Fight off the Effects of Aging Using Oxaloacetate with Alan Cash

In this episode, Alan Cash talks about oxaloacetate and the beginning of his journey in developing it as a nutritional supplement. He shares the ongoing research on oxaloacetate's benefits, especially for patients suffering from brain damage. He also dives into oxaloacetate's ability to increase muscle use before fatigue and reduce anxiety and depression levels in women experiencing PMS.

If you want to learn more about oxaloacetate's many benefits and applications, then this episode is for you!

3 Reasons to Listen:

  1. Learn what oxaloacetate is and how it can help slow the biological effects of ageing.
  2. Discover the numerous potential health benefits of oxaloacetate.
  3. Get to know Alan’s journey in developing and manufacturing oxaloacetate as a nutritional supplement.

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Episode Highlights

[09:36] How Alan Found Out About Oxaloacetate

Alan got sick and needed to undergo brain surgery. He found out that his pain and illness were related to ageing. As Alan researched more about ageing, he discovered calorie restriction, wherein organisms tend to live longer when they eat less.

Increasing the ratio of Nicotinamide Adenine Dinucleotide (NAD) to NADH helps fight off ageing. Alan started looking into biomechanical pathways and found that oxaloacetate that can change the ratio of NAD from NADH to 900% in just two minutes.

Alan started testing oxaloacetate using worms and realised that the activated pathway was the same as calorie restriction.

[21:53] What is Oxaloacetate?

Oxaloacetate is a naturally occurring molecule in our bodies during metabolism. It exists in every cell of the body and, therefore, is non-toxic. 

Oxaloacetate is considered a hot molecule right now, given how it can help moderate metabolism on a cell-by-cell basis. Increasing oxaloacetate affects metabolism, which is vital to some people.

[25:38] Patenting Oxaloacetate 

Tohoku University in Sendai, Japan, conducted research in the 1960s which found how oxaloacetate reduced fasting glucose levels in type one and type two diabetics. 

At first, Alan ran into the problem of being unable to get a patent for oxaloacetate, a naturally occurring compound in the human body. He persevered and eventually was able to own patent rights based on how oxaloacetate can maintain its stable form of enol-oxaloacetate. 

After rigorous testing, their products now have a shelf life of two to three years or more.

[31:00] Oxaloacetate and the Warburg Effect

Oxaloacetate is a potential drug for brain cancer such as glioblastoma. It also has the potential to reverse the Warburg effect, in which fermented glucose turns into lactate that a tumour feeds off.

Giving Oxaloacetate to cancer cells changes the cancer metabolism cell by cell. There’s a specific dosage where cancer cells stop reproducing.

[38:03] Oxaloacetate and Glutamate

Glutamate is a compound that fires off the neutrons in the brain. Excessive glutamate excites the neurons until they die, a process known as excitotoxicity. Many studies describe how we may reduce the risk of excitotoxicity. 

Alan is looking into cognition through clinical trials with Alzheimer’s disease patients. The study showed how oxaloacetate reduced glutamate levels. In the same clinical trial, they also found how oxaloacetate increased the amount of glucose the brain can take in.

The brain can take in more glucose due to the signalling protein PGC-1 Alpha enabling the production of more mitochondria.

[38:03] Oxaloacetate Can Improve Muscle Use

Oxaloacetate also improves muscle use by 10% more before it goes into fatigue. 10% is a significant improvement for both top-end athletes and daily living. Alan has done a clinical trial that showed a 25% to 30% drop in fatigue levels within six weeks, even for people with chronic fatigue syndrome or ME/CFS for up to 30 years.

NF-κB turns on genes that release a cytokine storm, which at high levels can lead to chronic inflammation seen in arthritis or long COVID patients. Animal models show that oxaloacetate led to a reduction of NF-κB’s translocation to the nucleus by 70%, which turns off the cytokine storm. 

People experiencing chronic fatigue can benefit from oxaloacetate’s mechanism of producing new mitochondria. 

[51:34] Increase Focus and Attention Using Oxaloacetate

In animal models, oxaloacetate turns on the mechanism to increase the number of neurons in the brain and increase the length of the axons, the little tendrils that connect neurons.

Alan did a critical trial on the effect of oxaloacetate on premenstrual syndrome (PMS), wherein he found a 50% drop in anxiety, depression and suicide ideation. Drugs have an immediate pharmacological effect. Another is the genomic effect with a cumulative property that takes about a month or more to see.

Even after getting better from your illnesses, keep the ball rolling and don’t stop intaking your medicine and supplements.

7 Powerful Quotes

‘We could see when we gave the oxaloacetate to them if they live longer, or if they didn't, so we could eliminate what were the critical genes. And, we were able to follow along with a pathway, and it turned out to be the exact same pathway as calorie restriction, which is really exciting.’

‘First of all, is oxaloacetate toxic? Well, it turns out it's a human molecule. It's in metabolism. It's in practically every cell of your body.’

‘Experiment and see what works and understanding some of these mechanisms is really important because then we can actually start to connect the dots of cells.’

‘The reality is most people are not going to have the perfect diet, not going to be in a perfect environment, can't maybe even afford to have great food, or organic food, or all of these things that restrict us from having the ideal.’

‘None of us are going to know what's around the corner for us but, if we can be in that preventative space and be understanding this more and more, then that is to me the most fascinating conversation we can have.’

‘What happens then is that they stop all their protocol, and the thing that they were doing and, “Now I'm fixed. I don't need it anymore.” And I'm like, “Hang on a minute, you don't drop the ball now. You're already underway. You got to stay underway. You got to keep it going.”’

‘You want that cumulative, and those epigenetic changes, and those long term changes.’

Resources

About Alan

Alan Cash is a physicist, biologist and geologist. He's also a professional entrepreneur and the CEO and Founder of Terra Biological LLC and MetVital, Inc. 

