Alan Cash: Most of medical science as we understand it is not treating the cause it's treating the symptoms. You know you've got a cold your nose is running, okay let's give you things that stop your nose from running instead of, "Hey let's kill the virus." The problem was that as we get older things like this happen. My background is not in biology I'm a physicist and as a physicist we tend to take a lot of data and look at it and try to find simple things. Like F=MA or E=MC2. We try to distill all this information in to something unique and simple and fundamental. And when I looked at aging with this mindset, what I saw was almost nothing works except Calorie Restriction. They've been doing it since 1830's - it's when they take animals and they determine a baseline and then they feed them 25% less than what they normally eat in that baseline. And the animals surprisingly, even though they're getting less energy they live longer. They live about 25 to 50% longer and it's not restricted to one type of animal. I mean they've tried this in yeast and in spiders and in guppies and in rats and mice and dogs and monkeys. And they've even done clinical trials in people and what they keep seeing that this is incredibly healthy for you. There are some cultures that practice fasting on a regular basis and probably because they've seen some major improvements in health. So the scientist in me, I'm going to try this. So I tried it for 30 days, I restricted my diet down by about 25%. You can go a little bit more than that, obviously if you go too far you starve to death but that's down around 45 to 50% restricted. So 25% is pretty mild.

Jesse: So how many calories a day does that wind up being? Let's say me for example, I'm about 180 pound guy. So what would I be taking my daily caloric intake down to?

Alan Cash: That's about 1500 calories.

Jesse: Wow yeah that's not a lot.

Alan Cash: You know compare that to like my daughter who plays high level volleyball. She probably burns through 6000 calories a day. It's quite an adjustment. I did it for 30 days and my wife suggested that I was irritable.

Jesse: *Laughs*

Alan Cash: She was pretty happy when I gave up that idea. You know there are people who do it most of their lives and they're incredibly healthy. I mean in clinical trials when we calorie restrict humans we see a virtual elimination of high blood pressure, atherosclerosis seems to go away, diabetes drops out. Even in primates calorie restriction eliminates Type 2 diabetes. So I started looking for what is the cause of calorie restriction.

Jesse: One thing that I wonder is what is the level of energy that a person actually feels? I mean you might live a heck of a lot longer but on the other hand are you going to be sluggish and lethargic throughout all the days of your extremely long life?

Alan Cash: You know that's a great thought experiment and you would think that, "God you restricted energy, I got to be tired all the time." But when you calorie restrict animals you can always tell which group it is when you walk in to lab because they're climbing the cages. They're looking all over the place for food. I've done it myself. I restricted food and I was like, "Hey let's go do something. Blah blah blah blah blah.”

Jesse: *Laughs* It's exactly the opposite of what I thought you were going to say. That's really interesting but it makes sense.

Alan Cash: It is contradictory to the thought experiment but I guess that's why we do experiments, because sometimes we see things that we don't expect. But there are some downsides to calorie restriction. And again it goes back to what is the cause of calorie restriction. What is the molecular mechanisms that are being turned on in the body that cause you to live longer. And there's been a lot of work since the 1930's in calorie restriction but it's only in the last 15 to 20 years that we could look at for instance gene chips; where we could look at 20 to 25 thousand genes all at the same time and see what happened. And so that's one of the things that we did. We looked at the difference in calorie restricted animals and in normal control animals and it turns out about 10% of their genes change in expression significantly. If you think about that, that's a lot, just by eating less.

Jesse: Uh huh.

Alan Cash: Your DNA doesn't change, it basically stays the same throughout your life other than you know random breakages and mutations and what not, but pretty much your DNA stays the same, but your genes turn on and off all the time. So there are programs in our bodies that are changing these genes all the time and it turns out that one of the biggest ways to change your DNA expression is to eat differently. So if you go out and super-size everything and get all your McDonalds french fries and eat super high-fat diet, high calorie diet, your body will actually produce proteins to help you break down those fats and to use those as energy. If you go the opposite way and say, "Well I'm not going to eat as much and I'm going to restrict down my carbohydrates, so that I'm not just pumping myself with glucose," your body does the same thing but with different genes that are turning on and off. And it turns out that in calorie restriction the genes that are turned on are things that rebuild our cells, they clean up our cells - it's called autophagy. And they also create more mitochondria in the cells, so that if you do get some food you can process it much more effectively. So I started following the energy pathways of calorie restriction. How do we produce glucose and what I saw is this one compound called oxaloacetate, it's part of the Krebs cycle, it's one of those metaboloids you don't hear about a lot, it doesn't come up in dinner parties very often.

