Exclusive Interview with Durk Pearson & Sandy Shaw®

Putting More Power into Your Life

first heard about growth hormone (GH) releasers from reading Life Extension: A Practical Scientific Approach (1982), the bestseller by research scientists Durk Pearson & Sandy Shaw. A few years later, when they published The Life Extension Weight Loss Program (1987), I remember eagerly awaiting their first GH-releaser formulation.

Motivated by a growing body of research, Durk & Sandy have updated their formulation several times over the years, all the while keeping their focus on the larger context of antiaging. Their approach is in many ways similar to the guiding principle of the great architect Frank Lloyd Wright, who designed his buildings from the inside out, letting the function of the spaces within determine the nature and form of the overall structure.

True to Durk & Sandy’s concern for the interior of the human body—its principles and its mechanisms—the driving force behind their GH-releasing formulations has been their goal to control the aging process. How? By understanding the body’s metabolic pathways and interceding with nutrients that can modify growth hormone and nitric oxide activities. By going, in other words, to the body’s first principles in order to control life’s outcomes.

Durk & Sandy have given us something to be truly excited about, something that can put more power into our lives.

— WILL BLOCK

Arginine Is the Precursor to Nitric Oxide

LE: Several years ago, Dr. Gregory Fahy, the organ transplant cryobiologist, told me that he thought that your growth-hormone-releasing formulation was your greatest product. Now that the two of you have produced a significantly improved formulation, tell us about your original conception.

DURK: We started by looking at the changes that occur during aging, especially the degradation of immune functions and wound healing and the loss of lean body mass and strength. Taken together, it sounds like a loss of growth hormone activity, which does indeed occur as you get older. You release less GH from exercise and less during sleep.

SANDY: Furthermore, the way in which GH is released during the night becomes less like cyclic pulses and more like a slow dribble.

DURK: Back in 1976, while we were at a conference on the biology of aging, Sandy fell and broke her foot. She didn’t get a cast, though, and she wound up hobbling around on crutches. We had been reading about GH and GH releasers, and we thought enough was known about the amino acid arginine to try it. So Sandy did, and the results were spectacular: five weeks later, not only was her foot healed, but there was no x-ray evidence that it had ever been broken.

SANDY: That, of course, didn’t prove anything, but it was the start of our interest in arginine. There was a lot of research going on, and it eventually led to the discovery, in 1988, that arginine was the body’s precursor to nitric oxide (NO). This simple molecule is critical for dilating blood vessels and helping to regulate blood pressure and, therefore, blood flow.

DURK: We learned that anticholinergic agents, which inhibit the production or action of the neurotransmitter acetylcholine, also block the effects of arginine in releasing growth hormone. So we included choline (an acetylcholine precursor) and vitamin B5 in our formulation, the B5 because it enhances the conversion of choline to acetylcholine.

SANDY: Around 1990 it was shown that acetylcholine activates an enzyme that catalyzes the production of NO from arginine. This enzyme is of a type called nitric oxide synthase, or NOS, and there are four different versions of it. The version that’s activated by acetylcholine is endothelial nitric oxide synthase (eNOS), which is found in our blood vessels. It’s crucially important for maintaining cardiovascular health, and significant deficiencies in eNOS activity are characteristic of cardiovascular disease.

Another version of NOS is neuronal nitric oxide synthase (nNOS), which is found in neurons throughout the central and peripheral nervous systems, where NO performs a wide array of important functions. Yet another version is mitochondrial nitric oxide synthase (mtNOS), which is found in our cells’ mitochondria, the tiny organelles that generate almost all of our energy. The fourth version is inducible nitric oxide synthase (iNOS), which is found in cells of the immune system, where NO is generated to combat infections; the downside of this is that infections can cause your system to be flooded with NO, which can lead to collateral damage from inflammation.

Why Nitric Oxide Is an Antiaging Molecule

DURK: Last year a paper was published in Science1 entitled “Calorie Restriction Promotes Mitochondrial Biogenesis by Inducing the Expression of eNOS,” which we summarized in the October 2005 issue of our newsletter, Life Extension News.* This is a fundamentally important paper, and I think the authors deserve a Nobel Prize because of the profound implications of their work. Two years earlier, they had discovered that NO from eNOS induces mitochondrial biogenesis, the creation of new mitochondria in our cells, and now they’ve found a link between that and the mechanism of caloric restriction, which extends the lifespans of many different kinds of organisms, from yeasts to mammals.