Alan is also the clinical trials supervisor and medical researcher. He’s currently pursuing the advancement and development of nutritional supplements containing oxaloacetate, which is known as a caloric-restriction mimetic compound. His research has brought profound breakthroughs addressing cognitive decline and anti-aging.

If you want to reach out, you may connect with Alan via LinkedIn.

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To pushing the limits,

Lisa

Transcript

Welcome to Pushing the Limits, the show that helps you reach your full potential with your host, Lisa Tamati, brought to you by lisatamati.com.

Lisa: Hey everybody, welcome to the show this week. Now today, before I get underway, just want to thank you for staying loyal to the show and giving us ratings and reviews, we really, really appreciate it. We're getting up there now and the download numbers. We really, really appreciate it, it's been going now for seven years. A lot of hard work, I can tell you a big team behind the scenes. We're very, very grateful to all our patrons who helped keep us on air. For those if anyone is interested in actually sponsoring the show, we would absolutely love to hear from you if you think you've got a product that's aligned with what we do. So all about longevity, anti ageing, high performance mindset. Being the best version of yourself that you can be. Today's guest is Alan Cash. Now Alan is a physicist. He's also a biologist, and he's also an entrepreneur, a very, very interesting man. Today, we're going to be talking about a molecule called oxaloacetate.

Now, that might sound very boring, but I can assure you it's not. I came across this molecule in my research for my mum trying to find things for cancer. It came up on one of her advanced genetic testing tests that we did that oxaloacetate, she would respond to that for her cancer. So I went on a deep dive into what the heck is oxaloacetate and found Alan's research. So I want to share with you today all about oxaloacetate. What it does, bear in mind, Alan is not a medical doctor, this is not medical advice. But I encourage you to search out the links that we'll have in the show notes, hopefully, for you with all the references to do your own research into this molecule. I am also going to be bringing benagene, which is a supplement that Alan after all his research, 20 years of research has now produced, I'm going to have that in my anti-ageing and long health supplement range. So make sure you do check out there.
If you want more information, of course, you can reach out to me. Now what does oxaloacetate do? We have to be very careful what we say it doesn't doesn't do because it's a lot of clinical research around going around it. But I'm super excited about this molecule, it's a, it activates anti-ageing genes, and increases the energy production in the cell and helps with your endurance. So for all those athletes out there that are wanting more muscle endurance, more cardiovascular performance, this is one that you might want to check into. It helps reduce inflammation. Of course, inflammation is at the base of many of the ageing diseases that we see in preventing inflammation and things like cytokine storms, if you have been dealing with any types of viruses or any arthritic conditions or any other inflammatory conditions, where the inflammation is sort of turned on in the body and you can't turn it off. This is an interesting molecule to research.

Now, Alan actually came across this in his research around calorie restriction. Calorie restriction is one of the things that we can conclusively say in the scientific evidence that it extends lifespan when you don't eat so much. Which is a pain in the butt because most of us like to eat nice things and we don't want to starve ourselves all the time. So that got Alan thinking about what are the types of pathways that are being impacted by this? And how can we make a mimetic? A mimetic is something that sort of mimics the pathways that are involved when you do calorie restriction. He came across a oxaloacetate. Now originally, the research was done in Japan, by a group of scientists over there for diabetics and had huge results. He was like, Well, why is this not being researched? Further, he flew to Japan, talked to the scientists and they said well, we can't patent it, therefore, it's not going to go any further this research. Therein lies the problem with the whole system to be honest. He then decided he was going to go and find a way anyway to research this chemical and this molecule and he has.

Now it is naturally occurring chemical it's in the body. It's in every cell of the body. So it's pretty much a non-toxic and very safe thing to be thinking about and helps. So as it acts as a calorie restriction mimetic, so it's like having your cake and eat it too. It's probably a bad analogy because you shouldn't eat cake but you know what I mean? So without having to starve yourself, you get the benefits of the fasting. There are a number of molecules that do this. I've covered a few of them in this podcast, and I'm on quite a lot of them. It's one of the ways that I helped maintain my body shape and my function and my metabolic health, above all, not to mention my brain function. So yeah, on that point, healthy brain function, because it acts like it's a ketone body. Ketones are very, very beneficial for brain function, any sort of neuro inflammation, things like that. We've discussed it in depth on this podcast prior. It also acts as an antioxidant and inactivates, reactive oxygen species. So lots of reasons to be loving this molecule. It really optimises health on the cellular level. So great for athletes, it's also got some interesting research. I encourage you to go and do the research and not just listen to this and jump into it for but for things like brain cancer, when there's not a lot out there that you can do for that or other types of cancers.

As I said, I've been using it in my mum's protocol. So many reasons to be loving this molecule. I really enjoy learning more about it. So without further ado, we'll go over to the Show With Alan. If you want some more information about the programs that we run, I would love to help you. Of course, we I do a lot of health optimization consulting. On the individual level, Neil and I also do corporate wellness programs. We have our epigenetics and DNA programs that we run as well that helps you understand your genes better, and how to optimise those genes. We'd love you to reach out and find out a bit more about epigenetics and our DNA testing programs, and about our Health Consulting as well. 

We also have Running Hot Coaching, as well as for all those athletes out there that are wanting to run better do more. So make sure you check all that out. My anti ageing and health supplement range we have NMNbio, which sits on its own website at NMNbio.nz, and that's with Dr. Elena Seranova, who's been on the show a number of times. That's, again looking at longevity and anti ageing science and is this this is yet another molecule that we can put into the mix alongside that but in NMNbio, we have nicotinamide mononucleotide, quercetin and TMG, also known as trimethylglycine, in our range at the moment, and then over on lisatamati.com, which is my main website. I have a few other products as well like Perfect Aminos, which I have with Neil and I can put the links below to that one. We have exogenous ketones from Keto Pro in the UK, which is a fantastic product and keto bars. We have colloidal silver, and we have black cumin seed oil, and that list is growing all the time. Now we're going to be having benagene which is what we're talking about today. That is the oxaloacetate molecule that we're discussing with Alan.

