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

Dr. Mark Hyman
Saying that you could take this compound made by bacteria as a supplement, you're gonna see about a 10% improvement in strength in cardiovascular fitness and a reduction in inflammation.

Dr. Anurag Singh
Mostly the trials we have run-in placebo controlled randomized trials, see in the absence of exercise, in the absence of changing their diets, you get about a 12% improvement in strength, you get about a 10% improvement in b o two levels. Leading immunologist, doctor Anurag Singh. Explores how mitochondria and inflammation shape our health. Aging and energy. Exercise is the best mitochondrial drug.

Yeah. So just getting people moving in their seventies and eighties three times a week for thirty 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 exercise. Two is

Dr. Mark Hyman
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Dr. Mark Hyman
Anurag, welcome to the doctor 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 Mhmm. In terms of your health, longevity, well-being, energy, brain function

Dr. Anurag Singh
Yeah.

Dr. Mark Hyman
Immune health, pretty much everything. Mhmm. It comes down to something that actually is a topic, that I love, which is how our bodies make energy Mhmm. 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 kinda 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 Mhmm. If you wanna live a healthy and long life.

We're gonna kinda 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 and super 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 kinda let's start with the work that you're doing around mitochondrial research and 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 and so for many years

Dr. Mark Hyman
You're MD PhD, so you're you're you're like a double doctor.

Dr. Anurag Singh
So Well, as you said, medical schools briefly educate the students, the future doctors about, yeah, this is the biochemistry class and they learn about mitochondria. But I actually think, 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, 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 two year old running around bouncing off the walls and a 92 year old just sitting motionless in a chair? Yeah. 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, 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 in mitochondria is happening. The green is becoming red.

Dr. Mark Hyman
So your body battery kind of

Dr. Anurag Singh
Fatigues 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've you've got three ways to sort of soup up your mitochondria and make more energy. One is exercise.

Dr. Anurag Singh
Yeah.

Dr. Mark Hyman
Two is is inducing mitophagy. Yeah. And three would be

Dr. Anurag Singh
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?

Dr. Anurag Singh
Fatigue and and then the lack of energy at the you know, as I say, you go through the emotions of the day and at the end of the day, you 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 to, if you're one of those who exercise 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, at

Dr. Mark Hyman
the

Dr. Anurag Singh
whole body level, just brain fog. 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
Yeah, I think was like, what is it, 17,000 of these in every brain cell?

Dr. Anurag Singh
And close to 10,000, 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. Mhmm. So we we tend to think about things downstream. Okay. You've got heart disease.

You've Alzheimer's. You've got Parkinson's. You've got cancer. You've got diabetes. You've got Mhmm.

All these horrible things that happen as we get older. But we don't think upstream. You know, what do these things have in common? Mhmm. There may be just different manifestations of the same problem Mhmm.

Depending on the person. Mhmm. 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. And we're gonna talk about how they're linked. Sure.

You know, when you really look at all the hallmarks of aging, there's sort of meta ones and there's secondary ones. This is 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 tell them you're 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 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 meta frameworks that can explain even mitochondrial 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 Mhmm. And that the food you're eating is messing up your body Mhmm. Particularly causing inflammation and causing mitochondrial dysfunction.

So, you know, when you look at diseases like Alzheimer's or diabetes, or even cancer, these are fundamentally mitochondrial problems and the treatments can be mitochondrial treatments. But again, as I said, no, we don't learn as doctors how to treat our mitochondria. We're even gonna 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're still learning how to high throughput it, right? Like if you were to go and get your lab work done, you'll do a standard lipid profile, kidney profile, cardiac profile. Mitochondria is today not part of it. Inflammation is, so you do look at C reactive proteins and 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, MeScreen that is using blood cells to look at how the mitochondria are 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 setup, 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 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, looking at the ATP recovery Yeah.

Dr. Mark Hyman
And ATP is the energy, it's basically the

Dr. Anurag Singh
It's the molecule of energy, yeah.

Dr. Mark Hyman
Yeah.