*Reprinted in Life Enhancement, December 2005, p. 25. Or see Effects of Caloric Restriction May Be Partly Due to Enhanced Expression of Endothelial Nitric Oxide Synthase. See also “Can Nitric Oxide Increase Lifespan?” by Will Block, in the January 2006 issue.


LE: Isn’t there a relationship between your age and the number of mitochondria in your cells?

SANDY: Yes indeed. As you age, mitochondria decline both in quantity and in functional quality—older people have proportionally more defective ones in their cells than younger people do. The more damage the mitochondria sustain, the less capable they are of producing ATP, the universal energy molecule, and the more likely they are to release large quantities of harmful superoxide free radicals. So it’s very important to maintain the vitality of your mitochondria.


Dr. Denham Harman
DURK: In 1956, Dr. Denham Harman postulated that free radicals are involved not just in age-related diseases but also in the aging process itself. He later pointed out that the primary hotbed of free radical activity is the mitochondria, because that’s where the oxidative reactions of cellular energy metabolism occur. These organelles have their own genome, distinct from the nuclear genome, and the former is subject to much higher damage and mutation rates than the latter. That’s because about 1% of the electrons involved in those oxidative reactions I just mentioned go astray to form superoxide free radicals, which can then be converted to hydrogen peroxide and hydroxyl radicals—all very harmful.

It’s interesting to note that increasing the amount of the antioxidant enzymes superoxide dismutase and catalase in experimental animals, such as nematodes, fruit flies, and mice, increases their lifespan. This jibes with the free radical theory of aging and the vulnerability of mitochondria to free radical damage. And now we know that lifespan-extending caloric restriction apparently promotes mitochondrial biogenesis via the action of NO—which is produced from arginine.

A decline in mitochondrial numbers and function may explain why most young people can eat a lot of food without showing the consequences, but when they get older, eating the same amounts, even with ample exercise, makes them fat. This appears to be true even when their white adipose tissue (fat tissue) is rich in mitochondria. Here’s where the role of NO becomes apparent. If you curtail NO production by knocking out the gene for eNOS, the amount of fat burned in white adipose tissue drops dramatically. But if you use NO donors to increase NO production, you burn more fat. I think the increased number of mitochondria has something to do with that, and it may explain why Sandy lost a lot of body fat when she first used our arginine formulation, along with some exercise, in 1976.

SANDY: Getting back to the Science study, the authors used normal mice with and without caloric restriction (CR), as well as mice that had been genetically engineered to lack eNOS, again with and without CR. In the normal mice, CR induced a significant amount of mitochondrial biogenesis in white adipose tissue, but in the eNOS-deficient mice, it did not. This was evidence that CR induces mitochondrial biogenesis—at least in part—by enhancing the expression of the gene that codes for eNOS. When that happens, more eNOS is produced and, therefore, more NO (as long as there’s sufficient arginine present).

Furthermore, the authors found that the increased production of eNOS was accompanied by increased production of the energy molecule ATP. Not only that, the increased eNOS production enhanced the expression of a longevity gene, SIRT1, that regulates—and can greatly extend—lifespan in a number of lower organisms, including yeast, nematodes, and fruit flies …

LE: … and recently in a species of fish—a vertebrate!—using supplemental resveratrol, which was already known to upregulate this longevity gene in lower organisms.

SANDY: Right—that’s a tremendously important scientific advance. Mice are vertebrates too, of course, but the Science study was about caloric restriction, not resveratrol. With the normal mice, the authors found that CR increased the expression of SIRT1 by about 120% compared with the non-CR group. With the eNOS-deficient mice, by contrast, CR still increased the expression of SIRT1, but only by about 30% compared with the non-CR group.

DURK: So it looks as though NO has a lot to do with aging, even if you don’t develop cancer, which can be caused by mutation-inducing superoxide radicals, and even if you don’t develop cardiovascular disease, which has a lot to do with inadequate NO production. The latter problem is called endothelial dysfunction, and it’s likely to be accompanied by the production of lots of superoxide radicals.

LE: So, does increasing NO production have an antiaging effect?

DURK: Yes, assuming that the mitochondrial biogenesis and SIRT1 expression that NO production by eNOS promotes do indeed have antiaging effects—which seems very likely, based on the Science study.

