People have been trying to do something about aging since the time of the pyramids. The only research I could find that had any effect on aging was a relatively obscure scientific field called “Calorie Restriction” (CR) research. Apparently–since discovered at Cornell University in the 1930s–if you restrict an animal’s calorie intake by about 25%, you see a corresponding increase in lifespan of 25%.
Initially, this was not understood, as you would think that giving an animal sufficient energy would allow them to live longer; however, the results showed that animals fed less lived longer. After 80 years of research into CR we see that almost all animals respond in nearly the same manner to CR, with an increase in average and maximal lifespan. From single-celled animals such as yeast to worms to flies to spiders to guppies to mice to rats to dogs to monkeys, we see that CR increases lifespan. Not only do the animals live longer, but they are healthier.
CR in animals has been shown to reduce cancer incidence by 55%, eliminate Type 2 diabetes in Primates (monkeys), and reduce the prevalence of age-related cognitive decline in animals. In human clinical trials of CR, the most notable finding was a considerable reduction in atherosclerosis (hardening of the arteries). We don’t know if CR will increase lifespan in humans, as the tests would take about 100 years to complete (American women live an average of 81.2 years, and American men live an average of 76.4 years). CR may, however, help increase the healthspan of people—the time that we remain healthy, which may be more important than improving our lifespans.
If CR is so revolutionary, why are we all not doing it? For anyone who has tried a diet, we know why: it is hard. Imagine being on a diet for your entire life.
In the mid-2000s, when I had my brain problem, researchers at Harvard University and MIT were decoding some of the biochemical reasons why calorie-restricted animals live longer. I had some spare time on my hands after surgery, so I started researching the biochemistry behind CR. It turns out that CR causes a specific ratio change in energy molecules, the ratio of Nicotinamide Dinucleotide (NAD+) to its reduced partner (NADH), increasing the ratio between the two compounds. This ratio is then “noticed” by a protein, AMPK, which links processes in the cellular environment and cellular programming in the nucleus. Essentially, CR allows the cells to reprogram what the cell does, and it results in the animals living longer and healthier.
Understanding this NAD+/NADH ratio change as the start of the CR metabolic state was a huge breakthrough; the major news outlets covered it. As I recovered from my brain problem, I read the initial news, then dug in deeper to understand what was going on. I thought to myself, if we need to change the NAD+/NADH ratio to slow down aging, there must be some compound that does this. This compound would preferably be natural, rather than some Frankenstein molecule, and even more preferably be a compound already found in the human body. I started looking for this molecule and came up with “oxaloacetate”, an energy molecule in each of your cells. Oxaloacetate is a crucial molecule in the “mitochondria”, little sub-structures in the cell that help produce over 90% of the energy we use daily.
Since I am not a biologist, but a physicist, I took the idea to a brilliant biologist friend of mine at UCSD and asked him what he thought. His response surprised me. He didn’t say a thing; he just got up and motioned that I should follow him. He took me downstairs from his office and used a key to open his biochemistry laboratory. Walking over to a lab bench, he used his arm to sweep away the papers that had accumulated there and said, “Here. Here is where you will test your theory.”
I looked at him in surprise, and said, “I’m not a biologist. I don’t know how to test this.”
He didn’t buy my argument. “How tough can this be? We’ll get some flies, feed them oxaloacetate, and see if they live longer.”
As it turned out, we started with tiny worms called Caenorhabditis elegans (C. elegans) to test the theory. I had to learn how to raise worms, transfer them to plates of food, film them under a microscope, and count the number of bites of food they consumed. After a few months of work, I could report that the worms lived about 25% longer when you added oxaloacetate to their diet. I had tears coming down my face as I plotted the data. I made worms live longer!
The research did not stop there. We ordered various types of worms from a scientific supply house, each with a specific gene deactivated. In that manner, we could follow the biochemical cascade that led to gene expression changes and an increase in lifespan. We published the work in the scientific journal “Aging Cell”, as a method to “mimic” the same metabolic state as CR and extend lifespan. You can download the article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988682/
The research was exciting, and I was having a great time prying into the secrets of the CR metabolic state.
Our research did not stop with worms. We went on and tested flies and mice, and also saw about a 25% increase in lifespan. As a scientist, I was having a great time; I also started thinking about making oxaloacetate a supplement for humans to induce the CR state in people. Searching through the literature base in the US National Library of Medicine, I came across an interesting older article from Japan. They had used oxaloacetate on diabetic patients in a clinical trial. In 1968 they looked at oxaloacetate’s effect on Type 1 and Type 2 diabetics. The oxaloacetate was extracted from a medicinal plant used to treat diabetes in Japan. The test showed a reduction in fasting glucose levels in all the patients, without any noted side-effects. The average reduction in fasting glucose levels was 25%. This was exciting stuff—a natural compound that was tested to improve diabetes without side effects. I started looking for any follow-up work but could not find anything. Undeterred, I flew to Japan and met with the professors at Tohoku University, where the research was performed (just northeast of a place called Fukushima). Fortunately, the professors spoke English, as I do not speak Japanese well.
I asked about the 1968 study, and they acknowledged that their department had performed the study. I asked about the follow-up work, and they stated that there was no follow-up. I asked why—here, they discovered a natural compound, commonly found in the human body, that treated diabetes with no side effects noted—why was there no follow-up?
The professors looked at me and stated, “Oxaloacetate is a natural compound. No patent available.” That ended our rather short conversation. Although oxaloacetate seems to have a future for diabetic patients, it was never pursued because as a “natural” compound, there would be limited patent rights.
The fact that oxaloacetate supported proper blood glucose levels was more evidence for me, as one of the side effects of the CR metabolic state was some help in controlling blood sugar level-related conditions…Having oxaloacetate work to support proper glucose levels, without side effects, cinched my decision to provide oxaloacetate to the population as a nutritional supplement for its anti-aging effects.
It turned out that making a nutritional supplement was a lot more difficult than just putting oxaloacetate into capsules and selling product. As oxaloacetate had never been sold before as a nutritional supplement, I had to provide the safety information I relied upon in making a “New Dietary Ingredient” notification with the US FDA and Health Canada. Three years and about a million dollars later, I had performed GLP (Good Laboratory Practice) toxicity studies in animals, found a method to stabilize the oxaloacetate thermally, and put the product out into the Canadian and USA marketplace. It is called “benaGene”, short for “beneficial genes.” benaGene doesn’t change your genes, it just helps to turn on the genes that you already have in your DNA to promote good health.
benaGene was well accepted in the marketplace, and I soon had a small business with one product, benaGene (oxaloacetate). Most of the customers were either medical doctors or biochemists, who could understand the importance of increasing the NAD+/NADH ratio.
One major advantage of having a product in the marketplace is that you receive a lot of feedback from your customers. However, my most important customers were my wife and daughters.
Being the only male in a house full of women, I have an understanding of mood swings and emotional PMS symptoms. Once the girls went away to college, we began to notice that all three had some mild mood issues or social problems about once a month. Our daughters started taking benaGene oxaloacetate based on research into potential anti-aging benefits (who doesn’t want good health), and yet the thing we noticed the most was an improvement in PMS mood changes.
That was the first hunch that led to a scientific journey involving robust clinical trial testing of oxaloacetate for relieving PMS. Eventually, we collaborated with research scientists, medical doctors and women from across the US in exploring the potential of oxaloacetate to relieve PMS, and developed Jubilance PMS.
Read about how aging, oxaloacetate and aging come together to form a new solution for PMS – Jubilance for PMS – in the next article in the series, The birth of benaGene, a new anti-aging supplement: Thermally Stabilized Oxaloacetate.
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