marked strength gains after four months ([49:38]).

Dr. Hyman shares his personal experience, stating, “I take a thousand milligrams a day of Mitopure Urolithin A. I've noticed it definitely does help my energy, it helps my exercise” ([49:55]).

Impact on Immune Health A groundbreaking revelation in the discussion is the link between mitochondrial health and immune function. Dr. Singh explains that urolithin A not only rejuvenates mitochondria but also enhances immune cell function. He reports that supplementation led to the return of declining immune cell populations, making them more effective at combating infections ([53:10]).

Potential Future Applications Looking ahead, Dr. Singh is optimistic about the broader applications of urolithin A, including potential benefits for brain health, neurodegenerative diseases, and recovery from illnesses like cancer. He envisions a future where mitochondrial rejuvenation could play a central role in enhancing immune and cognitive functions ([56:54]).

Lifestyle and Supplementation Recommendations Both experts emphasize the importance of a holistic approach to mitochondrial health alongside supplementation. Dr. Singh outlines five key strategies for maintaining healthy mitochondria:

1. Eat Well: Focus on whole foods rich in fiber, antioxidants, and good fats while reducing sugar and processed foods.
2. Keep Moving: Engage in regular physical activity to stimulate mitochondrial biogenesis.
3. Prioritize Sleep: Ensure adequate and quality sleep to support cellular repair and energy production.
4. Nutritional Supplementation: Incorporate supplements like urolithin A, CoQ10, creatine, and B vitamins to support mitochondrial function.
5. Reduce Toxin Exposure: Minimize exposure to environmental toxins, antibiotics misuse, and certain medications that harm mitochondria.

Dr. Hyman adds, “Supplements like urolithin A should be part of an ensemble of strategies, not used in isolation” ([75:00]).

Conclusion The episode concludes with Dr. Singh highlighting the transformative potential of mitochondrial-focused therapies in extending healthspan and combating age-related decline. He underscores that longevity is a marathon, advocating for early and sustained efforts to maintain mitochondrial health through diet, exercise, and targeted supplementation.

Dr. Hyman echoes this sentiment, encouraging listeners to integrate these insights into their daily lives to optimize their health and longevity.

Notable Quotes:

• Dr. Anurag Singh: “Mitochondrial dysfunction and the lack of energy and fatigue as we age, is the root cause of the central hallmark of aging.” ([06:25])
• Dr. Mark Hyman: “Most of these conditions at the end of the day come down to problems with mitochondria and inflammation, which are linked.” ([09:35])
• Dr. Anurag Singh: “Urolithin A is actually a very potent gut metabolite produced by the gut microbiome that has these immense rejuvenation effects in mitochondria.” ([46:26])
• Dr. Mark Hyman: “I take a thousand milligrams a day of Mitopure Urolithin A. I've noticed it definitely does help my energy, it helps my exercise.” ([49:55])

Final Thoughts This episode of The Dr. Hyman Show provides a comprehensive exploration of mitochondrial health and its profound impact on aging and various diseases. Dr. Anurag Singh’s research on urolithin A offers promising avenues for enhancing longevity and improving overall health, making it a valuable listen for anyone interested in optimizing their well-being.

Transcript

[Dr. Mark Hyman]

You're saying that you could take this compound made by bacteria as a supplement. You're going to see about a 10% improvement in strength and cardiovascular fitness and a reduction in inflammation.

[Dr. Anurag Singh]

Mostly the trials we have run in placebo controlled randomized trials, we see in the absence of exercise, in the absence of changing their diets, you get about a 10 12% improvement in strength. You get about a 10% improvement in VO2 levels.

[Unknown Speaker]

Leading immunologist Dr. Anurag Singh explores how.

[Dr. Anurag Singh]

Mitochondria and inflammation shape our health, aging and energy. Exercise the best mitochondrial drug. So just getting people moving in their 70s and 80s three times a week for 30 minutes, that's the basic, you know, having a rejuvenation effect on the mitochondria.

[Dr. Mark Hyman]

You got three ways to sort of soup up your mitochondria and make more energy. One is exercise. Two is.

[Unknown Speaker]

In functional medicine, we always.

[Dr. Mark Hyman]

Start with the gut.

[Unknown Speaker]

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[Dr. Mark Hyman]

Heinrag welcome to the Dr. Hyman Show. It's great to have you. So we're gonna talk about one of the most important things that almost nobody really understands today in terms of your health. Longevity, wellbeing, energy, brain function, immune health, and pretty much everything. It comes down to something that actually is a topic that I love, which is how our bodies make energy, the problems that happen with energy, and the little tiny organelles like mini organ systems in our cells that make energy called mitochondria. Now people hear that word, they probably think of high school biology. They're like, what is he talking about? Maybe they remember something called the Krebs cycle or the citric acid cycle, which is basically how your body turns food and oxygen into energy in these little tiny factories, energy powerhouses in your cell. And we kind of learned about it in medical school and then we promptly forgot about them because unless you were some specialist dealing with some rare inherited genetic mitochondrial disease, you never thought about it, you never treated it, you never diagnosed it, and you never paid much attention. And yet it seems that mitochondria, as it turns out, are probably one of the most important things you do need to pay attention to if you want to live a healthy and long life. We're going to kind of dive deep into the mitochondria today. What it means, what it is, what we can do to optimize it, what new innovations are in the marketplace that help us to actually work with our mitochondria better and soup them up a little bit and clean them up, which is important. And how they play a role in so many diseases, including aging. So kind of, let's start with the work that you're doing around mitochondrial research and why it's so central to aging and why, why don't we talk about it more?

[Dr. Anurag Singh]

Well, I'm also a trained physician and so for many years, MD, PhD.

[Dr. Mark Hyman]

So you're like a double doctor.

[Dr. Anurag Singh]

So. Well, as you said, medical schools briefly educate the students, the future doctors, about, you know, this is the, you know, in the biochemistry class and they learn about mitochondria. But I actually think the, you know, and we talk about these biological hallmarks of aging, these 12 biological hallmarks of aging a lot. I actually think mitochondrial dysfunction and the lack of energy and fatigue as sort of we age, is the root cause of the central hallmark of aging. And the studies I have done, whether it's with old people looking at their muscles or their brains, every time you look at a 70 year old who's exercising versus a 70 year old who's sedentary, frail, the answer is always mitochondria.

[Dr. Mark Hyman]

That's right. Or even you look at like a, you know, why is a 2 year old running around bouncing off the walls and a 92 year old just sitting motionless in a chair? The answer, in a sense, is mitochondria. The number, function and activity of the mitochondria.

[Dr. Anurag Singh]

And so these are, as you said, these are powerhouses of the cell and they are really the energy provider. These are the batteries, Right? So think of your cell phone battery, right? When it's all green, you can make a number of calls. You feel confident about your phone on a Daily level. But the moment it gets red, that's when you worry. That's exactly what aging and mitochondria is happening. The green is becoming red.

[Dr. Mark Hyman]

So your body battery kind of fatigues.

[Dr. Anurag Singh]

Out and you have to recharge it.

[Dr. Mark Hyman]

And doctors for sure don't really know how to diagnose problems with the mitochondria or even symptoms that relate to mitochondria. But one of the most common presenting symptoms, the doctor, is fatigue. So just to summarize, you got three ways to sort of soup up your mitochondria and make more energy. One is exercise. Two is. Is inducing mitophagy.

[Dr. Anurag Singh]

Yeah. And three would be, I think, other supplementation strategies.

[Dr. Mark Hyman]

Supplementation strategies like creatine, carnitine, CoQ10. So can you talk about the kind of symptoms that people might have if their mitochondria aren't up to snuff, Fatigue.

[Dr. Anurag Singh]

And lack of energy, as they say, you go through the emotions of the day, and at the end of the day, you feel like there's not much fuel left in the tank. That feeling, that's mitochondria, the energy deficit you have created during the day. The second is if you were to. If you're one of those who exercises a lot, as you age, you start realizing that it takes longer to recover from an exercise. That's because your mitochondria are not in that perfect sort of balance between the bad and the good mitochondria. And now you have accumulated the bad mitochondria, and so you're taking longer to recover from exercise. The other things are, if, you know, at the whole body level, just brain fog, you know, for example, the muscle and the neuron cells have the highest density of mitochondria. Thousands and thousands of mitochondria in a single neuron or single muscle cell.

[Dr. Mark Hyman]

I think there's like, what is it, 17,000 of these in every brain cell.

[Dr. Anurag Singh]

In every. And close to 10,15,000 in a skeletal muscle cell. So imagine that much energy that just goes away. And so that contributes, I actually think, brain muscle. And more data. Now we are seeing in immune. These are the three key elements that will dictate our health span and how the mitochondria are functioning in all these three.