The Many Benefits of Folic Acid

DURK: Among the recently published research on NO, three papers have led us to include a relatively large amount of folic acid (700 mcg per serving) in the new formulations.2,3,4 The first paper has to do with an enzyme, dihydrofolate reductase, that enhances the bioavailability of NO. It has long been known that a decline in NO production, along with a dramatic increase in oxidative stress, is associated with hypertension. What the authors found is that, under oxidative stress, the normal metabolic pathway that produces NO from arginine can become disrupted so as to lead in a different direction. This is called uncoupling, and in this case, it leads to the production of superoxide radicals instead of NO. The superoxide radicals can then react rapidly with the remaining NO to form an extremely powerful oxidizer called peroxynitrite.

SANDY: One of the conditions that can lead to uncoupling and superoxide production is arginine deficiency—which is unlikely to occur with the protein-rich diet in our society. Another such condition is probably pretty common, though: a deficiency of tetrahydrobiopterin, which is a cofactor in the production of NO—it’s easily destroyed by oxidative stress. The reason we’ve added folic acid to the new formulations is because it either enhances the availability of tetrahydrobiopterin or performs the same function.5


The urea cycle, greatly simplified. The enzyme (with its magnesium cofactor) for only one step of the cycle is shown here.
DURK: Besides, tetrahydrobiopterin is astronomically expensive, and so unstable that you’d have to keep the mixture in the freezer.

SANDY: The other two folic acid papers deal with endothelial dysfunction, a key feature of most cardiovascular diseases. The authors found that folic acid actually reverses that dysfunction and normalizes the action of eNOS. A short-term test using folic acid supplementation against oxidative stress in patients with hypertension had a positive result. Thus it appears that folic acid is a powerful protector of the cardiovascular system.

DURK: Folic acid lowers homocysteine, which interferes with eNOS. It also has a direct effect on eNOS, particularly under conditions of high oxidative stress and hypertension, by helping it produce NO rather than superoxide radicals. Remember, NO helps increase the number of mitochondria. That’s why things like hypertension seem to have a generalized accelerated aging effect on people. It’s not just that it’s more work for your heart—exercise is more work for your heart, but it doesn’t cause aging. Exercise also, incidentally, increases the number of mitochondria.

LE: Your multivitamin formulation already provides 200 mcg of folic acid per serving (800 mcg/day). If you’re adding 700 mcg per serving (up to 2100 mcg/day) to your growth-hormone releasing formulations, the combined total would be up to 2900 mcg (2.9 mg) of folic acid per day. Isn’t that a lot?

DURK: Yes, but I’d like to point out that pregnant women who have already had a neural-tube-defect birth are normally given anywhere from 5 to 10 mg of folic acid per day to prevent that from happening again. Folic acid is really safe. Its downside is that, above 10 mg per day, it can interfere with several of the anticonvulsant drugs, so epileptics should be cautious in that regard.

SANDY: But we’re nowhere near that amount. I’d like to mention, by the way, that folic acid and betaine (which we’ll get to later) are probably the single most effective combination for reducing homocysteine levels.

DURK: We’ve also added 200 mcg of vitamin B12 per serving, not only to lower homocysteine levels, but also to ensure that the high folic acid levels don’t mask the hematological symptoms of pernicious anemia (B12 deficiency). Even with deficient production of hydrochloric acid or intrinsic factor in the stomach, 200 mcg of vitamin B12 per day can almost always prevent pernicious anemia. In addition, we’ve added 12 mg of vitamin B6 per serving to further help lower homocysteine levels.

Citrulline for Enhanced NO Production

DURK: Several papers on the amino acid citrulline are important in regard to our improved formulations. Citrulline is an amino acid that’s not found in the diet, but it is synthesized in the body, via a mechanism called the urea cycle. In this metabolic cycle, arginine is converted to urea and ornithine; the ornithine is converted to citrulline, which is converted to argininosuccinate, which is converted to arginine, thus completing the cycle.

It’s important to realize that there are about half a dozen different metabolic pathways that arginine can take. Producing urea is just one of them. Another, of course is producing NO, and in that reaction, arginine is again converted to citrulline, but by an entirely different mechanism that does not involve ornithine. Once citrulline is produced by any mechanism, it has only one place to go, metabolically speaking, and that’s back to arginine.