Dr. Anurag Singh
Now, the other way is you take chunks of tissue. So that's what I do, I go in and take a muscle biopsy.

Dr. Mark Hyman
Muscle biopsy, that's fun.

Dr. Anurag Singh
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 skeletal muscle and you ask in an unbiased way, what are the top 30 pathways that are down regulated? They are all mitochondrial linked. And that just not us who has shown that, it's multiple groups that have shown that.

As you 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 as a doctor, I've been trying to look at mitochondria for many years in functional medicine. And we'll do, for example, VO two max testing.

Dr. Anurag Singh
You can

Dr. Mark Hyman
do Which is a maximal exercise Mhmm. Testing where they measure oxygen consumption and carbonized carbon dioxide production

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
As an indirect way of looking at your mitochondrial function. What we do know is that v o two max, which is basically how much oxygen you consume per minute per body per per kilogram of body weight, is one of the best predictors of longevity. Sure. It's in a linear way. The the higher the number, I mean, the more fit you are, the more your mitochondria can, you know, consume oxygen and produce energy Mhmm.

The longer you're gonna live. That's pretty cool. And and yet, you know, that's that's a little bit of a more, difficult test to get. But you can get it at gyms Yeah.

Dr. Anurag Singh
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. Okay. There's also labs in Germany that do extensive mitochondrial testing, looking at, you know, the the mitochondria inside the white blood cells in your blood and and looking at how they're functioning. And 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 disease of aging. But mental health is now, an area of deep research around mitochondria and cognitive function, not just things like dementia, but autism.

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
You know, it's found to have been really in part driven by mitochondrial dysfunction in these kids. They have a brain energy deficit. And Suzanne Goh showed this, who's a Harvard, Oxford trained pediatric neurologist. Mhmm. She's been on the podcast.

And Chris Palmer

Dr. Anurag Singh
Sure.

Dr. Mark Hyman
Ian Campbell, you know, have been on the podcast talking about metabolic psychiatry Mhmm. Where where depression, bipolar, schizophrenia, these are mitochondrial diseases. And by treating the mitochondria with diet and other approaches, they can 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
But mitochondrial medicine is just is this area that's sort of so promising and yet so neglected in traditional health care. 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 you sort of mentioned that in passing, I think it's important to double click on is Mhmm. Sort of new new discoveries around, the immune system's function and mitochondrial function and how how you been surprised by some of the things you've 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 out My

Dr. Mark Hyman
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, 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're 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.

Dr. Mark Hyman
Yeah. And, you know, one of the one of the fundamental hallmarks of aging is this phenomenon of cellular senescence Mhmm. Otherwise known as zombie cells. These are cells that should have died and been recycled that seem to live forever

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
And turn into zombies and then go around creating more zombie cells.

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
And and what these cells do is they 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 it's sort of a feed forward cycle.

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
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, mean, mitochondria have their own DNA that leaks out into the circulation and causes inflammation. 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 let's back up at 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 pretty much everything you can think of, and yet they're so fragile. 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, etcetera, or your sedentary habit. They accumulate what we call as ROS or reactive oxygen species, and they start becoming, 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, 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 sequel for energy, low fatigue, etcetera, sets in

Dr. Mark Hyman
with aging. 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 they've heard me talk about mTOR, things like rapamycin and other compounds for longevity. What they do is 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 also a mitochondrial recovery process where we're supposed to be chewing up and eating up and like Pac Man recycling our 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. Right?

Dr. Anurag Singh
Mhmm. Inflammation and the other senescence is all interlinked.

Dr. Mark Hyman
But there's 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, you know, one is you can improve what we call biogenesis so you can kind of seed near healthy mitochondria. And so there are strategies, exercise being a very powerful This is the whole PGC one alpha pathway where, you know, where you stimulate this mitochondrial biogenesis, you can improve the growth of near mitochondria. Then there is sort of the fission

Dr. Mark Hyman
and fusion. In English that means that if you exercise, you stimulate a pathway that makes new mitochondria, that helps you create

Dr. Anurag Singh
new 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 Resveratrol, 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, Coke Q10 that are integrated into the different mitochondrial cycle, you know, there's 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 Before

Dr. Mark Hyman
we get too much more into how to fix your mitochondria, I wanna sort of kinda just kinda double down on what are the other things, like our diet, toxins, stress, sleep issues. What what are the ways that our mitochondria become more damaged in our current environment and lifestyle?