[Dr. Mark Hyman]

In terms of what you described as the hallmarks of aging, the things that go wrong as we get older, that can explain most of the diseases of aging. So we tend to think about things downstream. Okay, you've got heart disease, you've got Alzheimer's, you've got Parkinson's, you got cancer, you got diabetes, you've got all these horrible things that happen as we get older, but we don't think upstream. What do these things have in common? There may be just different manifestations of the same problem depending on the person. And it turns out that most of these conditions at the end of the day come down to problems with mitochondria and inflammation, which are linked. We're going to talk about how they're linked.

[Dr. Anurag Singh]

Sure.

[Dr. Mark Hyman]

You know, when you really look at all the hallmarks of aging, there's sort of meta ones and there's secondary ones. That's how I think of them. I don't really see them described that way, but everybody's trying to like see them all as separate or different. There's stem cell exhaustion and telomere shortening and epigenetic changes and there's microbiome changes and there's mitochondrial changes and protein changes and inflammation. And this is a whole list of these that I've written about in my book Young Forever. And it's, it's really useful to understand them. But one of the meta frameworks that can explain even mitochondria inflammation is nutrition. They call these deregulated nutrient sensing, which is a fancy bunch of jargon for meaning that your body and your food aren't working well together and that the food you're eating is messing up your body, particularly causing inflammation and causing mitochondrial dysfunction. So when you look at diseases like Alzheimer's or diabetes or even cancer, these are fundamentally ultimately mitochondrial problems. And the treatments can be mitochondrial treatments. But again, as I said, we don't learn as doctors how to treat our mitochondria or even to diagnose them. What is the way that people can think about even diagnosing mitochondrial problems other than your history and your medical symptoms or your diseases.

[Dr. Anurag Singh]

So mitochondrial functional testing is still in its early days. We are still learning how to high throughput it. If you were to go and get your lab work done, you'll do standard lipid profile, kidney profile, cardiac profile. Mitochondria is today not part of it. Inflammation is. So you do look at C reactive proteins, some inflammatory cytokines. So there are new tests coming out. There are folks working on buccal swabs, for example, looking at the mitochondrial DNA content in your buccal cells. There's a group called, I believe MI screen that is using blood cells to look at how the mitochondria behaving in the blood cells to give you sort of an idea of how your mitochondria at A whole body level are the way I do it in randomized placebo controlled trials is a few ways. So I would put, for example, older adults in an MRI scanner kind of set up and they'll exercise there. And I can actually, using something called resonance spectroscopy, I can actually go into the muscle and look at the depletion of ATP, which is this molecule of energy, and how fast after they stop exercising, it comes back into this, into the muscle, is an indicator for me how good the mitochondria are. Because if your mitochondria are not good, it just takes longer. And that's how in a lot of clinical studies today, let's say investigators or translational investigators, are studying mitochondrial health. This, you know, looking at the ATP.

[Dr. Mark Hyman]

Recovery rate and ATP is the energy.

[Dr. Anurag Singh]

It's basically, it's the molecule of energy. Yeah. Now, the other way is you take chunks of tissue. So that's what I do. I go in and take a muscle biopsy. That's fun, which is not fun, which is not easy to convince people. But believe it or not, in clinical trials, older adults who have problems with fatigue, they're very motivated and they volunteer. And what you see blows your mind away because you look at the 30,000 genes in the skeletal muscle and you ask in an unbiased way, what are the top 30 pathways that are downregulated? They are all mitochondrial linked. And that just not us. Who has shown that. It's multiple groups that have shown that. As we were pointing out. I mean, these hallmarks of aging are like a subway system and they all intersect in the middle with mitochondria and inflammation.

[Dr. Mark Hyman]

Yeah, I think it's so important because, you know, as a doctor, I've been, look, trying to look at mitochondria for many years in functional medicine and, you know, we'll do, for example, VO2 max testing. You can do that maximal exercise testing where they measure oxygen consumption and carbonized carbon dioxide production as an indirect way of looking at your mitochondrial function. What we do know is that VO2 max, which is basically how much oxygen you consume per minute per body per kg of body weight, is one of the best predictors of longevity.

[Dr. Anurag Singh]

Sure.

[Unknown Speaker]

It's in a linear way.

[Dr. Mark Hyman]

The higher the number, I mean, the more fit you are, the more your mitochondria can, you know, consume oxygen and produce energy, the longer you're going to live. That's pretty cool. And yet, you know, that's a little bit of a more difficult test to get.

[Unknown Speaker]

But you can get it at gyms.

[Dr. Anurag Singh]

Yeah, we do that as well.

[Dr. Mark Hyman]

And I think that's helpful. Also we used to look at organic acid testing, which looks at sort of mitochondrial function by looking at a urine test. There's also labs in Germany that do extensive mitochondrial testing, looking at the mitochondria inside the white blood cells in your blood and looking at how they're functioning. And you can see that it's a lot of mitochondrial diseases. I mean, we didn't talk about it, we talked about some of the diseases of aging. But mental health is now an area of deep research around mitochondria and cognitive function. Not just things like dementia, but autism, you know, is found to have been really in part driven by mitochondrial dysfunction in these kids. They have a brain energy deficit. And Suzanne Go showed this, who's a Harvard, Oxford trained pediatric neurologist. She's been on the podcast and you know, Chris Palmer, Ian Campbell, you know, been on the podcast talk about metabolic psychiatry, where depression, bipolar, schizophrenia, these are mitochondrial diseases. And by treating the mitochondria with diet and other approaches, they can actually improve their function and help mitigate or relieve or put these diseases in remission, which is pretty remarkable.

[Dr. Anurag Singh]

It is.

[Dr. Mark Hyman]

The mitochondrial medicine is just is this area that's sort of so promising and yet so neglected in traditional healthcare. And that's what's so great about the work that you've done and that you're doing around the research. And you know, one of the things I think you sort of mentioned that in passing, I think it's important to double click on is sort of new discoveries around the immune system's function and mitochondrial function. And how have you been surprised by some of the things you found around this? Because when you look at aging, these are two things that really happen. We lose energy and we become more inflamed.

[Dr. Anurag Singh]

We started off thinking these were two different pathways because every randomized study we were doing. Now, as you mentioned, diet and exercise are the two biggest mitochondrial rejuvenation drugs, if I can call them, that exist.

[Dr. Mark Hyman]

My favorite drugs, diet and exercise.

[Dr. Anurag Singh]

The problem is it's very hard as a doctor to convince everybody to stick to it. And you see very poor compliance in the long term. And so you have to improve your cellular health and your mitochondrial health with other strategies, nutrition being one of them. So we started looking at it and what we saw is that every time we improved mitochondrial health, the inflammation levels were lower in these folks. Now, whether they were 80 year olds, whether they were overweight, obese individuals, or even athletes, believe it or not, even athletes where you think they would have the peak of mitochondrial and even overtraining is having an impact. And they are all inflamed. And so by just tuning the knob of inflammation or vice versa, improving mitochondrial health, we are still studying which are they closely interlinked or are they, you know, one precedes the other. But there is clearly a very close interaction between these two pathways.

[Unknown Speaker]

Yeah.

[Dr. Mark Hyman]

And you know, one of the, one of the fundamental hallmarks of aging is this phenomenon of cellular senescen, otherwise known as zombie cells. These are cells that should have died and been recycled, that seem to live forever and turn into zombies and then go around creating more zombie cells. And what these cells do is they spew out buckets of inflammatory molecules around the body. They're like basically pouring gasoline everywhere. And that's a disaster because it's sort of a feed forward cycle. And somehow what you're saying is that mitochondria play a role in this, either in, as a, as a cause or a consequence. And so, you know, in medicine we like to be very reductionist. But the truth is that anything that causes inflammation will cause mitochondrial dysfunction. And mitochondrial dysfunction itself, if I'm hearing you correctly, also drives inflammation.

[Dr. Anurag Singh]

Yes. Really, These damaged mitochondria that become leaky and the damaged mitochondrial DNA. I mean mitochondria have their own DNA that leaks out into the circulation and causes, you know, inflammation and vice versa. Inflammation can also be seen as a stressor for mitochondria that damages these mitochondria. So I think it's like a circuit loop between these two pathways.

[Dr. Mark Hyman]

Let's back up at a meta level and look at, you know, if these mitochondria are so important to our overall well being, to our energy, to our brain function, to our mood, to our metabolic health, to, you know, pretty much everything you can think of. And yet they're so fragile. Right. What are the things that drive mitochondrial dysfunction? Like what causes mitochondrial aging and breakdown and damage?