It’s not surprising, therefore, that one of the papers I mentioned found that supplemental citrulline increased the levels of arginine in young pigs (which are even closer to humans, in terms of nutritional requirements, than monkeys are).6 Arginine is a required nutrient for rapidly growing pigs, and a deficiency of it will stunt their growth. In these experiments, ornithine could not substitute for arginine, but citrulline could.

SANDY: One of the other citrulline papers, published in the journal Nitric Oxide,7 showed that supplemental citrulline was as effective as supplemental arginine in stimulating NO production in laboratory experiments. Yet another paper (actually just an abstract) found that citrulline effectively elevates plasma arginine levels for 24 hours in normal human volunteers.8 Here the authors were using quite high levels of citrulline.

DURK: Citrulline is not found in foods, so we’ve included a modest amount of it, 0.5 g per serving, in both the improved formulations. Arginine, of course, is found in foods—in a high-protein diet, you can get as much as 6 g/day. There have been a couple of studies in which very high levels of citrulline were given, either instead of arginine or with arginine. These experiments produced positive results, but they were short-term studies.

SANDY: We feel comfortable with the amount of citrulline we’ve included, but we wouldn’t feel so comfortable giving people multigram amounts—or taking that much ourselves, for that matter.

DURK: Not until we’ve seen a lot more about what happens over the long term. Much of the citrulline regeneration occurs in the kidneys, and we just don’t know how much metabolic stress multigram amounts would put on them.

SANDY: There’s also an interesting paper9 in which rabbits were put on a high-fat, high-cholesterol diet, from which they developed really bad cases of atherosclerosis. With supplemental arginine, there was a trend toward smaller, less invasive atherosclerotic lesions. An equivalent amount of citrulline alone had a similar effect. But together, arginine and citrulline had a very significant effect in reducing the size of the lesions and the damage done to the endothelium—and there was a decrease in superoxide production.

DURK: The authors also found that adding the antioxidant vitamins C and E to the arginine and citrulline made the treatment work even better. We’ve had C and E in our formulation ever since it was introduced in 1987, because of our concern about the possibility of nitrosamine production. Nitrosamines, many of which are carcinogenic, are compounds that result from the reaction of amino acids with nitrites, which are a byproduct of NO production. Fortunately, vitamins C and E can block that process.

SANDY: Based on the mechanisms described in these papers, the small amount of citrulline we’ve put into our new formulations should be quite beneficial in terms of increasing the amount of NO production and decreasing the amount of superoxide production.

Magnesium Aspartate for Enhanced NO Production

DURK: One of the enzymes involved in the conversion of citrulline to arginine is argininosuccinate synthase. This enzyme catalyzes the reaction of citrulline with aspartate (which is the ionized form of aspartic acid) to form argininosuccinate—and that compound, as we saw earlier, is converted to arginine. Because aspartate is essential to this process, we’ve added magnesium aspartate to our formulations. It turns out, by the way, that the lone nitrogen atom in aspartate becomes the N atom in arginine that winds up in the NO molecule (arginine has four N atoms). Even if that N atom were to come from citrulline, however, the aspartate would still be just as indispensable to the process as citrulline is.

Magnesium aspartate does two things. First, it supplies aspartate, which is necessary for arginine regeneration. Second, it supplies magnesium, and that’s relevant here because the enzymatic action of argininosuccinate synthase is magnesium-dependent. So both parts of magnesium aspartate are beneficial.

SANDY: Magnesium deficiency is very common in our society. The RDA used to be 800 mg, but practically no one was getting that much from the food supply. And because many entitlement programs, such as Food Stamps, require that RDA amounts be obtained from food rather than from supplements, the FDA realized that giving people enough food to provide 800 mg/day of magnesium was prohibitively expensive. So they reduced the RDA to 400 mg—a triumph of politics over science.

We’ve included magnesium aspartate in both the improved growth-hormone releasing formulations. Unfortunately, there’s a limit to how much magnesium you can take before you start getting the runs. So we’ve added a soluble fiber, making it a time-release formulation, which slows down the absorption of nutrients. That allows us to include the doubled amount of magnesium aspartate.

Another interesting point is that magnesium is particularly difficult to absorb. At one of the scientific conferences we attended, there was a German scientist who had done studies on the bioavailability of magnesium in different forms. She found that the most bioavailable was magnesium aspartate chelate, a form in which the magnesium ion is chelated by aspartate rather than being chemically bound in the usual way. This happens to be exactly what you need for the reaction catalyzed by argininosuccinate synthase.