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

Dr. Mark Hyman
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 a 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, when they get stressed and damaged, that impacts. That's how diet is playing.

Now, physical

Dr. Mark Hyman
Diet, would just say, it's the sugar and starch Oh, and the excess calories that overwhelm the mitochondria. Mhmm. And also the oxidized foods we eat, like The processed foods. Oils and processed foods. Yeah.

You know, people talk a lot about seed oils. Mhmm. In and of themselves, they may not be the issue. It's it's how oxidized they are. Mean, they they go rancid.

Are you eating rancid oils? Mhmm. 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 what your mitochondria are made of and how resilient they are.

If you're eating, you know, crappy fats versus good fats Mhmm. 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.

Dr. Anurag Singh
Half. And today the technologies are advancing, so we do something called metabolomics and we can actually find these mitochondrial metabolites 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. It is. You it's not just good for your cardiovascular health and metabolism, but it actually 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 a very understudied area of mitochondria in the mitochondrial space that how your sarcadian rhythm, how your sleep patterns affect mitochondrial health, and how some of these pathways point to 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 twenty years after sleep issues, they turn into neurodegenerative disorders. So they either get Alzheimer's or Parkinson's, and the fundamental root causes mitochondrial imbalance 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 Or both. I think it's kind of interlinked. I think lack of or poor sleep contributes to worsening mitochondrial health, and that kind of triggers this whole journey and acceleration to neurodegeneration down the road twenty years after, you know. So I think sleep is a key area. What else?

I think

Dr. Mark Hyman
Toxins.

Dr. Anurag Singh
Toxins, of course. A lot of damage from the sun. We have all these fluoride discussions today and all that. We see that actually if you put some sodium fluoride on muscle cells or any kind of cells, the mitochondria get stressed. 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

Dr. Anurag Singh
Yeah.

Dr. Mark Hyman
Any kind of insult, including the load of environmental toxins we're all exposed to, whether it's the the PFAS rubber chemicals, whether it's, you know, heavy metals, whether it's, you know, synthetic toxins

Dr. Anurag Singh
Yeah.

Dr. Mark Hyman
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 you can reduce your exposures. And then and then there's the microbiome, which is something that people haven't really talked about much. But when I I did some homework and and looked at the literature on this, because I would see this clinically, that people had microbiome issues, it it did affect their mitochondria.

Dr. Anurag Singh
Well, that's how we got into the space of discovering compounds Yeah. That were made by the gut micro So you're 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 three ms 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. Yeah. Has immense effects on mitochondrial health and beyond.

Dr. Mark Hyman
Yeah. It was just interesting you say that. I mean, I do wanna double click on that too because I was on a panel once at Cleveland Clinic with Stan Hazen Mhmm. Who's a preeminent 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, doctor Hyman?

Basically, when you're when you when you have, bacteria in your gut, they have DNA, and the DNA's job is to make proteins.

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
And you have probably a 100 times as much bacterial DNA as your own DNA. Mhmm. Because you've got a thousand species. They're all different. Mhmm.

They all have different DNA. You know, we might have 20,000 genes. There might be 2,000,000 bacterial genes.

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
And each one of those genes is making protein.

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
What happens to those proteins? Well, there's something that's active in your gut, but they also get absorbed

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
By your body. They get absorbed Mhmm. And they're in your blood. And then what are they doing there? Well, they're influencing everything.

We're gonna 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 I I we're gonna 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, a poor diet, lack of exercise, stress, lack of good sleep, environmental toxins Mhmm.

Overload of calories and sugar, changes in our microbiome Mhmm. That actually are not good, you know, what can we do about it? And, you know, we hinted a little bit about exercise, diet supplements. And people should understand that, you know, the supplements around mitochondria are pretty well studied. And there there is basically this chain, called the respiratory chain.