[Dr. Anurag Singh]

So there's this sort of, this may be a bit nerdy, but this is what is called as the oxidative stress pathway. So as in the life cycle of a mitochondria, you have the yin and the yang always. You have the healthy mitochondria. They're young, new, producing a lot of energy, poor diet. You know, if you're eating a lot of processed food, et cetera, or your sedentary habit, they accumulate what we call as ross or reactive oxygen species and they start becoming bit, as you were saying, zombie mitochondria. And over time the body has an evolutionary pathway called mitophagy that should clean these damaged mitochondria out in the favor of more near healthy mitochondria. But with aging, this balance shifts to having more damaged mitochondria. And, and they occupy the real estate in the cell. And what happens is now suddenly you have all these dysfunctional mitochondria, but they're not producing energy. And that's why the whole sequelae for energy, low fatigue, et cetera sets in.

[Dr. Mark Hyman]

So basically the problem is that as we age we accumulate more damaged mitochondria. And people have heard of time restricted eating or intermittent fasting, or maybe we've heard me talk about mtor, things like rapamycin and other compounds for longevity. What they do is they, they inhibit mtor, which is a longevity pathway. And that, what that does is that induces what we call autophagy, which means cellular cleanup. So it's like recycling of your, of your damaged cells. But what you're also saying here is there's a, also a mitochondrial recovery process where we're supposed to be chewing up and eating up in like Pac man recycling are old and damaged mitochondria. But often that doesn't really work that way. And we accumulate more damaged mitochondria and that in of itself causes us to be more tired, fatigued and have mitochondrial symptoms. And also accelerates in a feed forward cycle more mitochondrial damage.

[Unknown Speaker]

Right.

[Dr. Anurag Singh]

Inflammation and the other senescence is all interlinked.

[Dr. Mark Hyman]

But there's other causes for mitochondrial dysfunction besides just lack of recycling of the old mitochondria. So what other.

[Dr. Anurag Singh]

Yeah, so there are three ways today you can improve mitochondrial health. And this is really one is you can improve what we call biogenesis. So you can kind of see neuro, healthy mitochondria. And so there are strategies, exercise being a very powerful. This is the whole PGC1 Alpha pathway where you stimulate this mitochondrial biogenesis. You can improve the growth of your mitochondria. Then there is sort of the fission and fission.

[Dr. Mark Hyman]

In English that means that if you exercise, you stimulate a pathway that makes new mitochondria, that helps you create new.

[Dr. Anurag Singh]

Mitochondria and more energy. So that's kind of where the field is split into three ways. One where you have these NAD boosters, compounds like respiratory, at least from a nutrition perspective, or metformin, they're all hitting this sort of AMPK mitochondrial biogenesis pathway. Then you have this mitochondrial efficiency. So you take the pool of your mitochondria that are already functioning well and you get them to produce more Energy. So there's this idea that you can supplement with creatine or nutrients like L Carnitine CoQ10 that are integrated into the different mitochondrial cycle. There are five units of mitochondria and they all come together and so you can make them more efficient. And then there's the mitophagy part. Now there are many ways you can combine these together as well.

[Dr. Mark Hyman]

Before we get too much more into how to fix your mitochondria, I want to sort of just kind of double down on what are the other things like our diet, Toxins, stress, sleep issues, what are the ways that our mitochondria become more damaged in our current environment and lifestyle?

[Dr. Anurag Singh]

Yeah, I think you highlighted diet is the number one and lack of physical activity.

[Dr. Mark Hyman]

So when you say diet, what do you mean?

[Dr. Anurag Singh]

Diet means not eating a good fresh from the farm kind of, you know, rich in fiber. Fiber nourishes our microbiome. And that's how we, you know, a lot of the mitochondria are ancient bacteria that had this great relationship with the host, which is us. So the way they process the nutrients, you know, when they get stress and damage that impacts. That's how diet is playing now, physical diet.

[Dr. Mark Hyman]

I would just say it's the sugar and starch, excess calories that overwhelm the mitochondria. And also the oxidized foods we eat, like the processed oils and processed foods. You know, people talk a lot about seed oils in and of themselves. They may not be the issue. It's. It's how oxidized they are. In other words, they go rancid. Are you eating rancid oils and that? A lot of the ones we eat are, and that causes more inflammation and damage to the mitochondria. So the fats you eat play a big role in which your mitochondria are made of and how resilient they are. If you're eating, you know, crappy fats versus good fats like omega threes or even some saturated fats. So eating a highly processed high sugar and starch diet and a lot of extra calories that will overload your mitochondria.

[Dr. Anurag Singh]

Of course, yeah. I mean, we see that in the whole diabetic pandemic, sugar is the biggest stressor.

[Dr. Mark Hyman]

It's important you mention that because when you look at mitochondrial function in diabetics, it's like half of the normal population, half.

[Dr. Anurag Singh]

And today the technologies are advancing, so we do something called metabolomics. And we can actually find these mitochondrial metabolites in, in circulation things like fatty acid oxidation derivatives that show up in our bloodstream. So we can use. And we see that the impact of diet, the other one where we see is physical activity big time. The impact of inactivity on mitochondrial health is not talked about a lot, but I think it's immense. In addition to diet, I think that's the number two thing that contributes to how good or bad your mitochondria are.

[Dr. Mark Hyman]

And that's why exercise is such a longevity drug. You know, it's not just great for your cardiovascular health and metabolism, but it actually is, is incredibly important for keeping your mitochondria functional and healthy and operating at the right level.

[Dr. Anurag Singh]

Yeah, and you mentioned sleep. I think sleep is, is a very under studied area of mitochondria in the mitochondrial space that how your Sarcadin rhythm, how your sleep patterns affect mitochondrial health and, and how some of these pathways point to, you know, people. So we are actually now thinking of studying a group of individuals who have sleep disorders. And the professor who came to us actually found that these folks actually all 20 years after sleep issues, they turn into neurodegenerative disorders. So they either get Alzheimer's or Parkinson and the fundamental root causes mitochondrial imbalance in their brain that triggers these sleep imbalances. So I think that's another key area.

[Dr. Mark Hyman]

So what you're saying is mitochondrial dysfunction can cause sleep issues or vice versa.

[Dr. Anurag Singh]

Or both or both. I think it's, it's kind of interlinked. I think lack of or poor sleep contributes to worsening mitochondrial health and that's kind of triggers this whole journey and acceleration to neurodegeneration down the road 20 years after, you know. So yeah, I think sleep is a key area. What else? I think toxins. Toxins, of course a lot of damage from the, you know, we have all these fluoride discussions today and all that. We see that actually if you put some sodium fluoride in the, on muscle cells or any kind of cells, the mitochondria get stress. So there's all these things in the.

[Dr. Mark Hyman]

Yeah, pesticides, heavy metals. These mitochondria are very sensitive. They're very delicate and they're very sensitive. And they get screwed up pretty easily by any kind of insult, including the load of environmental toxins we're all exposed to, whether it's the, the pfas for every chemicals, whether it's, you know, heavy metals, whether it's, you know, synthetic toxins, flame retardants, pesticides, herbicides, these are things that are ubiquitous. We're all exposed to and they are hard to get rid of, but you can reduce your exposures. And then there's the microbiome, which is something that people haven't really talked about much. But when I did some homework and looked at the literature on this, because I would see this clinically, that people had microbiome issues, it did affect their mitochondria.

[Dr. Anurag Singh]

Well, that's how we got into the space of discovering compounds that were made by the gut microso. You're right, and I started to talk about it. So most mitochondria are ancient bacteria that kind of integrated with the host. Right. So they have this what I call. And I started studying what I call the 3M axis, which is muscle mitochondria and the microbiome. So I actually see the microbiome as a polypharmacy. Okay. So a lot of, let's say, focus has been on prebiotics and probiotics and how you should modulate to have a healthy gut microbiome. I actually think it's what the gut microbiome is producing has immense effects on mitochondrial health and beyond.

[Unknown Speaker]

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[Dr. Mark Hyman]

Yeah, it was interesting to say that. I mean, I want to double click on that too, because I was on a panel once at Cleveland Clinic with Stanhazen, who's a premium cardiologist there who's studying the microbiome and cardiovascular health. And it's connected to cancer, to diabetes, to Alzheimer's, you name it, right?

[Dr. Anurag Singh]

Yeah.