So without further ado, thanks for listening. We'll see you on the other side of this interview. Hey, everyone, and welcome back to Pushing the Limits this week. I have a fantastic, fascinating gentleman for you today. I have Alan cash. Welcome to the show. lovely to have you. You're sitting in San Diego. I'm sitting in New Zealand.

Alan Cash: Yeah, we both have great weather, right?

Lisa: Yeah, well, yeah, we've got a beautiful day to day. So we're heading into winter, you guys are on the way to summer. So you've got the best time here to you, Alan, today we're going to do a deep dive into a product that or a molecule that you've been studying for a very, very long time called oxaloacetate. You have a background as a physicist, can you give us a little bit of your background before we get underway and start talking about this interesting molecule?

Alan: Sure. I've been both a physicist and a geologist, which is a interesting combination in terms of looking at things like climate change lately, it's a little scary. But in my background, I've also been a professional entrepreneur. I've started a variety of companies, including a company that took DDT and PCBs out of soil, inexpensive. I did that in Australia and Japan. The US worked for the EPA, the Department of Defence, the Department of Energy, and then sold that company. While I was working for that company, I got sick. It wasn't because of the toxins that we were dealing with. It was because as we age, your arteries and veins continued to grow. They get longer and I wasn't growing. Well. At least I wasn't growing I'm taller, I was going a little wider. As that happened, the arteries and veins had to have someplace to go. So they fold over. They just keep doing their job. 

Unfortunately, one folded over next to a nerve. As my heartbeat, it served as a little saw, that eventually cut through the myelin sheath in the nerve, and then into the major nerve bundle in my brain. The effect was like putting a cattle prod to your head. It was on a pain scale, zero to 10, it was a solid 10 didn't know what to do. It would fire all at once. Then I would be pain free. I just be like, You know what just happened, so I went around to various doctors, my wife called up a lot of different doctors and said, I'll take the first cancellation. In that way, I was able to get in to see about 21 doctors in a week. Nobody knew what it was until I came to this neurologist. He said, Well, it's it's this impingement. We can give you a bunch of drugs to help with epilepsy, which will reduce the seizures and reduce the pain. So I took those and being the scientist I was watching my dosage versus the amount of pain I was in and quickly realised that I was going to get to the toxic limit very quickly. 

So I went on the internet, and I found two places in the United States that deal with this particular thing. One was on the East Coast, on the west coast in California. The other one was two miles from my house. I called them up and the head of the department answered the phone. I told him what was going on. He said, Oh, you've got to come in tomorrow. So I went in that day, it was a Friday, and he asked me two questions, you know, was it in an immediate start of this problem? And have you had an MRI? I said yes to both of them. He looked at my MRI results, he said I can't see anything. So that's probably what it is. He said, we can go and do surgery where we'll separate the two things and put in a little piece of Teflon. Then they won't be able to, you know, interfere with each other. He said, but I can't get the nurses this weekend. So I'll rearrange the hospital's operating schedule. On Monday, we'll go Monday morning.

Lisa: Wow.

Alan: They did a three hour brain surgery on me where they went into the back of my head. They followed the vein, or the artery until they could find where it crossed over. Then they just gently pulled it apart and put in a piece of Teflon and sewed me up. Wow. I've been pain free for the last two years, which is an amazing story. If if we can find out what the mechanism is, and correct that we can then correct the symptoms. At that point, you know, I was very thankful, obviously because my life had returned. It was pretty bleak there for a while. The other thing is that I realised that this was all caused by ageing. So as a physicist, I started looking into, you know, how does ageing affect us? And what can we do about it?

And what I found is that there's not much we can do about it. You know, there. I mean, people have been trying to do like pyramids and things like that just doesn't work. There are some things that do work, and they're very limited. One is calorie restriction. When we give animals 25% less than they would normally eat if you gave him a bowl of food every day and said eat what you want. If they eat 25% less, they typically live about 25% longer. Yeah. That doesn't make sense at all. Because it seems like if you're if you're eating less and getting less energy, you should have less energy to live with. But that's what we've seen and we've seen it all the way from single cell yeast all the way up to primates. Monkeys that we we've done calorie restriction studies on everything. 

There are some exceptions like lobsters. We don't really understand lobsters. But lobsters. But outside of being a lobster restriction seems to work throughout the animal kingdom in reducing ageing and reducing the side effects of ageing. You know, some of the chronic diseases, yes. Which is incredible. So the question you have to ask yourself is, why are we all fasting on a regular basis? Because I tried it for a month, and my wife was so happy when I stopped. She suggested that I was irritable.

Lisa: Of course, that's not true, I'm sure.

Alan: So I started looking at the molecular basis of fasting and what was happening in the body. I realised that some work being done out of MIT and Harvard Medical School, primarily in yeast models, was looking at something called the NAD to NADH ratio. Yeah. Some of your listeners may be familiar with NAD or NADH, it's nicotinamide adenine dinucleotide. So we call it NAD. And NADH is just with, you know, it's the reduced version, or the oxidised version, I can't remember which, but anyway, this ratio seemed to be key. So I thought, Hmm, this is interesting. Some people I think, Dave Sinclair, and Lenny garante. Yeah. If you could increase this ratio, you would, and they did it with genetic engineering, because they're really smart. I'm not that smart. So I started looking for a way to increase this ratio so that I could see the increases in lifespan. I started looking at the biomechanical pathways. I found oxaloacetate.

If you put in oxaloacetate, it degrades due to the enzyme dehydrogenase. In doing that, it takes NADH and turns it into NAD. A guy named Krebs actually measured this change. You know, Hans Krebs. Yeah. Yeah, you've heard of him. He found that within two minutes, you could change that ratio by 900%.

Lisa: Crikey.