LE: Is that what you’re using in the new formulations?

DURK: Yes—in both.

Glycine and Betaine for Inflammatory Protection

DURK: Two other nutrients that we’ve added to both formulations are the amino acid glycine and its trimethyl derivative, betaine. I use even more of these formulations than usual on days when I’m getting heavy exercise. Since becoming a rancher, I’m no longer totally sedentary, as I used to be. Throughout the week, I still spend most of my time lying on my back on my waterbed, reading. One day a week, however, I go out to the ranch, where it’s a different story. I’ll get back to that shortly and tell you what a difference the new formulations have meant to me out there.

SANDY: Meanwhile, it’s worth noting that both glycine and betaine have anti-inflammatory effects, which are useful in reducing the damaging effects of age-related inflammation.

DURK: Many people are going to be taking a growth-hormone releasing drink before exercising. If you overdo exercise and damage yourself a bit, which is pretty common, certain inflammatory immune-system proteins called cytokines are released, along with increased levels of superoxide radical. Glycine is an anti-inflammatory agent that reduces superoxide levels and protects against cytokines, including one called TNF-alpha, which is produced from monocytes that are activated by an antigen from an invading infection.10

SANDY: Bear in mind that inflammation is a process that can’t be blocked entirely—nor should it be. All natural processes in your body are there for a reason, and inflammation is one way that your immune system responds to the presence of a bacterial or viral infection. If you have an infection, it may not be advisable to take powerful, nonselective anti-inflammatories.

DURK: What you need are selective anti-inflammatories—which corticosteroids are not. In fact, the ads for inhalable corticosteroids for controlling asthma warn you that you may become more susceptible to infections when you switch to these products, because they disarm the inflammatory part of your immune system that deals with infections. What we’re using in our formulations is more selective. In a recent paper on the anti-inflammatory properties of betaine,11 the authors discussed the aging mechanisms that bring about a proinflammatory state. If you don’t take action to forestall this, you end up with more collateral damage.

SANDY: One of the damaging effects of inflammation is that it stimulates the proliferation and migration of endothelial and smooth muscle cells in atherosclerosis. Glycine inhibits such damage, which suggests that it may also be beneficial for inhibiting graft rejection, cardiovascular disease, and angiogenesis (the unwanted proliferation of new blood vessels); this is what researchers reported a few years ago.12

DURK: So we’ve added 1 g of glycine and 1 g of betaine to each serving of both improved formulations.

What’s the difference between the two formulations?

DURK: One has some additional, fairly expensive ingredients that are there for people who are under unusually high levels of prolonged oxidative stress. For example, we’ve added 40 mg of gamma-tocopherol from 100 mg of mixed tocopherols per serving. The four tocopherols, gamma included, are four of the eight different forms of vitamin E; the other four are called tocotrienols.

SANDY: Gamma-tocopherol is especially effective in promoting the decomposition of peroxynitrite. Recall that this powerful pro-oxidant is made by the reaction of superoxide with NO, so if you do have excessive superoxide production because of oxidative stress, gamma-tocopherol will help neutralize the resulting peroxynitrite. The 40 mg of gamma-tocopherol per serving is far more than you could get in a day from even a very good diet.

DURK: We also have 30 mg of coenzyme Q10 per serving (in a cold-water-dispersible form), because CoQ10 plays an essential role in energy production in the mitochondria. As a bonus—and perhaps not coincidentally—it’s also a potent antioxidant that helps neutralize the reactive oxygen species, such as superoxide radicals, that are generated in the mitochondrial energy-production process.

SANDY: We’re particularly concerned nowadays that so many people, especially as they get older, are being given statins to lower their LDL-cholesterol levels. Although that’s a good thing, statins have an unintended consequence that is not good at all. In inhibiting the biosynthesis of cholesterol, they also inhibit the biosynthesis of CoQ10. Thats because the enzyme whose action they interfere with, HMG-CoA reductase, is crucial for the biosynthesis not only of cholesterol but also of CoQ10. You can’t block the former without blocking the latter. We therefore strongly suggest that anyone using a statin also take a CoQ10 supplement.

This Is No Bull

DURK: We’ve experimented on ourselves with all the ingredients in the formulations, and I think my experiences are particularly relevant because of my dual life as a mostly sedentary but once-a-week physically active individual, as I mentioned earlier. We got into ranching when we realized that the mitochondrial genome in sexually reproducing animals (including humans, of course) was inherited only maternally, not from both parents, as the nuclear genome is. Ranchers were completely unaware of this.