Basically, when you when you pour in food and and auction the ones let's just say one side of the factory assembly line Mhmm. Out the other side comes energy. Mhmm. 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.

Yeah. 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, 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't 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 the 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 thirties and forties, you know, what can I do already? So when I'm in my seventies and eighties, you know, I can, my mitochondria are enabling me to get up from a chair and cross the zebra line in fifteen seconds, you know?

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

Dr. Mark Hyman
Yeah. I I think it's so important people have to kind of really get that, you know, if you wanna 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.

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
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 I think a lot of misconception I hear is that this is pretty much set in stone. It's irreversible. Oh, I I hear now a lot of people 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 sequelae 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 phenomenon. 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 sort of hinted at some things, you know, like diet and exercise and supplementation that can help. Let's first talk about, like, what are the natural ways that you can actually trigger mitochondria renewal, the making of new mitochondria? You mentioned biogenesis, which means just making new life, new mitochondria. And also, mycophagy, which is cellular cleanup. So what are 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. Any kind of exercise, just moving 8,000, 10,000 steps a day, just doing your resistance or endurance or a mix of both training has profound. These are as we talked about. These are mitochondrial drug exercise, the best mitochondrial drug.

So just getting people moving in their seventies and eighties three times a week for thirty minutes, that's that's the basic, you know, of having a rejuvenation effect on the mitochondria. The fact that we are unable to get people at that age to do that is a problem, I see, you know? And that's why And then diet, mean,

Dr. Mark Hyman
talk Before you jump there, in terms of exercise, what are the differential effect of strength training

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
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 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 a yoga class for thirty minutes. I think that's very essential.

Dr. Mark Hyman
Yeah. I mean, the way I think about it is that like cardiovascular fitness, particularly VO two max training helps increase the efficiency and function of your mitochondria, and may may help you recruit new mitochondria. But also strength training increases the number, the math, 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

Dr. Mark Hyman
And what's sarcopenia?

Dr. Anurag Singh
So sarcopenia is this age related muscle disorder. So when we are in our thirties, we peak in our muscle performance around a third decade of life. And following that, every ten years we are losing 10% of muscle strength and muscle mass, okay? And that accelerates even bigger than 10% in our sixties. So by the time we are hitting our sixties and seventies, 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 a loss of muscle and strength and the quality of the muscle.

Dr. Mark Hyman
But those aren't inevitable. 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.

Dr. Anurag Singh
Yeah. Yeah.

Dr. Mark Hyman
So and I actually am more, quote, 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 the Yeah.

Dr. Anurag Singh
Muscle is the sponge, you know? It just needs a little stimulus to get it going.

Dr. Mark Hyman
Then you're talking about Well, of

Dr. Anurag Singh
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 60, 70, 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 that, 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 RDA is point eight 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, think with aging, it should be up, so about one, one point two even per grams of per kilogram. So the whole Most older adults are eating 40 grams less. So they That's why, you know, there's the idea, oh, you give them protein shakes with ten, twenty 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 eighties, 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 I think there's been work by the protege group, Don Lehman, we've had on the podcast talking about how as you get older, you might need even a gram per pound of ideal body weight. Yep. So if you're seventy kilos, you know, or let's say a hundred and, you know, fifty pounds, you need up to a 130 to a 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, one, it's hard to get that much because you're also carrying with a lot of starch and rice or beans. But if you but if you use animal protein, you're going to get a 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 and having more ketones. Presparmer has done a lot of work in there and a lot of other groups. Eric Werdow, a collaborator, is looking at them. And just getting your body to more using fat as a source instead of carbohydrate, glucose, has this profound effect on getting mitochondria wrapped up.

They like processing towards their preference for fuel utilization is more fat than 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. Mean, these are all mitochondrial problems. And they all respond extremely well to ketogenic diets.

They respond better than any other current therapy. Yeah. Absolutely. And I've seen kids with autism just sort of wake up Mhmm. 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 two diabetes.