Alan: With oxaloacetate, I thought, you know, that's insane. So then the question was, is will it actually work to mimic calorie restriction? And so I brought this idea, you know, I'm a physicist, I don't know what I'm doing as far as biology. So I brought it to a guy, a professor at UCSD, Dave Williams, and he's this. This guy's brilliant. He's one of the smartest people I've ever met in my life. I told him the story. He just looked at me. Then he got up and walked out of his office. Really offended this guy. Then he turns around to me, and he says, "Well are you coming?" Funny thing is Dave's in New Zealand also.

Lisa: Oh, wow.

Alan: Yeah. So I get up and I follow him and he goes downstairs, he takes up this big ring of keys and he puts a key in a big steel door and opens it up. There's this huge laboratory back there that that he's in, you know, the head researcher. He walks over to one of the benches he takes his arm goes and just pushes everything aside. It goes. This is your spot. Talking about a physicist, I don't know what he goes, how tough can this be? We'll get some flies. You'll give him oxaloacetate; they'll either be alive or they'll be dead. Then you'll know

Lisa: So you started your career and rated

Alan: Yeah, yeah. Well, I yeah, I had done some research before because I am a physicist, but I had the we started off with actually little worms called C. elegans because you are much more known. Flies are kind of an outlier. Insects are a little bit weird. But we did try flies eventually. Then we went to mice, and then we went to humans. But that's, that's how I got my start with oxaloacetate is is in worms and my wife thought I had lost my mind because I was going into the college, you know, UCSD every, every day, looking in microscope, counting worms that I given oxaloacetate and shift. What do you what are you doing? And so we established that they live longer, which was really cool. Because there are not a lot of things that do that. 

Then we started ordering specialty worms that had certain genes that were defective. We could see if when we gave the oxaloacetate to them if they live longer, or if they didn't. So we could eliminate what were the critical genes. We were able to follow along with a pathway. It turned out to be the exact same pathway as calorie restriction, which is really exciting. We published that in the journal ageing Cell. You know that that was fun. You know, everyone should have a hobby, right?

Lisa: This seems a bit more than the hobby.

Alan: Yeah, yeah. Then I thought, you know, then we did, like I said, we did flies we did mice, we saw lifespan increases in both of them. We thought, Well, what about human beings? You know, first of all, is oxaloacetate toxic? Well, it turns out, it's a human molecule. It's in metabolism. It's in every practically every cell of your body. Because it's in the citric acid cycle, in your mitochondria to produce energy. That's exciting. So we spent some money doing some toxicity testing, we tried to see how much we could give animals before they they didn't do well. We couldn't get enough into them. 

We got up to like 5000 milligrams a day, which is the equivalent to about 3600 capsules of our nutritional supplement in one day. They were still like, we did long term testing and looked at, you know, all sorts of liver function and blood work. We had to do autopsies on the animals. So the good news for the animals is some of them got the oxaloacetate. They got to live longer.

Some of them got the oxaloacetate. We had to sacrifice them to see what was going on. So it was a mixed bag for them. But what we saw is, is the stuff is essentially non toxic. So we thought, you know, this might make a really interesting nutritional supplement. But I wonder if anyone's given oxaloacetate to people before, I mean, it's fine to do all these animal tests, and it's really cool to find something that allows animals to live longer. You know, Dave Sinclair actually came and visited our lab when he found out

Lisa: He's one of my heroes. I love his work

Alan: And yeah, yeah, I mean, he, he looked at me and just said, "There's not many people who can extend lifespan."

Lisa: Exactly.

Alan: Like, oh, okay. I'm with a biologist. So, it, yeah, it is exciting to be able to do that. Will it work in people? You know, we haven't run a long enough tests to really be able to know. I mean, you'd have to do it for 100 years. Yeah. You know, so we look at short term things now, that are a little bit more measurable. Some of the exciting I mean, oxaloacetate is is a hot molecule right now. Because it turns out that it helps to moderate metabolism on a cell by cell basis. When we can increase the amount of oxaloacetate it actually changes how metabolism occurs in the cell. Right? That's can be really important to some people.

Lisa: This is where I wanted to dive in if I can and start talking about this as you have developed a natural health supplement called oxaloacetate. I came across this research because I was searching for my mom who has cancer and lymphoma, and oxaloacetate came up on one of her advanced gene tests is being something that she will respond to. So this has how it came on my radar. Then I started to do the research and came across your work. I know that this was done in I think, in the 60s in Japan, where they did diabetic research, it found was actually beneficial for diabetics. But it wasn't further that story was fascinating. Can you tell me a little bit about that story?

Alan: We, when we were thinking about this as a nutritional supplement, I came across a clinical trial that was done at Sendai University, or no excuse me, Tohoku University in Sendai, Japan, which is by a nice little town called Fukushima, which had some other problems. Yeah. Anyway, I flew to Japan, to talk to them about this study that was done in the 1960s. They spoke English, because my Japanese was not very good. I held a paper and said, you know, is this paper from your department? 

And they said, Yes, yes, we did that work. And I said that that's great. I only found one study that showed that oxaloacetate reduced fasting glucose levels in Type-1 and type Type-2 diabetics. He said, That's pretty important. They said, ‘Yes, it was very good result.’ And I said, ‘Where's the follow on work? I mean, did someone die?’ And they said, ‘No, no, no, no one died. You know, what's wrong with you?’ Um, they said, it's a natural compound. I said, Yeah, it's a natural compound. And they said, Yeah, no patent rights.

Lisa: Therein lies the problem.

Alan: And that was the end of our conversation. Well, you know, I figured I was looking at this a different way. I thought, if this is a helpful compound, let's get it out there. Yeah. You know, and, as it turned out, we were able to get some patent rights because oxaloacetate has a big problem. If you put a jar of it on your kitchen table. In about a week, it will break down into carbon dioxide and pyruvate. Neither of which are toxic, but neither of them are oxaloacetate. They don't have the same property. But we had to figure out how to stabilise it.