[Dr. Mark Hyman]

And maybe part of its way it's affecting it is through the mitochondria, who knows? But Stanhazen said that a third to half of all the metabolites in your blood come from your microbiome and you're probably wondering, what is he talking about? What are you talking about, Dr. Hyman? Basically, when you have bacteria in your gut, they have DNA and the DNA's job is to make proteins and you have Probably a hundred times as much bacterial DNA as your own DNA, because you've got a thousand species, they're all different, they'll have different DNA. We might have 20,000 genes. There might be 2 million bacterial genes. And each one of those genes is making proteins. What happens to those proteins? Well, there's something that's active in your gut, but they also get absorbed by your body. They get absorbed and they're in your blood. And then what are they doing there? Well, they're influencing everything. We're going to talk about what some of these things are. They're called postbiotics. Postbiotics are essentially different than pre or probiotics. They're things that are made by bacteria that then are used by the body for different functions. So we're going to get into why we're here to talk about this, because I think the question is if our mitochondria are so important, if they're so damaged by our current lifestyle of poor diet, lack of exercise, stress, sleep, lack of good sleep, environmental toxins, an overload of calories and sugar, changes in our microbiome that actually are not good, you know, what can we do about it? And we hinted at a little bit about exercise, diet, supplements. And people should understand that the supplements around mitochondria are pretty well studied. And there's basically this chain called the respiratory chain. Basically, when you pour in food and oxygen to ones, let's just say one side of the factory assembly line, out the other side comes energy. And that to get through, to get to energy, there's a lot of steps. And all those steps require enzymes, and all those enzymes require helpers. And all the helpers are vitamins and minerals or other compounds that are used by the body, like creatine or carnitine and so forth. There's ways of actually supplementing to optimize mitochondrial function and health. I use this in autism, I use this in cardiomyopathy patients with heart failure, very effectively metabolic cardiology. Now we have metabolic psychiatry. So in a way, when we say metabolic, what we're talking about actually is mitochondria, because that's where a lot of the metabolic function happens.

[Dr. Anurag Singh]

Yeah, 200%. I think today we are in the midst of a metabolic crisis, and I think the answer to a lot of that reversal and prevention lies in mitochondrial health and reversing the mitochondrial health of the population. Right. And so whether it's neurodegeneration or whether it's, as you said, cardiovascular incidents, I actually think, you know, and I started studying A lot of sarcopenia and frailty, older adults who can move well. And the fundamental thing that I always found was the poor mitochondrial health was uniform in somebody who can get up properly from a chair, somebody who's super inflamed when they're in their 80s and 90s. And I think that sets in very early on. I believe that sets in even when these folks were 40 and 50. So that's the cumulative of the ignoring the diet and the physical activity and the stress and this poor sleep or toxins. It's really, you know, 30, 40, or throughout our adult years, what we are seeing. So I actually think health span or mitochondrial health is something people need to think as a marathon, a longevity marathon that they think in their 30s and 40s, you know, what can I do already? So. And I'm in my 70s and 80s, you know, I can. My mitochondria are enabling me to get up from a chair and cross the zebra line in 15 seconds, you know.

[Dr. Mark Hyman]

Yeah.

[Dr. Anurag Singh]

So that's where I come from. That's how I started into mitochondrial.

[Dr. Mark Hyman]

Yeah, I mean, I think it's so important. People have to kind of really get that, you know, if you want to really be upstream of all these diseases, you have to start thinking about mitochondrial health and what causes mitochondrial harm and how to optimize mitochondrial function. And so, you know, what is sort of a big myth or misconception? You hear about things like energy fatigue.

[Dr. Anurag Singh]

Yeah. I think a lot of misconception I hear is that this is pretty much set in stone. It's irreversible. Oh, I hear now a lot of people who got post Covid fatigue who have this sort of what we are still struggling to define as. What is that long Covid syndrome, they all are super fatigued and they think it's set in stone and they're struggling to find something. And I think there's a lack of research now, but I think all roads need to look into this whole sequel of poor mitochondrial health, because I think that's also a key element there. So I think general education about mitochondria, as you said. I mean, everybody just has this high school textbook knowledge.

[Dr. Mark Hyman]

I think what you said is important, and we didn't talk about it earlier when we talked about the cause of mitochondrial dysfunction. But infections.

[Dr. Anurag Singh]

Yeah.

[Dr. Mark Hyman]

I mean, when you have a virus and you have the flu and you feel exhausted and tired and achy, why is that? Because it's basically poisoning your mitochondria. And so that passes usually and you recover. But. But it's it's an interesting phenomena. So we sort of get a short term acute mitochondrial dysfunction. Let's talk about solutions because, you know, we now have understood that these are critically important health and aging, that there's a lot of things that damage them. And we've sort of hinted at some things, you know, like diet and exercise and supplementation that can help. Let's first talk about, like what, what are the natural ways that you can actually trigger mitochondrial renewal? The making of new mitochondria. Mentioned biogenesis, which means just making new life new mitochondria, and also mitophagy, which is cellular cleanup. So what are the, what are the natural triggers for these things?

[Dr. Anurag Singh]

I think there are enough studies on exercise interventions. That's the one I'm most familiar with. You know, any kind of exercise just moving 8,000, 10,000 steps a day, just doing a resistance or endurance or a mix of both, training has profound. These, as we talked about, these are mitochondrial drug exercise, the best mitochondrial drug. So just getting people moving in their 70s and 80s, three times a week for 30 minutes, that's the basic of having a rejuvenation effect on the mitochondria. The fact that we are unable to get people at that age to do that is, is a problem. I see. You know, and that's why. And then diet, I mean, before you.

[Dr. Mark Hyman]

Jump there, in terms of exercise, what are the differential effect of strength training or resistance training and cardiovascular training like walking or biking or running or whatever?

[Dr. Anurag Singh]

They all have been studied and they all have different impacts on, on mitochondrial improvements. Resistant training, less so as something like high intensity training or aerobic training in terms of the impact on mitochondrial health. But any kind of movement, I believe is good for mitochondria. So we just need to get people moving, whether it's walking or just spinning in the yoga class for 30 minutes. I think that's very essential.

[Dr. Mark Hyman]

Yeah, I mean, the way I think about it is that Cardiovascular fitness, particularly VO2 max training, helps increase the efficiency and function of your mitochondria and may help you recruit new mitochondria. But also strength training increases the number, the mass, right? You get more muscle mass, you get more mitochondria. So building muscle is really important.

[Dr. Anurag Singh]

Muscle quality. I think this is another, you know, if you look at the entire sarcopenia field, whether it's.

[Unknown Speaker]

And what's sarcopenia.

[Dr. Anurag Singh]

So sarcopenia is this age related muscle disorder. And so when we are in our 30s, we peak in our muscle performance around a third decade of life. And following that, every 10 years, we are losing 10% of muscle strength and muscle mass. Okay. And that accelerates even bigger 10 than 10% in our 60s. So by the time we are hitting our 60s and 70s, we have lost enough muscle mass and strength that a lot of individuals are classified if they can't get up from a chair or walk a certain distance in six minutes, and they're classified as sarcopenia. So it's really loss of muscle and strength and the quality of the muscle, those aren't inevitable.

[Dr. Mark Hyman]

I mean, I just had a major health crisis where I had a back surgery from a back infection. I lost 20 pounds, 15 pounds actually. And in the last four months, I've gained back 20 pounds of muscle even at 65 years old. And I actually am more ripped now than I was at 40 because I didn't really do any strength training. And I think it's interesting to see how even as we get older, no matter how old we are, the body will respond to.

[Dr. Anurag Singh]

The muscle is a sponge, you know, it just needs a little stimulus to get it going.

[Dr. Mark Hyman]

Then you're talking, when you're talking about.

[Dr. Anurag Singh]

Diet, well, of course there's a lot of nutrients, right. So all the high protein. We talked about high protein supplementation. As you age, there is this concept of anabolic resistance that after 60s, 70s, if, if you keep doubling your protein. And what people forget is that mitochondria is where a lot of protein synthesis is actually happening. So we are just doing a trial actually in Canada, where we are combining high protein supplementation with a mitochondrial intervention to see if we can rev up just, just that, you know, the muscle quality through that. So I think diet itself, and you talked about less sugar eating, calorie restriction, as intermittent fasting has these immense mitochondrial effects. So eating 15% less, as we have seen in multiple randomized trials, that has a big impact on boosting mitochondrial health.

[Dr. Mark Hyman]

When you say protein, how much are we talking about here? Because the, you know, the RDA is 0.8 grams per kilo, which is the minimum you need to prevent a deficiency of protein, but not maximum amount you need for optimal health.

[Dr. Anurag Singh]

Yeah, I think with aging it's should be up so about a 1 1.2 even per grams of per kilogram. So the whole. Most older adults are eating 40 grams less. So that's why, you know, there's the idea, oh, you give them protein shakes with 10, 20 grams twice a day, so you're countering that deficiency. But they don't digest all these. It's not that you can give them a bolus of protein, and they'll digest it because their body and their cells won't metabolize it. But I do, and I look at my parents who are in their 80s, they have. They don't get enough protein from the diet. So that's a big problem today for most of us.

[Dr. Mark Hyman]

So as you're older, you need more. And, and I think there's been work by the Protege group, Don Layman, we've had on the podcast talking about how as you get older, you might need them. Even a gram per pound of ideal body weight.

[Dr. Anurag Singh]

Yep.