Jesse: Can you give a quick elevator version of the Krebs cycle for people that aren't familiar with that?

Alan Cash: In your cell there are these little things that look like ellipses or jellybeans and they are called mitochondria and they produce most of the energy that allows your cell to function. They burn glucose and they do it very efficiently. They are really cool little things. And within the mitochondria there's what we call the Krebs cycle. We call it that because this guy named Krebs back in the 60's, biochemist genius, he figured out the step by step process of how glucose breaks down in these mitochondria and provides your cell with energy. And it has some compounds you've probably heard of like citrates which is a relative of vitamin C. But all these little compounds, the Krebs cycle metaboloids are formed together and together they provide us with energy. So we were looking at one of those particular metaboloids. And so I went and found my friend at UCSD who is a very very smart biologist and I don't doubt that someday he'll win the Nobel prize, he's just brilliant. And I explained to him what I was trying to do. How we've seen in yeast this increase in life span with an increase in the NAD to NADH ratio and how calorie restriction seems to be working along these lines and I wanted to do the same thing and see if it could mimic calorie restriction, without having to eat a lot less. Because I really like ice-cream. So we started with worms and I put oxaloacetate in to the agar of these worms and just let them live and counted them, you know they were either alive or they were dead. You poked them with a little needle and if they didn't move, you know that was a dead one. Just did counts after counts after counts. They're microscopic, I mean you can just barely see them with the eyes. So I spent hours and hours and hours looking through a microscope, counting worms. My wife thought I had gone crazy but the worms lived 25 to 50 percent longer. We then tried it in flies and the flies lived 25% longer. And then we tried it in mice. I didn't want to wait 3 years to see if this was working. So Steve Spindler at UC Riverside came up with just a brilliant idea of screening for calorie restriction, looking at gene response. So I thought well we could raise a control group that ate what they wanted. We could raise a calorie restricted control group and then we could raise a group on oxaloacetate and give them as much as they wanted to eat. And in about 3 months we could take some of their tissue and look and see how the genes are responding. And when we did that we had a 99% correlation with calorie restriction and oxaloacetate. I mean they were almost identical.

Jesse: Should there have been in that study a fourth group that was both calorie restricted and getting oxaloacetate supplementation?

Alan Cash: You know you are right and there should have been. Because what if you could do both and live a 100% longer. I mean what the heck, but no we didn't do it. You've got to remember too that this was all being done from the Bank of Alan, which is not the biggest bank in the world but you know, it was interesting to me so I underwrote all these tests. We were fortunate in that I had raised enough mice that I could let some of the ones with the oxaloacetate live out their lifespan. So during the next 2 - 3 years I just continued to feed them with the oxaloacetate and I had a control group and I compared who's going to live and who's going to die and kept track. And as it turned out the oxaloacetate mice lived longer. So I started looking through literature and they had done a clinical trial with oxaloacetate in humans. So here was our test compound and they've already tested in human beings and what they found is that there were no side effects. The tests were done in diabetics. Calorie restriction eliminates Type 2 diabetes and the addition of oxaloacetate to these diabetics reduced fasting glucose levels by 25% in 45 days with side effects. And I thought to myself, first we were getting lifespan effects, now we're getting the anti-diabetic effect and my gosh where is the follow on study? So I'm looking through the literature, there's got to be something on it because here's a treatment for diabetes - the scourge of modern man right now and there's no follow up. I can't find a thing. So I hop on a plane I go to Japan, this is up by a place called Fukushima, which will become famous later on, and it's at the University of Sendai - Tohoku University. And I go to the department where this was written and unfortunately the author of the study had passed away, but they knew of the study. I said, "Are you familiar with this?" And fortunately they spoke English because their English was much better than my Japanese. They looked at it and said, "Yeah we are familiar with this." And I said, "You reduced fasting glucose levels in diabetics by 25%." And they said, "Yeah it was pretty amazing." And I said, "And you did it with a natural compound." And they said, "Yeah we did." And I said, "Where's the follow on work?"

Jesse: They've got a lot less diabetes in Japan than in America so maybe it was less of a wild factor for them.

Alan Cash: Well, what they said to me was, "Yeah it's a natural compound - no patents." That was pretty much the end of our discussion. You know you can't blame them because when the average cost of bringing something to the market is $800 million, at least in today's money, and you can't protect it with intellectual property; who's going to spend that kind of money?