And we did that by it turns out that oxaloacetate occurs in two major forms, one is a keto form, in which the four carbon molecules are in a straight line. The other one is an enol form in which the four carbon molecules are in a L shape. The keto form spontaneously breaks down in moments, and the enol form is stable. So what we had to do is first manufacture it into the enol form. Then we had to deal with the fact that there's a catalyst that changes it from the enol form to the keto form and back.

And typically what happens with oxaloacetate is changes from the enol form to the keto form, and then the keto form disappears, and then the oxaloacetate is gone. Well, the catalyst is water. So we manufactured it in the anhydrous way. We have to manufacture it so it's very, very dry, and only in this eternal form. Then when you swallow it, it turns into regular oxaloacetate, keto and enol, and it's used up by the cells in about an hour. So it doesn't matter if it takes a week to break down. So we were able to get a composition of matter patent done on the anhydrous enol oxaloacetate which has about a two year shelf life so we can send it out now as a nutritional supplement, medical food, or or drug

Lisa: And it was combined with vitamin C.

Alan: We found that vitamin C helped to stabilise it. So for our nutritional supplement, we combine it with vitamin C to get a longer shelf life for our medical food and our drug. If you combine it with anything else, the FDA makes you do a clinical trial on both ingredients separately, and then the combination. So your cost just tripled. So we're, yeah, isn't that interesting? So we're just doing it with oxaloacetate. We just keep it in the refrigerator and refrigerated we get, you know, so far about a three year or more shelf life.

Lisa: It's for the medical food.

Alan: Yeah, for the medical food and for some of the applications we're looking at as a drug.

Lisa: So we'll if we go into a little bit into that research, they're doing some research around brain cancer and using this medical food for brain cancer. What are the mechanisms of action? Why it would be beneficial for some, perhaps for some people with brain cancer or cancers in general? Like what are some of the reasoning behind the mechanisms that could be working?

Alan: Yeah, I'm there. I have to be a little bit careful here because I manufacture a nutritional

Lisa: Yeah, and you're not a doctor?

Alan: Yes, supplements are made to keep healthy people healthy, and are not to be used as drugs. The dosages we use in our drug studies are much higher than we use for nutritional supplements. But what's going on with oxaloacetate as a potential drug for things like glioblastoma, which is brain cancer. The FDA has looked at our data, and they've given us something called an orphan drug designation, and they track designation to try to move this along faster. Because the data is very compelling. Is that because oxaloacetate can modify metabolism, there's a certain metabolism of cancer cells, where you take in a lot of sugar, a lot of glucose, and instead of running that, that glucose through pyruvate, and then into the mitochondria and burning it with oxygen, okay, which is what the mitochondria does, they're little power plants within our cells. Instead of doing that, there's a mechanism that's very primitive in our evolution, where you can ferment that sugar.

That goes into lactate. So they call this the Warburg effect. familia. Yep. Yeah, Otto Warburg. He was a German scientist back in the 1930s. And discovered this, and pretty much most solid cancer tumours have this Warburg effect going on, where the cells are making energy in a different way. They're doing that as a defence mechanism. Because, you know, there may have been some insult or some problem. Some gene didn't turn on properly. It said, okay, don't go to this other mechanisms.

Lisa: Primitive form.

Alan: Yep. When it does that, unfortunately, it makes a lot of what we call ROS, which is-

Lisa: Active. Yeah, reactive oxygen species.

Alan: Yeah, exactly. Those mess with everything in the cell, they're kind of a random shotgun thing where they're floating around, and if they hit DNA, they, they can damage it. You know, your cell can repair these things, but only to a limited extent. So you've got, you've got all these bullets flying around now that your cells making this odd energy in order to continue on, and then the lactate that it produces exports out of the cell, and helps to feed other parts of the tumour that can't get energy from anywhere else. Because the vasculature hasn't grown in there. So it doesn't need oxygen, it can survive in these anoxic conditions. It allows the tumour to grow and it also allows the tumour to spread to other areas. The body so not only does the tumour get bigger, but it becomes more lethal.

What oxaloacetate has been shown to do just recently is reverse the Warburg effect, actually force the cell into making energy out of the mitochondria, instead of fermenting it in in the cell in the main part of the cytosol of the cell, and making lactate. So you would think, well, okay, if we can change cancer metabolism cell by cell, the tumour should grow less. We've been able to show that when you give oxaloacetate to cells, the proliferation of those cancer cells drops off like a rock, but only at a certain amount. So you have to feed it enough so that it works. But before that, it has no effect on the cell, and then all sudden, and the cell stops reproducing.

Lisa: The dosage is as an important thing. Yeah.

Alan: Yeah. So you want to get to the dosage up high. Then there's always the question is, is it getting to where you need it to get to?

Lisa: Exactly.

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Alan: We just recently looked at oxaloacetate and the mechanism of how it brings itself into the cell. How are we getting it in there? How much is getting in there? It's all been pretty fascinating research. So that's one way that it works. Another way that it works is there's another compound in the brain called glutamate. There's a lot in your cells, okay, so there's a lot in yourself and then outside of your cells. Glutamate is used to fire off the neutrons in your brain. So it's essential. But a lot of people have too much glutamate.

Lisa: I definitely do.