[Dr. Mark Hyman]

So if you're 70 kilos, you know, let's say 100, you know, 50 pounds, you need up to 130 to 150 pounds of grams of protein per day, which is more than most people eat, especially as you get older. It's really important. So I think it's important that protein and protein quality, it matters too, because if it's plant proteins 1, it's hard to get that much because you're also carrying with a lot of starch, rice or beans. But if you, but if you use animal protein, you're going to get much more concentrated protein at a lower calorie count and also with higher levels of leucine, which is the amino acid you need to actually make muscle.

[Dr. Anurag Singh]

And then there are nutrients like, you know, the good fats like mcts. I mean, just having your body in sort of a ketosis state, having more ketones. Ketones. Perspalr has done a lot of work in there and a lot of other groups. Eric Verde, I collaborate is looking at them and just getting your body to more. Using fat as a source instead of a carbohydrate. You know, glucose has this profound effects in getting mitochondria revved up. They like processing towards their preference for fuel utilization is more fat than glucose.

[Dr. Mark Hyman]

Yeah. So the mitochondria love to eat fat. And that's why you see, for example, certain diseases, like whether it's autism or Alzheimer's or schizophrenia or bipolar disease or depression, diabetes. These are all mitochondrial problems. And they all respond extremely well to ketogenic diets. They respond better than any other current therapy.

[Dr. Anurag Singh]

Yeah, absolutely.

[Dr. Mark Hyman]

And I've seen kids with autism just sort of wake up up getting on a keto diet or people with Alzheimer's or obviously with diabetics. We see with the data really strong on that reversing type 2 diabetes. So having you mentioned MCT oil, that's a particular kind of fat that's absorbed differently than other fats it is a great fuel source for mitochondria. I'll use it, actually, before I work out or exercise, go for a long bike ride or something. I'll often have some of that beforehand, and it'll really keep my endurance up and keep my metabolic function high.

[Dr. Anurag Singh]

And the last class of nutrients that I have, I'm very familiar with is these sort of antioxidants, polyphenol. So all the berries, the pomegranates, the nuts, kind of, you know, kind of the Mediterranean diet. And. And that if you look at. And again, studies have been done with folks who have been on Mediterranean diet versus other diets and showing how big an impact that has on medical, mitochondrial health. So that's how, you know, I think that's where people need to think about from a diet, what to integrate into.

[Dr. Mark Hyman]

So, yeah, so from the diet perspective, you know, more colorful plants. And I think I want to get into one particular one, which is derived from a compound, one of these compounds called ellagic acid, that's found in berries and nuts and pomegranate, which is a really important advance, I think, in terms of mitochondrial therapeutics, which I use regularly in my practice, something called mitopure, which is basically a compound called urolithin A, which you're involved with in studying. And Eric, one of the key researchers in this whole field. So before we get into that, you know, we touched a little bit about supplements besides. Besides something like urolithinate, like CoQ10, of course, carnitine, creatine, and there are lipoic acid and acetylcysteine. There's a whole bunch of things that you can use to manage the energy production cycle, the B vitamins. So you need. You need all these things. NAD is something we talk a lot about in terms of longevity and aging, which is a derivative of vitamin B3 or niacin. But it's used by the body to make energy. So there's a lot of ways to actually soup up your mitochondria. What I want to sort of get into is this discovery of this compound called urolithin A, which is one of those things we call the postbiotic. It's something that's made by gut bacteria that then is absorbed and then it has biological function. Now, most of us who've taken antibiotics, which is pretty much everybody. I mean, I. I gave a talk to about a thousand people the other day, and I said, who here has not taken antibiotics ever in their life? I think there was like one person that raised their hand that Kind of wipes out some of the key species that make this postbiotic. And you're, you've actually concentrated it, purified it from plants, from pomegranate and I don't know if other sources. What is this compound? What does it do, how does it work, what does the data show about its effectiveness? So start out with what it is and how it works and let's talk about then what does it do to the body?

[Dr. Anurag Singh]

So this is a 15 years journey of research trying to discover why are pomegranates superfoods. Right. So what we discovered was that we initially thought it was these polyphenols, these ellagitannins that are in the pomegranates that were responsible for all the health benefits. And so we started studying them, we started looking at the gut microbiome derivatives, which we thought were just byproducts and waste products of this metabolism. And we chanced upon this family of urolithins. Now the body can either make in majority cases, if you can produce urotinate, but there are other urolithins you can make. So what we discovered was that this molecule, urolithin A, is actually not a waste product. It's actually a very potent gut metabolite produced by the gut microbiome that has these immense rejuvenation effects in mitochondria. And not everybody has the right gut microbiome. Again bringing the story that we were talking about in the gut microbiome before. Now I've done studies where I've gone in different parts of the world. So the, the Europeans have the highest number of producers. So if you go to the French and the Italians, you find out of 100 people you sample, 40% will make from the diet naturally, real world level, they will have some levels of URL Lithinia in their bloodstream. You go to the US and Canada, that number drops to 10%.

[Dr. Mark Hyman]

Wow.

[Dr. Anurag Singh]

You go to my origin country, which is India, where every kid growing up in their first year is given antibiotics for everything. The insulin drops to 5%, 5% in India, 5%. And I'm one of those that I can drink six glasses of pomegranate juice or eat six bowls of walnuts and pecans. My body just refuses to make this molecule. So that's how we discovered this molecule and then we started discovering its benefits. So the fact that majority of the adult, healthy adult population doesn't make it means now you have a case to supplement most of the population with it. And then what is it actually doing? What is Actually doing is what we started talking about is it revs up this cleaning up process. So it's really like a super pac man molecule which takes the debris out from the damaged mitochondria and puts them into sort of more healthy status. And the data is showing that if you give it to different species, you get these immense improvements in muscle strength and endurance. Mostly the trials we have run in placebo controlled randomized trials, we see in the absence of exercise, in the absence of changing their diets, you get about a 10, 12% improvement in strength. You get about a 10% improvement in VO2 levels. So this aerobic endurance we talked about and you also get lower inflammation. So that's the data that's.

[Dr. Mark Hyman]

Well, that, that's just so mind blowing because you just said, I'm just gonna again, double click on this. You're saying that you could take this compound that's made by bacteria as a supplement and without ever getting up off the couch, just by taking this, you're gonna see about a 10% improvement in strength in cardiovascular fitness and a reduction in inflammation.

[Dr. Anurag Singh]

It's not a magic pill, Mark. So what we do see is that it hits the same biology as what regular exercise would, would do. So the same PGC1 Alpha. So a month in into taking orally the molecule. And we have, we have done studies where we have figured out the right doses that trigger this therapeutic sort of effects as well. So the first studies I did was I started giving, you know, increasing doses of this molecule to older adults who are sedentary. And I found a sweet spot around the 500 milligram to a gram dosing of this molecule where a month in, no big physiological effects. But if I went in and took blood in biopsies, I could see the damaged mitochondria turn and become into healthier mitochondria. There was more PGC1 alpha, there was less damaged mitochondrial DNA. Two months in into supplementation is where I pick up things like physiological changes. So peak VO2 is improved because now it's like mimicking the effects of intermittent fasting or regular exercise, hitting the same pathways and then longer term, four months up, we start seeing these real long term benefits that I mentioned about, which is improvement in strength. So it's not like you just pop a few days and you.

[Unknown Speaker]

No, no.

[Dr. Mark Hyman]

But over time, over a few months, it's basically like exercise in a pill.

[Dr. Anurag Singh]

It is hitting the same pathways. And so that's the case. I always say it cannot replace exercise, it cannot replace good diet, but it can be this third pillar of this foundation of cellular health.

[Dr. Mark Hyman]

And so that's really fascinating. And you publish a lot on this. I mean, there's many studies in major medical journals, including JAMA and other journals, Cell Reports Medicine. And I've read these studies and they've been really compelling to me. And that's really why I take it every day as an older guy. Yeah, I want to get all the benefits I can. So I take a thousand milligrams a day of mitopure urolithin A. And I've noticed it definitely does help my energy, it helps my exercise. Really interesting. And I want to keep my muscle healthy as I get older. And there's not a lot of ways to sort of overcome this sort of accumulation of damaged mitochondria. So mitophagy is not an easy thing to induce. Right. And so this is kind of a unique. A unique therapy in terms of that. Yeah, so with very little side effects because it's a.

[Dr. Anurag Singh]

It's a natural molecule, evolutionary, it's been present. Our ancestors probably all made it because they were, you know, hunting and eating from the farm and etc. What I do think this molecule is different from all the NAD boosters or CoQ10 or we talked about L, carnitine, creatine like molecules is those can only work if you take the bad, damaged zombies mitochondria out from the real estate. Right. So if your cell is. Think of its cell as a. As a. As a town hall and it's all clogged up by bad, damaged mitochondria, unless you clean the waste out, unless the waste removal truck shows up, which in this case is mitopure. That's where I think the future research will go is how do you combine some of these nutrients together? You know, first you clean out the waste and then you can even potentiate the effects of things like NAD or creatine. And so that's area of research we are now also building on.