Mhmm. So so having you mentioned MCTOL, 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 to go for a long ride, 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, polyphenols. So all the berries, the pomegranates, the nuts, kind of, you know, it's kind of the Mediterranean diet. 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 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 wanna get into one particular one, which is derived from a comp one of these compounds called lagic acid that's found in berries and nuts and pomegranate

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
Which which is a really important advance, I think, in terms of mitochondrial therapeutics, which I use regularly in my practice, something called, Mitopur, 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 urolithin A, like CoQ ten

Dr. Anurag Singh
Of course.

Dr. Mark Hyman
Carnitine, creatine, and there are lipoic acid and acetylcysteine. There's a whole bunch of things that you can use Mhmm. To manage the the energy production cycle, the b vitamins. Yeah. So you need you need all these things.

NAD is something we we talk a lot about in terms of longevity and aging, which is a derivative of vitamin b three or niacin. But it's it's used by the body to make energy. So there's a lot of ways to actually soup up your mitochondria. What I wanna 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 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, pomegranate Mhmm. And I don't know if other sources.

What what is this compound? What does it do? How does it work? What does the data show about its effectiveness?

Dr. Anurag Singh
Yeah. Sure.

Dr. Mark Hyman
So start out with like what it is and how it works.

Dr. Anurag Singh
Yeah.

Dr. Mark Hyman
And let's talk about then what what does it do to the body.

Dr. Anurag Singh
So this is our fifteen years journey of research trying to discover why are pomegranates super foods. Right? So what we discovered was that we initially thought it was these polyphenols, these LEG tannins 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 urolitins. Now the body can either make in majority cases, if you can produce urolithin A. 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 on 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 Europeans have the highest number of producers. Oh. Yeah.

So if you go to the French and the Italians, you find out of 100 people you sample, forty percent will make from the diet naturally real world level, they will have some levels of urolutinase in their bloodstream. You go to The US and Canada, that number drops to ten percent.

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 five percent.

Dr. Mark Hyman
Five percent in India? Five percent.

Dr. Anurag Singh
Wow. 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 it's 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 run-in placebo controlled randomized trials, see in the absence of exercise, in the absence of changing their diets, you get about a 12% improvement in strength, you get about a 10% improvement in v o two 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 just so mind blowing because what you just said, was gonna, again, double click on this. You're saying that you could take this compound that's made by bacteria as a supplement Mhmm. 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 PGC one alpha. So a month in into taking orally the molecule, and 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 increasing doses of this molecule to older adults who were sedentary, and I found a sweet spot around the five hundred milligram to a gram dosing of this molecule, where a month in, no big physiological effects, but if I went in and took blood and biopsies, I could see the damaged mitochondria turn and become into healthier mitochondria. There was more PGC one 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

Dr. Mark Hyman
lose No, but over time, over a few months, it's basically like exercise and 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 and so that's really fascinating. And and and you publish a lot on this. I mean, there's many studies in major medical journals including, you know, JAMA and other other journals, Cell Reports Medicine. And and I've I've read these studies and they've been really compelling to me. Mhmm.

And that's really why I take it every day. I mean, as an older guy, yeah, I wanna get all the benefits I can. So I take a thousand milligrams a day of Mitopur urolithin A. And I've noticed it definitely does help my energy. It helps my my exercise.

Really interesting. And and I want to keep my muscle healthy as I get older. And and and there there's not a lot of ways to sort of overcome the the this sort of accumulation of damaged mitochondria. So mitophagy is not an easy thing to induce.

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
Right? And so this 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 hunting and eating from the farm, etcetera. 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 zombie mitochondria out from the real estate, right? So if your cell is think of a cell 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 the 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 function mitochondria, but if you have damaged mitochondria, they just are sort of like deadweight.

Dr. Anurag Singh
And that's what makes Mitopur or Urolatinase 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 is, can you combine intermittent fasting with certain things like NAD or Mitopur together and augment the effects? I think this is where I think research is going.

Dr. Mark Hyman
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 bidirectional effects of inflammation and mitochondrial dysfunction?