SANDY: We get ranching magazines, and there are many full-page ads for bulls. But the ads say nothing about the females and the mitochondrial genome, which contributes so greatly to the ability of all cattle to utilize energy from the food they eat. We decided it would be worthwhile to develop our own strain of cattle with an improved mitochondrial genome, to see how well they would fare under extremely difficult environmental conditions.

DURK: And we’ve done that—we’ve developed a strain of cattle whose mitochondrial genome is the result of long-term natural selection under severe conditions, followed by rigorous human selection (ours). What we needed to start with was a seed herd of cattle that were already as tough as nails from living in a harsh climate. So we looked around Nevada for the very worst range we could find, because that would put the greatest stress on the animals.

SANDY: We found a ranch where some of the herd had long ago been let loose in remote mountain regions that were pastures in name only—they were very dry areas with nothing but desert scrub. There the cattle had to fend for themselves, living as wild animals, with no human assistance, no supplementary feed, no veterinary care, nothing. They were reproducing and doing everything else on their own until roundup time.

DURK: During the summer, these animals lived on a mountain under a bunch of piñon pine trees, where theres darned little to eat if you’re a cow. When winter came, they moved down to a canyon off of Death Valley called, so help me, Last Chance Gulch. I’ve never seen a nastier, more barren place in my life—it’s amazing that any cattle could survive there.

SANDY: The ones that did survive and thrive under those harsh conditions were likely to have the best mitochondrial genome, owing to natural selection. And in hindsight, based on what we now know from the Science paper we talked about earlier, they were probably gaining additional mitochondria through mitochondrial biogenesis, because they were calorically restricted cows, that’s for sure.

DURK: So they were the cows we wanted. When BLM regulations drove the rancher out of business and he had to sell his livestock, we told him we weren’t interested in the cattle hanging around the ranch house and getting supplementary feed during the winter. We wanted those extreme cows that had been making it on their own.

SANDY: We took this seed herd up to a valley at 7400 feet on a friend's ranch, keeping them there all year round through two winters, when cows normally go down to lower altitudes. There’s a different climate zone for every 1000 feet of altitude, roughly, and during the winter, 7400 feet is really tough. Nevertheless, these cows not only survived, they gained weight and had calves, and the calves survived.

DURK: This was possible because the cows had very efficient mitochondrial function: under conditions of cold stress, the mitochondria provided enough thermogenic heat through enhanced energy metabolism to see them through. This mitochondrial efficiency made a huge difference. Last year, our calving efficiency—the ratio of the number of market-viable calves produced to the number of heifers and cows exposed to bulls—was 98%! That kind of success rate is unheard of in this business.

SANDY: It sounds like we’re giving a tutorial on developing a high-producing cattle herd—just buy heifers from us for breeding stock, and you too can prosper!

DURK: The University of Nevada was bragging about their 91% calving efficiency, but they admitted to using calving barns and veterinarians to help the cows give birth. Ours did it out on the range without any help. This demonstrates the great importance of having good mitochondria (and plenty of them) in order to survive under stressful conditions.

SANDY: Since that time, we’ve maintained the mitochondrial genome by maintaining the female line and bringing in various bulls.

DURK: So that’s how we got into the ranching business. I soon found out, of course, that there’s a lot more to ranching than improving mitochondria. You have to go out onto the range and drive T-posts into rock-hard ground, and you have to hold 60-lb reels of barbed wire at arm’s length while walking backward to string fences. All that, and a lot more, has given me prolonged, heavy exercise for the first time in my life. I’ve bought exercise machines in the past, but I just couldn’t muster the willpower to stick with them.

SANDY: Exercise programs certainly do you good, but they’re not satisfying in the way that real exercise is, when you’re accomplishing something other than flexing your muscles for the sake of flexing your muscles.

DURK: That’s for sure. When you string wire and build a fence, you can see the fence. When you bury a pipeline to bring geothermal water to a trough for your cows during the winter, it’s great to see and feel that warm water in the trough. And when you carry 50-lb sacks of feed supplements … well, you think we take a lot of dietary supplements, but our cows are getting far more than we are.