[Dr. Mark Hyman]

So essentially what you're saying is that some of these mitochondrial boosters like NAD or CoQ10 or Carnitine or lipoic acid or other things that we'll use work better. If you clean up the old mitochondria, they work best on pretty good functioning mitochondria. But if you have damaged mitochondria, they just are sort of like dead weight.

[Dr. Anurag Singh]

And that's what makes mitopure or urolithin A so unique, is because it's one of the only molecules that is really clinically shown to activate mitophagy clean out the debris and then potentiate the other, probably the effects even of exercise. And these are studies, at least we need to think about. Can you combine intermittent fasting with certain things like NAD or mitopure together and augment the effects? I think this is where I think.

[Dr. Mark Hyman]

Research is going in terms of inflammation. We chatted a little bit about before the podcast about this, this new kind of insight you've had around the relationship between inflammation, which is one of the hallmarks of aging, and mitochondrial dysfunction. Can you kind of talk about the sort of bi directional effects of inflammation and mitochondrial dysfunction?

[Dr. Anurag Singh]

The early trials we did, as I mentioned, whether it was the older adults, you know, sitting on their couch potato, not getting to move, or the overweight folks, or even the elite athletes, the hallmarks, wherever we would see improved mitochondrial health in the background, we will always see lowering of C reactive protein. We would always see lowering of Interleukin 1 beta or TNF alpha.

[Dr. Mark Hyman]

Those are cytokines.

[Dr. Anurag Singh]

These are cytokines, Inflammatory cytokines. Yeah. As you said, the zombie cells are spewing these cytokines out. And we started wondering, and I'm a trained immunologist, so I wondered. And then we partnered with Professor Eric Verdin, who's a leading aging research researcher and immunologist as well. And he said, well, let's do a trial where we give this molecule for a month to healthy 40, 50 year olds and we look at every single immune cell in the body, at the impact it's causing and the mitochondria in it. Now, this has not really been done with any other nutrients or even exercise for that matter. So we started doing, we did this trial and then Eric Scripp ran a whole scan of 80 plus immune populations. These are two. You know, these are. As an immunologist, you talk about different kind of T cells. The T cells are these cells in your body that fight infections. And then you can also profile things like NK cells, which are called natural killer cells. As we age, the number of these immune cells declines in our bodies. And that's why you get sick more. You don't respond very well to vaccines, et cetera. What we actually now find with supplementation is that a lot of these immune cells that are declining with aging, they come back with mitopure supplementation. And when they come back, they have more mitochondria, just like what we were seeing with the skeletal muscle or what other groups have shown with the neuron cells. And these immune cells are more wired to fight infections. So if you Throw an infection on them, they engulf it and kill it much faster. To me, this is probably, and hopefully it gets published very soon. But I think it's one of the breakthrough findings connecting our immune health and the declining immune health. I think now I'm changing my mindset that that's actually the first hallmark that sets in in our bodies is the declining of immune aging and the immune fitness. And then all these other hallmarks start to percolate around it and gradually. So this is the latest research we have that's interesting.

[Dr. Mark Hyman]

So essentially what you're saying is that with this compound which affects mitochondrial health, that by improving mitochondrial health, you improve.

[Dr. Anurag Singh]

Your immune health, which is a fascinating concept that you can take. And so now what we are looking at is the trials, the randomized studies, we are even thinking is, can we actually give it to even people who have beaten cancer, for example, who have taken a lot of chemo, Their immune cells are damaged because chemo radio damages even the good cells. And can we bring the immune system back? Because a lot of these cancer patients who recover from cancer, they, you know, they have one low fatigue and low. They have muscle wasting. But the number two reason is they. They have a lot of infections because the immune system goes for a toss. So can we bring their immune system back and rejuvenate it much faster? So the number of ideas we have is how to use mitochondrial medicine to rejuvenate the immune health.

[Dr. Mark Hyman]

Oh, it's really mitochondrial rejuvenation and also immune rejuvenation.

[Dr. Anurag Singh]

Yes.

[Dr. Mark Hyman]

Which is something we don't really think about in medicine. And it's sort of the opposite of how we practice medicine. We use compounds or drugs that inhibit or block or interfere with some biological process, like an anti hypertensive or an antibiotic or a calcium channel blocker or an ACE inhibitor. So we're inhibiting, blocking and anting everything. These are doing the opposite. They're actually enhancing health, they're optimizing function, they're rejuvenating different biological systems that are critical for health and longevity. And when you look at chronic disease as a whole, and then we talked about everything from schizophrenia to autism to Alzheimer's to diabetes, cancer, these are all mitochondrial immune issues. They're all kind of the same at the root.

[Dr. Anurag Singh]

Alzheimer's, I mean, it's a classic example. For many years it was proteostasic disease with all these accumulation of myelite plaques and the lack of proteostasis. Now it's turned around. It's really an inflammatory disease of the glial microglial cells. And that's where I think a lot of aging diseases need to be reversed or early on by tackling inflammation and.

[Dr. Mark Hyman]

Mitochondrial health in sort of the whole space of longevity. There's a lot of compounds that people are talking about looking at, and some of them are, some of them, you know, have good data, some of them are questionable. You mentioned metformin. This is something that works on a similar pathway. But one of the consequences of metformin is that it inhibits mitochondrial complex 1, which while, while it seems like it helps with blood sugar and many things you'd want to have it help with, it also interferes with mitochondrial function, which worries me particularly. Right.

[Dr. Anurag Singh]

No, it's. So there's near Bullseye has been studying metformin for a long time and now he has this big trial, I believe the TAME trial, looking at the long term effects.

[Dr. Mark Hyman]

I think that got canceled.

[Dr. Anurag Singh]

Yeah. Okay.

[Dr. Mark Hyman]

They couldn't get the funding for it because it wasn't a patentable drug.

[Dr. Anurag Singh]

So that's the challenge. Right. Or you look at rapamycin, which has, as you were talking about, MTOR inhibition effects, but rapamycin was basically sirolimus, an immune suppressive drug. So again, what is the impacts on immune health is unknown. So that's where I feel the longevity field today needs to have a more360 approach where they sort of look at compounds that affect the key organs. And so the three. And I talked about it. So there is this. I don't know if you know about the XPRIZE initiative. So xprizes, you know, has this health span prize, longevity prize. And, and they're looking for compounds or intervention strategies that hit or can improve 10 years lower, you know, 10 years health span increase on muscle, immune and brain. Because those three organs, I think together, if you can hit on all three of them with one intervention or multiple, I mean, there's no magic bullet in this case, but I do think urolatin, a mitopure comes close. And so now we are now looking at the third one, which we don't have much data, which is brain health. So that's where we are going into.

[Dr. Mark Hyman]

Looking at the next frontier in research for mitopure is looking at brain health. Yeah, that's a good idea because I think it could really enhance a lot of mitochondrial brain disorders, everything from Parkinson's to Alzheimer's to autism to depression to bipolar disease to schizophrenia, that the brain is, you know, again, has the most density of mitochondria of any organ in the body. And so it makes sense that by upregulating those and rejuvenating your mitochondria in your brain, you're going to do better. One of the, one of the things that we also talk about is sort of improvement in the cardiovascular biomarkers with, with urolithin A and heart health. Can you talk about its role in heart health?

[Dr. Anurag Singh]

Yeah. So we just published a paper in, in Eye Science. And so this was again, in models. So this is not a randomized clinical trial, but these were models of heart failure where. So the first thing our group of very brilliant mitochondrial scientists did is they actually looked at cardiac biopsies of people who had heart failure or had died of heart degeneration with the aging process. And again, the signature, the hallmark signature they picked up in the heart was poor mitochondrial health. And so then we went into models of heart failure, acute and chronic, and we found that giving mitopure supplementation in these models reversed a lot of this cardiac damage by improving mitochondrial health. And in the humans trials, we haven't done a trial in heart failure, for example, but in older adults, for example, we have focused on a class of molecules called the ceramides. Now, ceramides, if your heart cells are not performing well, you'll accumulate a lot of these ceramides that are like mitochondrial toxins, essentially. And so what we see is actually in all our trials, ceramide plasma levels of ceramides are going down. And so there's the Mayo Clinic that has now a score of ceramides that allows you to predict the prognosis of cardiovascular health. So now we are looking in that direction of how we can look at long term cardiovascular health. But we do know things like VO2 improve with Mitopure, which is also cardiovascular health. So I think we just need to put, you know, research is two words, reinsert. So every small step you have to keep building on the journey.