Alan: If you have like circular thinking where you try to calm it down that may be a sign of have too much glutamate. If you get head injury, the first thing that happens is the cells get ruptured, they release all this glutamate, like 1000 times more on the inside of the cells than on the outside. That excites your neurons. So fire off until they die, they die. It's called excitotoxicity. It's a big problem with any kind of brain damage from a stroke or injury or diabetic problems. So, oxaloacetate has been shown in many studies now to be able to go into the bloodstream and it combines with a liver enzyme, glutamate oxaloacetate transaminase, which is called AST nowadays, and bind up that glutamate and make alpha-ketoglutarate which is is not doesn't cause this excitotoxicity and by just bringing it down in your in your bloodstream like this. You can then also make the glutamate go across the blood brain barrier. In lower glutamate levels in the brain, so

Lisa: Wow, it's amazing. Like someone is someone who's, you know, worked with people with brain injuries and strokes and dementia and had a mum with her own brain injuries, anything that can stop that, that excessive glutamate is something that should be on our radar. So I just wanted to sort of highlight that that's a really important finding for people with anything from concussions to strokes.

Alan: So we don't have the research to prove that in humans, all that research was done in animals. That's one of the things we're looking at is cognition. We're looking at, for instance, Alzheimer's patients, finished a phase one clinical trial in that.

Lisa: Excellent.

Alan: And one of the neat things we saw there is, is not only did we reduce those glutamate levels, but we were able to increase the amount of glucose or sugar that the brain could actually take up and use.

Lisa: Wow. Because it's the other thing that happens, of course, with brain problems is your inability to uptake the glucose.

Alan: Yeah, yeah. So that's good. Then we also saw an increase in mitochondrial density. There's, there's a signalling protein called PG-1, PG-1 Alpha. Anyway, that up regulates and we're able to get more mitochondria to build. So we're producing more mitochondria, the little power plants of the cell. We allow the cell to take in more glucose, then we force that glucose to go into the mitochondria to burn instead of being fermented. So it's like a triple whammy, yeah. Providing energy for what you need to do. This has a lot of repercussions. We did some muscle testing, where we mounted a single muscle cell onto a plate that measured its force. Then we did the old frog legs experiment where you electrify it. That makes that happen, and we measure that force. Then we measure it over and over again, in like just short bursts, so that we can see over time, the muscle will all of a sudden start losing its ability to contract. You arbitrarily pick a fatigue point. So let's say 80% of where it used to be, you can pick say that's okay, that's fatigue. When we give oxaloacetate to that muscle, you know, just put it in solution and with with the muscle, we can get 10% more time out of that muscle before it goes into fatigue.

Lisa: That's huge for athletes, to athletes for picking up.

Alan: So we have some Olympic athletes that take oxaloacetate prior to both working out and also to competition. Because it's a human metabolite, it's not a banned substance. Especially if they're dealing with, you know, most athletic competitions are, are on 1/10 of 1% difference. Absolutely. Yeah, at the upper levels, that 10% difference in endurance would do.

Lisa: It's huge.

Alan: And, and more to the point. Imagine an older gentleman, like myself, who just needs a little bit of a boost to, you know, get through the day to be able to walk without tripping, things like that. I mean, there are a lot of different uses for this. We, as matter of fact, we just finished a clinical trial in something called chronic fatigue syndrome. It's also called MECFS. What we saw the some of these people had had a disease Well, it's not a disease according to the FDA, it's a condition. But they've had this condition for up to 30 years, where if they exercise at all, it might just wipe them out. They could take a week or two weeks or three weeks to get back on track where they can just barely, barely live and it's just shocking that we been able to do very, very little for these people. because there's not a lot that that affects fatigue. In muscles, I mean, you can give caffeine, but that caffeine really affects the nervous system, not muscles.

 Caffeine only works for a short period of time, and then you get used to it. You know, you can only have so many cups of coffee, and then it doesn't affect you anymore. So being able to affect fatigue is really exciting research. We showed in our clinical trial, that we're able to get about a 25 to 30% drop in fatigue levels within six weeks, even in people that that had chronic fatigue syndrome for up to 30 years.

Lisa: Wow. And that would be like showing them the mitochondrial density.

Alan: There are five things we've figured out, and we don't know which ones are the most important. One of the things we see in people who were heavily fatigued all the time, and we're starting to see this with long COVID patients too, which is really scary, is they have chronic inflammation.

Lisa: Because of ageing and stuff.

Alan: Yeah, there's something called the NF-kappa, B pathway. That's a protein that sits in the cytosol. When you have an event where you need a bunch of energy, to fight disease or to fight an injury, it translocates to the nucleus, it opens up the DNA chromatin. It turns on genes that then release a cytokine storm to deal with the disease or deal with the injury. That's a great thing. Unless you can't turn it off.

Lisa: Yeah, it's the turning off of that cytokine storm, isn't it? That's it. This is a chronic inflammation for everything from arthritis.

Alan: And so one of the things we've seen is, with high levels of oxaloacetate supplementation in animal models, and we're, you know, we're still testing this in people. But in animal models, we can reduce that NF-kappa B translocation to the nucleus by 70%. Yeah,

Lisa: And long COVID. Wow.

Alan: So we can turn off that cytokine storm. We think that's one of the things that's helping these people. Another thing we see with chronic fatigue is problems with mitochondria. So by making new mitochondria, we're perhaps helping that by increasing the amount of glucose that can come into the cell and be processed. We're improving the amount of fuel plus the number of burners that can burn the fuel the mitochondria. So there's a lot going on.

Lisa: Insulin resistance would improve in your ability to see AGEs your, you know, your end products glycation would reduce? Yeah, we we, we see all of that. So we're now in our second clinical trial, at the Bateman Horne Centre in Salt Lake City, we're independently and we're measuring all sorts of things in these chronic fatigue patients, and we have a controlled placebo group to compare against, and we shouldn't have that data by the end of the year. So hopefully we can help these people.

Maybe some of this research will translate to some of the long COVID people too. Absolutely, because this is always the frustrating thing that I've always been frustrated throughout my journeys into health and so on, is we understand the mechanisms of action, but we haven't got the clinical research and a lot of molecules that would be very, very interesting to study just don't have the backing, you know, either because they can't get patents or even therapies like hyperbaric oxygen therapy, which is starting to be more and more recognised, but honestly, it's such a brilliant therapy for so many things, but we need ongoing research. It's always frustrating is a patient or someone who works with people who have health issues when you have something that is possibly gonna be fantastic for them, but just sort of held up waiting for 20 years. 