Jesse: Well yeah but if it's naturally occurring compound, you don't have to spend that money, right?

Alan Cash: Well actually you do because in the United States nutritional supplements cannot prevent, treat, cure, diagnose any disease.

Jesse: Oh right. The fine print that's on all the vitamin bottles you buy.

Alan Cash: Yeah you can't do it. So even if it works you can't talk about it. We made a very big point when we decided to become entrepreneurs and go in to the marketplace and make a nutritional supplement. We had to not talk about diabetes because it's a disease. So talked about anti-aging. And we put this out on the marketplace, it turns out that we were able to get into Canada first in 2007 and in the United States the FDA wanted us to have this as a new dietary ingredient. And I said, "Now wait a second. Oxaloacetate is in every food you eat. It's in chicken, it's in peas, it's in potatoes, it's in apples, it's in spinach." And they said, "Well yes, but nobody has been selling food specifically for it's oxaloacetate content. So it's got to be a new dietary ingredient." So I spent about a million dollars of the Bank of Alan and we did toxicity studies and found that this stuff not surprisingly is about as toxic as vitamin C. So you can take an awful lot of it. And we presented this to the FDA and they said, "Well we'd like to see more studies." And it's like, "Why?" I mean this is a human metaboloid, I mean you know it's related to vitamin C, it's about as toxic as vitamin C. We tried to kill the mice. We gave them 5000 mg per kg of body weight. None of the mice died, none of the mice even got sick. And they were like, "Yeah but this is a new dietary ingredient." I think that FDA works on a basis of fear. They're afraid of making a mistake that will hurt people and because I wasn't a major pharmaceutical company, because I only spent a million dollars instead of 10 million or a 100 million, they were afraid. And we duked it out. I said, "I'm following the law. I want enforcement to weigh in on this." So they said, "Fine, we'll call enforcement on you." I said, "Fine!" We were yelling back and forth. This is not generally the the best way to deal with a regulatory agency. And they called me up the next day and there were two of them on the phone. I guess they needed to have witnesses. And they said, "Well you're right. You followed all the regulations and this is legal to sell in the United States." I said, "Okay we're going to go and do that, would you send me a letter?" "No, we're not going to send you a letter." I said, "What do you mean?" And they said, "We're not going to send you a letter." So I had to send them a letter, certified mail, basically stating all the things that had led up to this conversation and what happened and sent it to them and then I waited 6 months and then we introduced it in to the United States, and that was back in 2009. I haven't heard from them since. Now that doesn't mean that they won't be at my door tomorrow but so far we've been allowed to sell this in the US and we've really had very limited complaints. We've had 2 reported adverse effects, they were both headaches. We're not a 100% sure it was due to the oxaloacetate. But that's pretty low for any kind of supplement when you consider how broad the population is and how diverse the population is.

Jesse: What are the amounts of oxaloacetate that are in the supplement vs how much one would normally get in their diet?

Alan Cash: Yeah, that's a great question. The FDA asked me that exact same question and so we had to do a lot of research and it turns out that some foods have a lot of oxaloacetate and some foods have very little. But for the most part, for the average diet, our supplement gives you about a 100 times the amount of oxaloacetate that you'd get in your daily diet. And the foods that have the most oxaloacetate in them are foods that are very high in mitochondria. So like pigeon breast, squab has very high amounts. But even with squab you have to eat like 30 pigeon breasts in order to get as much oxaloacetate as in one capsule of our supplement.

Jesse: So at a 100 times a person is normally getting in their diet. Is that amount so high because most of it is not making it through your digestive tract and actually in to your blood stream? Is this something that's maybe largely broken down in the digestive process or why such a large ratio?

Alan Cash: Well it turns out that we have some PKAA data on that and as it turns out oxaloacetate is water soluble and as such it goes in to the cells so very quickly. As a matter of fact we tried to make time release version of it. We were shooting to slow down the absorption by the body over an 8 hour period. We took about 40 minutes. It's one of those molecules that the body just goes, "Oh I love this!" And pulls it in. So absorption is about a 100% and the reason it's so high and these pills that are in our supplement are tiny, is because of all the Krebs Cycle metaboloids, oxaloacetate is the one that is in very very very small amounts in your body. And we believe that it maybe a signaling molecule. For instance you need oxaloacetate in order to break down the triglycerides in to the energy components. Oxaloacetate is right at the crossroads there. So it does a lot of different things in the body but it's availability is very very small. So with just the small amounts that we're giving, you know 100 mg, that's nothing. It seems to do a lot. Now how do we know what to give people. Well what we did is we went back to that clinical trial and they had given people anywhere from a 100 mg a day on up to a 1000 mg a day. And there weren't any problems either at the 100 or at the 1000, it all seemed to work. So what we thought is that if we're taking this as an anti-aging compound, we want to take the smallest amount that has proven benefit. And if we're seeing a drop in fasting glucose levels in humans, that's exactly what we would expect to see with calorie restriction. And so where to start, at the lowest dose proven to show an effect in humans, which was a 100 mg.