Dr. Anurag Singh
The early trials we did, as I mentioned, whether it was the older adults sitting on their couch potato not getting to move, or the overweight folks, or even the elite athletes, the hallmarks of whatever 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 one beta or TNF alpha.

Dr. Mark Hyman
Are Those are cytokines.

Dr. Anurag Singh
These are inflammatory cytokines. 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 Werdin, a leading aging 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 Script ran a whole scan of 80 plus immune populations. As an immunologist, 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, etcetera. 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 infection. So, 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, the declining of immune aging and the immune fitness. And then all these other hallmarks start to percolate around it gradually. So this is the latest research we have.

Dr. Mark Hyman
That's interesting. So essentially, what you're saying is that with this compound which affects mitochondrial health, that by improving mitochondrial health, you improve your immune health.

Dr. Anurag Singh
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 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
Yeah.

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 we use compounds or drugs that inhibit or block or interfere with some biological process, like an antihypertensive or an antibiotic or a calcium channel blocker or ACE inhibitors or inhibiting, blocking, and antiing 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 to cancer, these are all mitochondrial immune issues. They're all kind of the same at the root.

Dr. Anurag Singh
Alzheimer's, I mean, is a classic example. For many years, was a proteostasis disease, you know, with all these accumulation of myeloid 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 in mitochondrial health.

Dr. Mark Hyman
In sort of the whole space of longevity, there's a lot of compounds that people are talking about, looking at. Some of them are meh, 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. Mhmm.

But one of the consequences of metformin is it inhibits mitochondrial complex one

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
Which while while it seems like it helps with blood sugar and many things you'd wanna have it help with, it also interferes with mitochondrial function, which worries me particularly. Mhmm. Right? Mhmm.

Dr. Anurag Singh
No, is So, Nir Balzai 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, has, as you were talking about, mTOR inhibition effects. But rapamycin was basically sirolimus, an immune suppressive drug. So, again, what does it impact on immune health is unknown. So that's where I feel the longevity field today needs to have a more three sixty approach, where they sort of look at compounds that affect the key organs.

And so, three, and I talked about it, so there is this, I don't know if you know about the XPRIZE initiative. So XPRIZE has this health brand prize, longevity prize, and they're looking for compounds or intervention strategies that hit or can improve ten years, lower, you know, ten 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 for But I do think urolitinibIridopur 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 this.

Dr. Mark Hyman
Looking in the next frontier in research for Yeah. Might appear as is looking at brain health. Yeah. That's a good idea. Because I think it's, you know, 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. Yeah. And so it makes sense that by upregulating those and rejuvenating your mitochondria in your brain, you're gonna 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

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
And heart health. Can you just 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, you know, 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 human 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, the plasma levels of ceramides are are Going down. 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. Now we are looking in that direction of how we can look at long term cardiovascular health. But we do know things like v o two improve with Mytopure, 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 Right,

Dr. Mark Hyman
right, that's true. Reinsearch and every lot of that. There's a whole field, like, now of metabolic psychiatry, but there's also a field of metabolic cardiology, which has not really been part of traditional cardiology. There's a cardiologist named Steven Sinatra who is an old school nutritional doctor who I knew and who I know is quite amazing. And he taught me a lot about metabolic cardiology.

So when I have heart failure patients

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
I will give them a mitochondrial cocktail of supplements, including CoQ10

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
Carnitine, creatine, ribose Yep. Lipoic acid Sure. And acetylcysteine, the B vitamins. And basically, what happens is quite remarkable. They they prove their cardiac function by objective metrics like what we call ejection fraction, which how much your heart can pump out with each pump of blood Mhmm.

And each beat, that that's a direct measure of, you know, your your how well your heart's functioning. And so I'd be very curious about, like, looking at, you know, ejection fractions and and how that works. But you can't really just do one thing. Like people are like, oh, I'm just gonna take this medicine and or this supplement and I'm not gonna exercise or eat well. You're eating a lot of sugar and you're not exercising, you're you might get some benefit, but not really.