As you know, I'm a biohacker I'm a bit like, you know, Dave Asprey. Try everything out on myself, you know, and experiment and see what what works and understanding some of these mechanisms is really important, because then we can actually start to connect the dots of cells and sort of work out, you know what, and when, where there's low risk, you know, when you've got. So like with your natural health supplement, I'm excited to get that because then I can try things for myself, I've definitely got a bit in the mix for my mum, in in, hopefully delay this ageing, because we're all running out of time, Alan, and we need to hurry up and get this research done. It takes so long, doesn't it, it's such a long winded process all of this.

Alan: You know, we try to dot our is and cross our ts.

Lisa: You have to.

Alan: The, you know, the toxicity studies, we, the animal studies, we're now doing the human studies, and hopefully that that works out so that we can help people. But in the meantime, I need to caution your listeners, I am not a medical doctor. So think of me as the guy changing the tire down the street, probably have the same knowledge base. The other thing is that our nutritional supplements are to try to keep healthy people healthy. They're not really designed to treat diseases. So just, you know, something to keep in mind. We're seeing that.

Lisa: Absolutely. Absolutely. We have to be very, very cautious. I wanted to just back up and talk about the hippocampus. I listened to one of your lectures or one of your interviews we were talking about. It's the oxaloacetate looks as if it's actually helping produce new neurons. That was like, 'Whoa, is that is that a thing?' Like can we produce new neurons even later on in life? What's state of research,

Alan: We used to think that the brain was very much an organ that once it was made, it didn't change, and that was really bad news for us that went to college and enjoyed, well.

Lisa: Too many beers.

Alan: But no, what we've seen, at least in animal models, is that the oxaloacetate turns on some of the mechanisms to not only increase the number of neurons in the brain, but to increase the length of the axons, the little tendrils that connect to other neurons. So you get a double whammy, you get more brain cells, and you get longer connections that can interact. Now, what does that mean? We don't know. It's better than the alternative of losing brain cells. That's one of the reasons we're looking at it for Alzheimer's. The other reason is that we've seen this increase in glucose uptake in the brain, which typically Alzheimer's patients lose the ability to pull up glucose into their cells into their neurons, which is why it's sometimes called, referred to as a type three diabetes. Yes. Oxaloacetate in clinical trials at higher dosages have been shown to improve that. So we'll see if anything comes of that. But

Lisa: Is it sort of similar to the keto diet, for example, uses exogenous ketones, what is you know, like oxaloacetate? That is a type of ketone from what I understand? It's exogenous ketones?

Alan: Yeah, chemically, oxaloacetate is a ketone. When most people talk about ketones, they're actually speaking about two other ketones that your body produces when you're in starvation mode. Oxaloacetate is not one of those. But it doesn't seem to matter because the brain can process oxaloacetate as an energy source. Even if you don't have, you know, even if you're in starvation mode, so that's kind of cool.

Lisa: So is it like beta hydroxybutyrate, in that way that you know, like if you've got beta hydroxybutyrate, that's going to help, you can burn it for a fuel source?

Alan: Yeah. Yep. Absolutely

Lisa: And that's why it can help. Wow, this is we've covered quite a lot of ground, Alan. How would this work, you know, for things like attention and focus. Again, with all the disclosures that we're not allowed to, you know, prescribe anything or even talk about medical diseases. But from a mechanism of action point of view, this should help with focus and attention. Being able to be calmer, if glutamate is not so pronounced in the brain.

Alan: Yeah, we, we've done a couple of clinical trials now that address that, for instance, anxiety, depression, and even suicidal ideation were shown issues. It was interesting. I, one of my doctors told me, you know, we had a patient, she came in, and she said, this stuff is great. I don't have PMS anymore. Being a guy that, 'Oh, that's good'. It was like, 'No, you don't understand.'  And I didn't understand. I didn't understand that, you know, about 10% of women who men straight, also have these terrible, terrible emotional swings. Some of them, it starts when they're, you know, 13 or 14 years old. It continues on, till they're, you know, in their 40s or 50s. They hide, you know, every month for two to three days, they'll they'll just disappear, and they'll just hide.

And it's because they know, if they're around people, they'll just snap their heads off, you know, and, and they don't want to lose their job, they don't want to lose their friends. They don't want to lose their their lovers. They want to be able to interact with their children. So they just hide. We did the clinical trial, and in oxaloacetate, and PMS. We did it as a double blinded, placebo controlled crossover trial, which is like the gold standard. We saw a 50% drop in depression, a 50%, drop in anxiety, percent drop in suicidal ideation. So it probably saved some lives. We've got that as a product, a separate product. It's but it's, again, it's oxaloacetate.

We then also looked at at a clinical trial we did in chronic fatigue syndrome, and one of the things we did was look at it as if it were muscular chronic problems, or if it were mental fatigue, like brain fog. We saw that oxaloacetate improved both of them. Which is really, really interesting. Because a lot of people you'll talk to that, like have a long COVID or other.

Lisa: Year inflammation going on. That lasts a long time. They'll go through all sorts of fatigue. It's not it's not just muscular fatigue. It's also it's also brain fog. Yeah, absolutely. So So Alan, you know, what can you do personally, in for you and your family? You know, not from medical advice point of view. But are you taking this regularly yourself after studying this molecule for how many decades now? It's been how long? 

Alan: Yeah, I've been taking it since we identified it as an anti ageing product. I'm actually 147. Well, it's not true. So I I've been taking it for over 10 years. Thankfully I'm very blessed with good health right now and and hopefully that stays. I can't blame it on oxaloacetate. It may be just genes, good genes, who knows, but it may have something to do with the oxaloacetate Yeah, you know, for anti ageing, you know, we're all wanting to find anti ageing things. I have a couple of products in the in the range that I have, like, nicotinamide mononucleotide, which, you know, Dave Sinclair talks a lot about, and again, that's looking at the NAD, you know, it's increasingly your NAD in the body, so so that would, you know, without understanding the whole, all the mechanisms involved, there would seem to be like, something along those same paths or pathways. We're trying to take advantage of the only thing that we really know that has increased longevity, and that's calorie restriction.