Jesse: I'd like to hear about how this effects hippocampal neurogenesis?

Alan Cash: Well we had a weird thing happen. You know one of the benefits of getting a new compound out there, in to the marketplace is you get feedback and we got feedback from all sorts of people. All of a sudden I get this large order and I'm like, "Huh, that's odd." It was from Kansas. So I called up the person and said, "Why you ordering so much of this compound?" And they said, "You know I'm a University professor." I said, "Oh okay you’re going to study it. That's great! Hey I'll give it to you for free. I'll underwrite that research. You know what the heck." And they said, "No, no. It's for me." And I'm like, "Well okay. You know what's up there?" And they said, "I've Parkinson's disease." And I'm like, "Yeah, so?" And they said, "Well my neurologist recommended that I take this." I said, "Well what were the effects?" And she said, "Well I was in a wheelchair. I couldn't stand for more than 2.3 seconds. I couldn't comb my hair. I had trouble buttoning buttons. But you know the thing that bothers me the most is I can't type, because I can't type up my research." And I said, "Well is it helping at all?" And she goes, "Yeah, yeah. It's helping a lot." I said, "Well let me send you a survey and you can try to define how much it's helped you." There are these surveys you can take, it's called a PDQ 39 form which looks at Parkinson's disease quality of life. There are 39 questions. It's things like, can you tie your shoes? How do you feel today? You know gives a scale of 0 to 5, it's been shown to be statistically significant as far as defining how you're doing in Parkinson's disease. So you know I said, "Try to do one that was before and then give me one that's now." And so she did that and sent it back and I called her back and I said, "You've had a 90% remission in Parkinson's disease. I've looked through the literature, that doesn't happen." And she said, "Yeah and not only that I've cut my dopamine dose in half." What was interesting though is she was a professor of pharmacology and so based on that the University of Kansas said, "We're going to do a clinical trial." So they put oxaloacetate in clinical trial for Parkinson's disease and there was a 2 year trial, it's just finishing up now. It's double-blinded placebo controlled, so I have no idea whether it worked or not. You know we had some very smart people like Russell Swerdlow over at U Kansas who is like, "Mr. Mitochondria." Guy's just brilliant. And he started looking at the oxaloacetate and what it does to the brain. What he saw, and this was just published in the journal Human Molecular Genetics, which is an Oxford journal. Well I'll just read you the title of the article, this was published in July 2014 so this is pretty new information - "Oxaloacetate activates brain mitochondrial biogenesis enhances the insulin pathways, reduces inflammation and stimulates neurogenesis.”

Jesse: Them's fighting words.

Alan Cash: And what's interesting is this ties in very much with another study that we did, that was done at the Pennington Institute which is in Louisiana, and this was done under a 2 year grant from the Alzheimer's Association. And we took mice, what we call Alzheimer model mice. So these mice get a lot of tangles in their brain very early on and you can see the effect of that when they are put in a water maze. Because mice don't like to be in the water so they run around until they can try to get to a platform that gets them out of the water. It's not water-boarding it's water-mazing, it's a lot nicer. What we saw in that is that the mice that were fed oxaloacetate had a 50% increase in short-term memory and a corresponding decrease in hippocampal plaque density in the brain. So we thought that was pretty impressive.

Jesse: Well any final thoughts you'd like to leave people with?

Alan Cash: Yeah, I would like to talk about a new product that we have on the marketplace. The FDA has given us an orphan drug designation for brain cancer. Because when we add oxaloacetate standard chemotherapy it increases survival by 237% and in 30% of those animals that was done in that test we couldn't find the cancer afterwords. This is human glioblastoma tissue that's implanted in to animals. And so FDA thought that was pretty amazing and gave us an orphan drug designation. That doesn't mean that this is a drug, it's a medical food - it's called CRONaxal and thats www.cronaxal.com. So if you know of someone with a brain tumor you may want to just let them know about this because in our first 17 people that have MRI data on, we were able to stop the growth of these very aggressive tumors in 88% of them.