SANDY: And they seem to love it. During the winter, each cow gets 3.4 lb of supplements a day. There can be problems with cow bullies pushing the less aggressive ones away from the supplement tubs, but Durk spreads the tubs around to make sure that even the timid cows get their fair share. And there are about 40 of those tubs! That’s a lot of exercise.

Of Railroad Ties and Exercise

DURK: But perhaps the heaviest exercise of all was when I got a sea-land container recently for storing the feed supplements out of the weather and away from hungry vermin. It’s 10 ft high, 8 ft wide, and 40 ft long. I got it with a load of railroad ties inside for building a foundation for the container and some other metal structures, because the soil here is corrosive. There were tons of railroad ties, weighing about 200 lb each, that I had to remove, sort, and stack.

At first, I would lift one end of the tie and drag it to where I wanted it, and then rest awhile. Then another one … rest … another one … rest, etc. Then I began using these new formulations (one or the other, depending on circumstances), and the results were spectacular! The following week, I was able to move a few of the ties in a row without resting. The week after that, I moved several more each time without resting. And the week after that, I worked for 5 hours moving railroad ties without resting. I took a 20-minute break for lunch—that’s all.

The only thing I can credit my rapidly increasing strength and stamina to is mitochondrial biogenesis. Now, of course, this wasn’t a controlled scientific experiment. The results could have been a placebo response, but that seems pretty unlikely in this kind of situation; besides, I’ve never been much of a placebo responder. All I can say is that, after about four weeks on the new formulations, I decided, what the hell—I picked up one of those railroad ties and threw it. I expected to be very sorry the next day, but I wasn’t—there were no aches or pains! I think the anti-inflammatories in the formulations must have helped.

SANDY: Although this is just an anecdotal report that doesn’t prove anything, it’s consistent with a lot of evidence from the literature that supports the plausibility of Durk’s conclusion. With supplements, it’s always reassuring when actual results jibe with reasonable expectations based on experimental data.

DURK: There was a week when I forget to take the formulation with me, but instead of driving back—the ranch is a long way from our home—I went and did the work anyway, taking it a little easier than usual. Boy, did I ache for about a week! That’s a mistake I’ll never make again.

SANDY: I’m taking one of the formulations because I’d like to live a very long time, and for that, one of the best things you can do is maintain your NO system and reduce inflammation. In fact, a recent paper that I read noted that interleukin-1 (IL-1, an inflammatory cytokine) is significantly involved in the aging process:13 it increases as you get older, and it contributes to the development of diseases such as atherosclerosis, cancer, and arthritis. So it’s sensible to take safe supplements that can reduce inflammation. I don’t take it for heavy exercise, though; I haven’t found any exercise that would get me as excited as ranching does for Durk.

DURK: One version of this product is for people who are subject to prolonged and unusually high levels of oxidative stress, such as those who do hard physical work or exercise for extended periods …

SANDY: … or for people who have high blood glucose levels owing to insulin resistance or diabetes, which induce a lot of oxidative stress.

DURK: That’s right. It is preferable if you have high glucose levels. For safety’s sake, however, we do wish to point out that a small percentage of diabetics exhibit increased glucose levels with arginine supplements. So if you are a diabetic, be sure to check your glucose response when using arginine-containing supplements.

There are, furthermore, certain people who should probably not use these formulations at all. Based on a new paper in the Journal of the American Medical Association,14 we recommend that people who have had a heart attack in the last year not use arginine-containing supplements without the approval of their physician. The study in question involved arginine supplementation in a group of elderly patients who had suffered heart attacks, and a small but significant number of them died, causing the study to be terminated. We discussed this paper in the October 2005 Life Extension News.*


*See L-Arginine Therapy in Acute Myocardial Infarction: Why the Negative Results? Could It Have Been Prevented?


SANDY: The other improved formulation is both less expensive and more suitable for short-term needs, because it doesn’t have the soluble fiber that slows down the absorption of the nutrients. It’s the best choice, for example, for preparing for moderate exercise of half an hour to an hour or so—you don’t need the time-release factor for that.

DURK: The same thing applies for sex. If you plan to take an arginine supplement before sex, you really don’t need a release over the next few hours—you need it over the next hour or so. The advantage of having these two formulations is that, depending on what you’re going to be doing, you can use whichever one is more favorable for the purpose at hand.

SANDY: We’re excited about these new products, and we’re really happy to be taking them ourselves. Our cows are happy too, by the way—they love their supplements!