Mhmm. So you gotta you gotta combine it with everything else in a healthy lifestyle. What about skin health? Because we don't tend to think about mitochondria and skin health, but Mitapur is produced 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 launched these products, of course, 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. And as a scientist, you take it in 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 overaging, over time of adult health span, they get damaged. 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 shoot up with aging. And what top we saw in these trials was that MMP levels were going down. So That's a marker

Dr. Mark Hyman
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, one of the organs that is receiving the most external insult from, you know, whether it's harmful sun rays or pollution, etcetera. 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 are 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. Mean, this is 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 in any tech company, I think that if you bring the evidence on the table, people will buy and get convinced, that's where I think the dietary supplement world is ripe for disruption.

Dr. Mark Hyman
It's true. It's amazing. And I think, you know, we're gonna 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 kind of convinced me Mhmm. 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.

Dr. Anurag Singh
Yeah.

Dr. Mark Hyman
And and and 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. 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 it through a buccal swab. So again, talked about it, the different complex activities. Mitochondria like a factory, as you mentioned, complex one, two, three, four, five, you can profile them and their performance and their activity. And you can also look at mitochondrial DNA and the damage in the mitochondrial DNA. So this requires complex genetic technologies sometimes, I think it's still further away.

But I believe companies like MeScreen have some good technologies where they can take blood draws and tell you how good your mitochondria in your blood cells are. Mhmm. And integration, in terms of urolitinib, real cool research I think will come out is is this immune story we talked about, but the the frontier of of how it can impact cognition and cognitive health and 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.

Dr. Mark Hyman
You won the X Prize on?

Dr. Anurag Singh
On the health span. We are one of them, not, you know, one of the top finalists.

Dr. Mark Hyman
Oh, you're a top finalist.

Dr. Anurag Singh
And the whole reason the

Dr. Mark Hyman
You haven't actually won the prize yet.

Dr. Anurag Singh
Not the big prize, but we are one of the finalists that gets the first prize. And then we compete with other top guys for the $80,000,000 prize. So that's a recognition of the research we've put in 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, right? From neurodegenerative diseases to neurodevelopmental issues to mood issues, right? Absolutely. This is important.

Dr. Anurag Singh
Sleep, yeah, as well.

Dr. Mark Hyman
Sleep. Yeah. I I definitely think there's a mitochondrial connection to sleep. I I think that's true. One one of the things we didn't talk a little bit more about I think is some of the diagnostics.

And I I've been using some of the diagnostics in buccal swabs and organic acid testing for a long time. Mhmm. There's some newer tests out of Europe I'm I'm curious to share with you that I think are really Yeah. The ME screen is is looking at blood work that you can do at home. It's a home test.

Right? Yep. And we're gonna put the link to that. It's mescreen.com. What what are they actually measuring when they look at that?

Dr. Anurag Singh
They're measuring how the stress your mitochondria are. They they they look at a constellation of mitochondria read readout. So they look at something called as reactive ROS, right? So if your mitochondria are stressed, they can

Dr. Mark Hyman
Or free radicals. Free radicals.

Dr. Anurag Singh
Are looking at complex one and complex two 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
Yeah. Because I think I think being able to measure it and what's happening is important because, you know, we wanna look at your mitochondria and we wanna see the effect of interventions, we wanna know what you're doing. And, again, it's not something we've really thought of focusing on in medicine. There is one mitochondrial story I wanna want you to kind of finish up by telling, which I think is important Mhmm. Which is what 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

Dr. Anurag Singh
Statins.

Dr. Mark Hyman
Statins. Right? So cholesterol medication. Tell us why why these medications are harmful to mitochondria, what they do Mhmm. And if we should really be worried about it

Dr. Anurag Singh
or not. At a higher level, there are mitochondrial toxins and they deplete these sort of electron transport chain and co q ten 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 have, they come to you with muscle pain and things like, in the extreme cases, rhabdomyolysis, which is really disintegration of the We haven't done anything with nutritional interventions and statins, but I think the body of evidence is that they really are damaging to the mitochondrial network and the electron transport chain.

Dr. Mark Hyman
Yeah.

Dr. Anurag Singh
And co q ten levels are very low all those who get statins.