Lisa: Without having to do the calorie restriction so much.

Alan: Yeah. Yeah. Yeah, there's that.

Lisa: Yeah. We like food.

Alan: Yeah, it's good stuff. Plus, it's, food is important. Also, socially. I mean, there are so many of our customs revolve around sharing food together. Yeah.

Lisa: I, that's why it's anything that is a calorie, you know, restriction mimetic, or a senolytic, or, you know, something that improves autophagy, and gets rid of senescent cells, or anything that's along those lines that we can take. Because yeah, we all hopefully we're, you know, becoming more aware of eating more healthily and unprocessed food and, you know, organic, where possible, and you know, all of these things, but the reality is, most people are not going to have the perfect diet, not going to be in the perfect environment, can't maybe even afford to have great food, or organic food, or, you know, all of these things that restrict us from having the ideal.

So finding things that we can put into the mix that help improve that, and take advantage of the knowledge of these mechanisms of action and why that's helping, you know, why the lower calories helping people live longer, is just super important research, let alone from the whole possible drug development and disease management and all of these other things, which, you know, you're obviously going to spend the next few decades studying. This is the thing you've spent, how many years have you been involved in this? And, you know, we're near, I think people need to get a bit of an idea of how long it takes to study something like this. There's not, oh, we've discovered this great molecule. Two years later, we've gotten on the market and two years after that it's a drug it doesn't quite work.

Alan: Yeah, I started studying this in 2006. Principally, all I do is study this one molecule which makes me really boring at cocktails.

Lisa: Not for me, I would be just like, this is why these conversations for me it just totally fascinating. Because it is the deep research where we're going to find all these these these these fantastic things that we're going to be able to help us because at the end of the day, all of us want to live longer, healthier, have a longer health span, longer lifespan, and not get these horrible diseases that I ail so many of us and none of us are going to know what's around the corner for us but if we can be in that preventative space and be and understanding this more and more than that is to me the most fascinating conversation we can have.

I think people like you are superstars in my eyes, you know, perhaps I'm just science nerd, but I love it. Alan, you've been absolutely fantastic today. I want to thank you for your time, your patience with me, because I'm very excited about this molecule, as you can probably tell, and I want to share your research, I would love to get any references that you want to point me in the direction of and also your, your product, I'm actually going to be bringing it into the country and it's on its way. Now. I've talked to your team, and they've set me up. So I'm very excited for for for this to have this in the range. So thank you so much for your time today. Is there anything else that you'd like to get across before we wrap it up?

Alan: Well, I mean, if if you've got an issue with fatigue, if you've got an issue with perhaps your blood sugar is is a little higher than you want it to be. You know, this is something you may want to try. You know the downside of this is yeah, it costs a little bit of money. But the upside is if it works, it's in I keep getting emails from people This is life changing. You know, it's kind of funny. The first email you get from somebody, when you change their life is it's like four pages long, and they talked about their dog and the tree that they planted outside, you know, it just goes on and on. About two months later, you get another email that says, you know, it's still going good. Six months later, you get one line that just says, and that's good, because rather than focusing on all your problems, it's they've moved on, you know, they've moved on, you know, they're, they're no longer defined by their problems. They've got the solution, and they're just moving on to other parts of their life, which is really, really quite rewarding for me.

Lisa: That's fantastic. What I find to working with with clients is that, yeah, they wait, as soon as the pains gone, or the problem is disappearing. They've forgotten that they had it. They don't actually, sometimes what happens then is that they stop all their protocol, anything that they were doing and fix now I'm fixed. I don't need it anymore. I’m like, hang on a minute, you don't drop the ball. Now, you're already underway, you got to stay underway, you got to keep it going. So I was on that point with oxaloacetate. With your benagene product, accumulative effect as well. So there's a genetic changes that happen over time as well as the immediate effects.

Alan: Yeah, we see both. So so there's a pharmacological effect, which is immediate, like an improvement in fatigue that some people see. Then there's a genomic effect that occurs, as you keep your NAD to NADH ratio high, it activates something called AMPK and allows other genes to turn on. The cumulative effect of that usually takes about a month or more to be able to see. Now the good news there is because it's genomic, when you stop taking it, it works for about a month and a half until your system goes back to the way it was. Then you don't feel so good anymore. But, you know, if you forget to take it a day or two, it may not matter. As long as you take it, you know, consistently. So that's that's pretty cool, too.

Lisa: And then this is yeah, this is what so many things people. Yeah, they don't they eat, they want the immediate response. So the magic bullet, you know, like, I took it today, why am I not feeling better? And then, once they do start to feel better, then they like, we don't need it anymore. I'm fixed. Often that isn't the case. You want that cumulative, and those epigenetic changes, and those those, those long term changes. So some things we do in life, we cycle in and out. That's really good for the body. But some things we need that accumulative effect over a longer period of time, and oxaloacetate seems to be one of those that we just keep on taking, and we keep getting the benefits from it. Looking at your research. 

Thank you, Alan so much for today. It's been absolutely fascinating. I am looking forward to getting all those emails from my clients saying it's changed their lives. So it's gonna be interesting. Then I'll send you an email saying it's been really, really helpful for X amount of people. So, Ellen, you're making an impact in the world. Thank you so much for your time today and for your wonderful research. It's just absolutely fantastic.

Alan: Good talking to you today, and thanks for your interest.

That's it this week for pushing the limits. Be sure to rate review and share with your friends and head over and visit Lisa and her team at lisatamati.com

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