[Dr. Mark Hyman]

Right? Right. That's true. Reinsearch. I never thought of that. There's a whole field like now metabolic psychiatry, but there's also a field of metabolic cardiology, which has not really been part of traditional cardiology. There's a, a cardiologist named Steven Sinatra, who is an old school nutritional doctor who I knew and who I know, who's quite amazing and he taught me a lot about metabolic cardiology. So when I have heart failure patients, I will give them a mitochondrial cocktail of supplements, including CoQ10, carnitine, creatine, ribose, lipoic acid, N acetylcysteine, the B vitamins and Basically what happens is quite remarkable. They prove their cardiac function by objective metrics like what we call ejection fraction, which is how much your heart can pump out with each pump of blood and each beat. That's a direct measure of how well your heart's functioning. And so I'd be very curious about looking at ejection fractions and urolithin A and how that works. But you can't really just do one thing. People think, oh, I'm just gonna take this medicine and, or this supplement and I'm not going to exercise or eat well, because you're eating a lot of sugar and you're not exercising, you might get some benefit, but not really. So you gotta, you gotta combine it with everything else in a healthy lifestyle.

[Unknown Speaker]

What about skin health?

[Dr. Mark Hyman]

Because, you know, we don't tend to think about mitochondria and skin health, but mitochures produce a lot of skin products, which I found very interesting.

[Dr. Anurag Singh]

You know, about three, four years back when we, and sometimes you have to listen to the consumer when we launch these products. Of course people said, oh, I have more energy, I have more strength. But the number one feedback that we did not expect to hear was people started coming to us and telling, hey, my partner just told me your skin is glowing and looks better. As a scientist, you take it a pinch of salt, you say, ah, that's an anecdotal feedback. But we said, okay, let's look at skin cells between a 30 year old, a 50 year old and a 70 year old and see if mitochondria are actually damaging the skin cells. And the answer was yes. The answer is that the skin cells in the fibroblasts or the keratinocytes, these are the two main cells in the epidermis and the dermis. They have lots of mitochondria. And over aging, over time of adult health span, they get damaged in much the same way as muscle and brain cells do. And so we made these topical formulations with mitopure and applied it in randomized trials in middle age, older age, volunteers, and lo and behold, when we did the skin biopsies, the mitochondria health started turning. And when mitochondria health turned and improved, suddenly you had things like collagen pathways. These are, you know, collagen is the protein that keeps your skin together. And there are enzymes called matrix metalloproteinases, MMPs, that degrade collagen that just go shoot up with aging. And what top we saw in these trials was that MMP levels were going down.

[Dr. Mark Hyman]

That's a marker of inflammation.

[Dr. Anurag Singh]

That's a marker of inflammation. That's also a marker of how much collagen you're gonna degrade. And so we then started, of course you have to do the standard imaging and looking at things like wrinkles and hydration. And we saw all these markers improved over time. Again, not instantly, but over time. So there is this now great appreciation of that mitochondria in the skin. And skin is this, that you know, one of the organs that is receiving the most external insult from, you know, whether it's harmful sun rays or pollution, et cetera. So it's under so much stress. In addition to the intrinsic decline in mitochondria, it's also receiving this. So that's where we now see some great data that we're, we're getting ready to publish. But the products are a big hit with the topical products. With mitopure, people are loving it in the skin care business. Not many people actually even bother doing clinical studies. So that's where, you know, as a science driven company, we have taken the call.

[Dr. Mark Hyman]

Yeah, I mean that's really unusual. I mean, just to sort of highlight for everybody listening, you know, most supplement companies don't spend millions and millions of dollars on clinical research, which you guys have done.

[Dr. Anurag Singh]

Yeah, and yeah, and I think it's really changing how supplementation should be seen as really a technology. You know, much like people think about biotechs and any tech company. I think that if you bring the evidence on the table, people will buy and get convinced. And that's where I think the dietary supplement world is ripe for disruption.

[Unknown Speaker]

It's true, it's amazing.

[Dr. Mark Hyman]

And I think, you know, we're going to link to all these studies that we've talked about in the show notes. So there's plenty of peer review, randomized trials that you guys have done that are in major journals that have kind of convinced me by looking at the data. And you know, it's not a panacea but you know, we need all the help we can get at this point given the amount of insults or mitochondria from our diet, from lack of exercise, from stress, poor sleep, from toxins, from infections, from our microbiome. I mean, all these things just kind of burden us and we really haven't had a way of really treating mitochondria very well before. I mean, there's been some supplements you can use in lifestyle, but this is sort of a novel advance just in terms of practical applications. Where do you think the science is heading in addition, you mentioned a few things like, you know, the skin health and you mentioned the immune health. What else are you thinking about?

[Dr. Anurag Singh]

Higher level mitochondrial science is, is going to different ways where, you know, as I mentioned, now they're trying to integrate all these other hallmarks of aging and how they link to mitochondrial health. But more important, the holy grail is to find a constellation of biomarkers clinicians can measure in clinic, which is not yet available. You know, clinicians are not saying, oh, let me tell you how good your mitochondrial score is, or mitochondrial health. So I think that's coming.

[Dr. Mark Hyman]

What are those biomarkers?

[Dr. Anurag Singh]

These are biomarkers where you're looking at the performance of a mitochondria, whether you're getting through a buccal swab. So again, you talked about it, the different complex activities, mitochondria, like a factory, as you mentioned, a complex 1, 2, 3, 4, 5. You can profile them and their performance and the activity. And you can also look at mitochondrial DNA and the damage in the mitochondrial DNA. So this requires complex genetic technology sometimes. So I think it's still further away. But I believe companies like Miscreen have some good technologies where they can take blood draws and tell you how good your mitochondria and your blood cells are and integration in terms of urolithin A. The real cool research I think will come out is this immune story we talked about, but the frontier of how it can impact cognition and cognitive health and health span in general. So I'm happy to share that we actually were one of the X Prize winners on our research that will be announced in a couple of weeks. You won the X Prize on the healthspan? We are one of them. One of the top finalists.

[Dr. Mark Hyman]

Oh, you're a top finalist.

[Dr. Anurag Singh]

And the whole reason you haven't actually.

[Dr. Mark Hyman]

Won the prize yet, not the big.

[Dr. Anurag Singh]

Prize, but we are one of the finalists that gets the first prize and then we compete with the other top guys for the $80 million prize. So that's a recognition of the research we've put on muscle and immune. But I think the brain is what will take us to the next level.

[Dr. Mark Hyman]

That's incredible. The brain final frontier. Because the brain mitochondrial connection and the dysfunction in there does cause a lot of suffering. Suffering, Right. Neurodegenerative diseases to neurodevelopmental issues, to mood issues.

[Dr. Anurag Singh]

Right, Absolutely.

[Dr. Mark Hyman]

This is important.

[Dr. Anurag Singh]

Sleep. Yeah. As well.

[Dr. Mark Hyman]

Sleep, yeah. I definitely think there's a mitochondrial connection to sleep. I think that's true. One of the things we didn't talk a little Bit more about, I think is some of the diagnostics. And I've been using some of the diagnostics in buccal swabs and organic acid testing for a long time. There's some newer tests out of Europe I'm curious to share with you that I think are really fascinating. The ME screen is looking at blood work that you can do at home. It's a home test, right?

[Dr. Anurag Singh]

Yeah.

[Dr. Mark Hyman]

And we're going to put the link to that's me screen dot com. What are they actually measuring when they look at that?

[Dr. Anurag Singh]

They're measuring how the stressed your mitochondria are. They look at a constellation of mitochondrial readouts. So they look at something called as reactive oxy ros. Right. So if your mitochondria are stressed, they can.

[Dr. Mark Hyman]

Free radicals.

[Dr. Anurag Singh]

Free radicals. They are looking at Complex 1 and Complex 2 activity inside the mitochondria. They are also looking at the respiration, how good and bad the oxygen consumption is at a mitochondrial level. So that's what they're. And then they look at all these and they give you a mitochondrial score and sort of a holistic mitochondrial health score.

[Dr. Mark Hyman]

Important. Yeah, because I think. I think being able to measure it and what's happening is important because, you know, we want to look at your mitochondria and you want to see the effect of any interventions. You want to know what you're doing. And again, it's not something we've really thought and focused on in medicine. There is one mitochondrial story I want you to kind of finish up by telling, which I think is important, which is, I think, one of the greatest mitochondrial toxins and also something that is incredibly widespread use. It's a medication that's commonly prescribed, the most common medication prescribed in the world, which is statins. Statins, Right.

[Unknown Speaker]

So cholesterol medication.

[Dr. Mark Hyman]

Tell us why these medications are harmful to mitochondria, what they do and if we should really be worried about it or not.