Dr. Mark Hyman
Yeah. Because the same pathway that makes your LDL cholesterol also makes coenzyme q 10, which is one of the mitochondrial helpers, cofactors. Yeah. And so you're kind of screwing yourself. So anybody who's on a statin has to be on coenzyme q ten.

Mhmm. The question is, does it mitigate the damage or not? And how

Dr. Anurag Singh
To a certain level, I I believe it does. But co q ten is not also very highly bioavailable compound when taken orally. And and so there have been attempts at making liposomal co q ten and things like this to make it, you know. But I do think something like either NAD supplementation or cleaning out the waste with Mitopur could could go a long way. And this is something we 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 it's for a study, they see it as a drug trial.

And so that's always the

Dr. Mark Hyman
Yeah.

Dr. Anurag Singh
The risk of doing that trial. Yeah. And that's why we haven't done it.

Dr. Mark Hyman
Yeah. But I think I think it's important and I think, you know, I 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 the steroids also. If you throw steroids on muscle cells, we have seen that, that they have a very sort of detrimental impact.

Dr. Mark Hyman
You mean prednisone. Yeah. Like corticosteroids. Not like testosterone.

Dr. Anurag Singh
No, no, no. Yeah, more like cardio steroids. Yeah. And again, there's this buzz of the GLP one that, you know, with the GLP one story that in the twenty, thirty

Dr. Mark Hyman
percent You lose muscle.

Dr. Anurag Singh
You lose muscle. What's happening at the You know, it's almost like you're fasting, but you're not just fasting, you're not eating anything, right? And that has a It's a stressor to mitochondria. So I think you will see a lot of mitochondrial research come out with these GLP one drugs.

Dr. Mark Hyman
That they're bad for them.

Dr. Anurag Singh
Potentially, but the research needs to show that.

Dr. Mark Hyman
That's concerning. That's concerning because they're, you know, getting used for everything everywhere all the time. We we covered a lot of this, but I I wanna sort of bring it bring it home a little bit and conclude by talking about some of the science based evidence approach to longevity and to, how people can support their mitochondria and Mhmm. 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.

Dr. Anurag Singh
Low sugar. Exactly. Try to

Dr. Mark Hyman
Good fats.

Dr. Anurag Singh
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, you know? 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 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 three sixty holistic view of how you do approach mitochondria.

Dr. Mark Hyman
I think that's a that's very sound good advice. The 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 it affects your microbiome and it naturally make your lichen a. But two, you know, mitochondria historically came from bacteria. So they're basically a symbiotic relationship

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
With bacteria and humans.

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
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.

Dr. Anurag Singh
Mhmm.

Dr. Mark Hyman
And and the question is, do antibiotics hurt mitochondria because they're basically come from my bacteria?

Dr. Anurag Singh
They're certainly stressors. There's enough studies showing there are mitochondrial stressors. Now, I think it really depends on the duration of usage, the dose, 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 strategy 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 therapies. So I think this parallel sort of, I don't wanna say more medical diagnostic or 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. 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. Yep. There's also hypoxic therapies where 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 UroLatin 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, this is the way research is gonna go.

Dr. Mark Hyman
Fascinating, fascinating. So what is the most exciting that's coming down the pike 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. Know, twenty years back when I was training as a physician immunologist, I didn't think that medicine would bring me to a state place where suddenly by reversing your immune health, you can do that with a 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, things like intermittent fasting, things integrating nutritional supplementation. 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, Doctor Singh, for being on the podcast and for enlightening us with all the work you've done on mitochondrial health, how critical it 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. It's hard Mhmm. Tedious work sometimes.

But the results are pretty exciting, and I I think we're gonna look forward to hearing more and more over time about how this can apply to a broad range of problems from cardiovascular health to immune health, the 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 mitapure, which comes in many forms. It comes in powder and pills and now gummies, which are yummy. And we're gonna also, you know, talk about in the show notes some of the the sort of suggestions we talked about on 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, Mark.

Dr. Mark Hyman
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Dr. Mark Hyman
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Dr. Mark Hyman
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