DURK: Maybe that’s because I spent so much time, effort, and money to make them taste really good—just like our own drink-mix supplements. You get a real reward from seeing your cattle happy and feeling good. They’re looking good too. What more could you ask for?

SANDY: A word about the new grape flavor (it’s one of the three flavors): it not only tastes great, but it contains a variety of polyphenolic compounds, including anthocyanins, that are found in red and purple grapes, red wine, and cherries. Anthocyanins are the flavonoid pigments that give color to the grapes and to a variety of berries. They’re powerful antioxidants and anti-inflammatories.

DURK: Blueberries are especially rich in anthocyanins, and we’ve all heard about the extraordinary health benefits of blueberries. In fact, in a study on aged mice, it was found that blueberries actually retarded brain aging.

LE: May I point out that you have an article on the benefits of purple-colored foods in the October 2005 Life Extension News.*


*See Prevention of Obesity by Anthocyanins


SANDY: We’ve changed our diet recently. Now we’re eating everything blue and purple. Would you believe purple carrots and purple tomatoes? They’re called heirloom varieties.

LE: Would you believe a purple arginine drink? Thanks for a great discussion.

References

  1. Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, Carruba MO. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 2005 Oct 14;310(5746):314-7.
  2. Chalupsky K, Cai H. Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. Proc Natl Acad Sci USA 2005 Jun 21; 102(25):9056-61.
  3. Stroes ES, van Faassen EE, Yo M, Martasek P, Boer P, Govers R, Rabelink TJ. Folic acid reverts dysfunction of endothelial nitric oxide synthase. Circ Res 2000 Jun 9;86(11):1129-34.
  4. Stiefel P, Arguelles S, Garcia S, Jimenez L, Aparicio R, Carneado J, Machado A, Ayala A. Effects of short-term supplementation with folic acid on different oxidative stress parameters in patients with hypertension. Biochim Biophys Acta 2005 Nov 15;1726(2):152-9.
  5. Hyndman ME, Verma S, Rosenfeld RJ, Anderson TJ, Parsons HG. Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol 2002 Jun;282(6):H2167-72.
  6. Edmonds MS, Lowry KR, Baker DH. Urea cycle metabolism: effects of supplemental ornithine or citrulline on performance, tissue amino acid concentrations and enzymatic activity in young pigs fed arginine-deficient diets. J Anim Sci 1987 Sep;65(3):706-16.
  7. Flam BR, Hartmann PJ, Harrell-Booth M, Solomonson LP, Eichler DC. Caveolar localization of arginine regeneration enzymes, argininosuccinate synthase, and lyase, with endothelial nitric oxide synthase. Nitric Oxide 2001 Apr;5(2):187-97.
  8. Kuhn KP, Harris PA, Cunningham CG, et al. Oral citrulline effectively elevates plasma arginine levels for 24 hours in normal volunteers. Circulation 2002;206(Suppl II):II-339.
  9. Hayashi T, Juliet PA, Matsui-Hirai H, Miyazaki A, Fukatsu A, Funami J, Iguchi A, Ignarro LJ. L-Citrulline and L-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc Natl Acad Sci USA 2005 Sep 20;102(38):13681-6.
  10. Wheeler MD, Thurman RG. Production of superoxide and TNF-alpha from alveolar macrophages is blunted by glycine. Am J Physiol 1999 Nov; 277(5 Pt 1):L952-9.
  11. Go EK, Jung KJ, Kim JY, Yu BP, Chung HY. Betaine suppresses proinflammatory signaling during aging: the involvement of nuclear factor-kappaB via nuclear factor-inducing kinase/IkappaB kinase and mitogen-activated protein kinases. J Gerontol A Biol Sci Med Sci 2005 Oct;60(10):1252-64.
  12. L-Zhong Z, Wheeler MD, Li X, Froh M, Schemmer P, Yin M, Bunzendaul H, Bradford B, Lemasters JJ. L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. Curr Opin Clin Nutr Metab Care 2003 Mar;6(2):229-40.
  13. Dinarello CA. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 2006 Feb;83(2):447S-55S.
  14. Schulman SP, Becker LC, Kass DA, Champion HC, Terrin ML, Forman S, Ernst KV, Kelemen MD, Townsend SN, Capriotti A, Hare JM, Gerstenblith G. L-Arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA 2006 Jan 4;295(1):58-64.

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