[Dr. Anurag Singh]

At a higher level, there are mitochondrial toxins and they deplete these sort of electron transport chain and CoQ10 deficiency happens. And so a lot of trials have looked at how you can resupplement with CoQ10 and recover some of the damage caused by statins. They are also muscle toxins. So a lot of times you will see people with statins, they come to you with muscle pain and things like in the extreme cases, rhabdomyolysis, which is really disintegration of the muscle. We haven't done anything with nutritional interventions on statins, but I think the body of Evidence is that they really are damaging to the mitochondrial network and the electron transport chain. And CoQ10 levels are very low in all those who get. Get statins.

[Dr. Mark Hyman]

Yeah. Because the same pathway that makes your LDL cholesterol also makes coenzyme Q10, which is one of the mitochondrial helpers CO factors. And so you're kind of screwing yourself. So anybody who's on a statin has to be on Coke Enzyme Q10. The question is, does it mitigate the damage or not? And how?

[Dr. Anurag Singh]

To a certain level, I believe it does. But Coq10 is not also very highly bioavailable compound when taken orally. And so there have been attempts at making liposomal CoQ10 and things like this to make it, you know. But I do think something like either NAD supplementation or cleaning out the waste with mitopure could, could go a long way. And this is something we thought about long back. But doing a trial with a drug and a supplement always, you know, when you go to an institutional review board for a clinical approval as a first study, they see it as a drug trial. And so that's always the risk of doing that trial. That's why we haven't done it.

[Dr. Mark Hyman]

Yeah. But I think it's important and I think I do worry about it because some of the studies I've seen is even without any muscle pain, even without an abnormal blood test, which you can see damage to the muscle called cpk, that pretty much everybody on a statin, if you do a muscle biopsy, has damaged mitochondria. It's not like some people, like almost everybody. And that, to me is very worrisome considering the importance of mitochondria, particularly as we age. Right.

[Dr. Anurag Singh]

Yeah. And we are starting to see a little bit of that also with, you know, the, the steroids. Also, if you throw steroids on muscle cells, we've seen that, that they, they have a very sort of detrimental impact. Yeah, Corticosteroids.

[Dr. Mark Hyman]

Not like, not like testosterone.

[Dr. Anurag Singh]

No, no, no. Yeah. More like cardio steroids. And again, there's this buzz with the GLP1 that, you know, with the GLP1 story that 20, 30, you lose muscle, you lose muscle. So what's happening at the, you know, it's almost like you're fasting, but you're, you're not just fasting, you're not eating anything. Right. And that has a stressor to mitochondria. So I think you will see a lot of mitochondrial research come out with these GLP1 drugs that they're bad for Them potentially. But the research needs to show that that's concerning.

[Dr. Mark Hyman]

That's concerning because they're, you know, getting used for everything, everywhere, all the time. We covered a lot of this, but I want to sort of bring it, bring it home a little bit and conclude by talking about some of the science based evidence to longevity and to how people can support their mitochondria and think about their mitochondria. So testing is coming. Yeah, we will learn more objectively what's going on, but in the meantime we kind of touched on some of these things. Would you summarize sort of a healthy mitochondrial lifestyle and supplementation program?

[Dr. Anurag Singh]

Well, there's a. So I, I would say five strategies that come to the top of my head. So eat well, eat a lot, eat your berries, eat your fiber, eat your, you know, whole foods. I think that's the key.

[Dr. Mark Hyman]

And low sugar, low sug.

[Dr. Anurag Singh]

Yeah, exactly. Try to cut down. Yeah, good fats. That's the key. Then keep moving. Right. So you make sure you walk, just not sit in the office all day. And that's the end. Your muscles, your brain cells need to have that stimulus of exercise. Sleep. Well, I think sleep. I truly believe that a lot of research will come out in the next five years on how sleep regulates everything from metabolism to mitochondria. I see nutritional and I see advanced nutritional strategies which we talked about, whether it's creatine, nad supplementation, vitamin, the B vitamins, they're all great. Vitamin D, we didn't talk about that. But it also has some great effects on mitochondria and immune cells. And then I think mitopure fits in the ensemble. Not in isolation, but in the ensemble. And I think the last bit on mitochondria, as you mentioned, is make sure you're not taking a lot of these toxins like drugs. We talked about antibiotics, we talked about statins. Make sure you do the. Consult your doctor and have a sort of 360 holistic view of how do you approach mitochondrial health?

[Dr. Mark Hyman]

I think that's very sound, good advice. The one thing I didn't think about, but I just thought about it as we were discussing this and you mentioned antibiotics. One, because it affects your microbiome and your ability to naturally make your. But two, you know, mitochondria historically came from bacteria. So they're basically a symbiotic relationship with bacteria and humans. And they, they, they're not the same in terms of their DNA. They're actually quite different than your DNA. They're. You come from your mother, but it's mitochondrial DNA. And, and the question is do antibiotics hurt mitochondria? Because they're basically come from mitochondria bacteria.

[Dr. Anurag Singh]

There's certainly stressors. There's enough studies showing their mitochondrial stressors now I think really depends on the duration of usage, the dose and certain class of antibiotics. They're probably worse off than the others. I think research is really lacking in that way.

[Dr. Mark Hyman]

Yeah, nobody wants to look at it.

[Dr. Anurag Singh]

Nobody wants to look at it. But I think the last tragedy that a lot of people don't talk about is these holistic strategies. Sauna. There's a lot of good evidence in sauna for mitochondria.

[Dr. Mark Hyman]

Saunas.

[Dr. Anurag Singh]

Yeah, saunas in near infrared, the red light therapy. So I think this, this parallel sort of, I want to say more medical diagnostic or you know, more electroceutical if I can call it strategy. But these are also something that can potentially augment a lot of these other benefits on mitochondria. I mean and research needs to come on that. I think that's where another under researched area.

[Dr. Mark Hyman]

That's amazing. Light therapy, other ways to enhance mitochondrial function. Yeah, there's also hypoxic therapies or you know, you get low oxygen states or hyperbaric chambers which you get high oxygen states. All these can be interesting mitochondrial therapies.

[Dr. Anurag Singh]

There's a great research coming out from one of our collaborators who just co discovered urolithin with us where he's seeing that living in cold rooms or colder areas is better for your mitochondria.

[Dr. Mark Hyman]

Yeah.

[Dr. Anurag Singh]

Than living in hot climates and tropical areas. So coming from India I'm not so excited. But you know, but, but this is the very research is going to go.

[Dr. Mark Hyman]

Fascinating, fascinating. So what is the most exciting that's coming down the pipe in terms of the research frontier?

[Dr. Anurag Singh]

Personally for me I think it's the immune link. How we can reverse a lot of this immune aging with this simple mitochondrial tools. 20 years back when I was training as a physician immunologist, I didn't think that medicine would bring me to a place where suddenly by reversing your immune health you can, you know, you can do that with the mitochondrial nutrient. So I find that for me all my training is coming to the right place in terms and I think in terms of the whole longevity field, it's the awareness and building around the biomarker approach, the you know, integrating things like intermittent fasting things, integrating nutritional supplementation and so I think that's more longevity. Clinics are sprouting everywhere. We can see that people are more aware that this is not just a buzzword. So I think, as I say, to end with this, longevity is a marathon start today.

[Dr. Mark Hyman]

That's incredible. Well, thank you so much, Dr. Singh, for being on the podcast and for enlightening us with all the work you've done on mitochondrial health. How critical is for just general overall well being and also longevity and the work you've done to pioneer the research on Urolithin A. It's not easy to do that work work. It's hard, tedious work sometimes, but the results are pretty exciting. And I, I think we're going to look forward to hearing more and more over time how this can apply to broad range of problems from cardiovascular health to immune health to longevity. So everybody, we're gonna, we're gonna put in the show notes links to how to find more about the research that we talked about around Urolithin A, links to the product itself, Timeline Nutrition's Mitrepure, which comes in many forms. It comes in powder and pills and, and now gummies, which are yummy. And we're gonna also, you know, talk about in the show notes some of the sort of suggestions that we talked about around mitochondrial health and renewal. So thank you again for being on the podcast and hopefully we'll keep having this conversation and learning more as time goes on.

[Dr. Anurag Singh]

Thanks for having me. Absolute pleasure.

[Unknown Speaker]

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[Dr. Mark Hyman]

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[Unknown Speaker]

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[Dr. Mark Hyman]

And every product to meet the most.

[Unknown Speaker]

Rig rigorous standards for safety, purity and effectiveness. These are the only supplements I recommend.

[Dr. Mark Hyman]

To my patients and they're also what I use myself.

[Unknown Speaker]

Whether you want to optimize longevity or reduce your disease risk, or you're looking to improve your sleep, blood sugar, metabolism, gut health, you name it. Doctorhyman.com has the world's best selection of top quality premium supplements, all backed by.

[Dr. Mark Hyman]

Science and expertly vetted by me, Dr. Mark Hyman.

[Unknown Speaker]

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[Dr. Mark Hyman]

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[Unknown Speaker]

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