Ribose QA

by Jerry Brainum

Synthesis Adenosine

ibose could potentially be the most significant new food supplement since creatine hit the m U market about six years ago. Until now, ribose was only meaningful to biochemists and medi -cal researchers. While it plays a pivotal role in the synthesis of adenosine triphosphate m % (ATP), the most elemental form of energy produced in cellular metabolism, and thus could -A- ^L. have important effects on energy and exercise recovery, until recently the only research on ri -bose had to do with its use in treating cardiovascular diseases.

Now, however, a new process of ribose production makes it more readily available to consumers. While I covered the basics about how ribose works in the body and why it could have a significant effect in ac -tive people, such as athletes and bodybuilders, in the previous article, I didn 'I answer all the questions about this substance. To complete the picture about the practical use of ribose, I inter\>iewed a man who is actively engaged in the marketing and research of it.

Clarence Johnson is the president and CEO of Bioenergy Inc., a company currently engaged in mar -keting ribose for public consumption. Besides being a business executive, Johnson has a solid scientific background. He has a master of science degree in microbiology from the University of Minnesota and has completed all but his defense of dissertation toward obtaining a doctorate in nutritional biochem -istry.

0: Since ribose helps the body produce ATP, why not just use direct ATP supple -ments?

A: ATP is a large and complex molecule not readily absorbed by the body. In addition, even if it could be efficiently absorbed, the ATP would not be shunted to tissues that are deficient in it. When tissues become energy depleted, they are, by and large, required to build their own energy stores.

Certain other adenine-nucleotide-pathway intermediates have been researched. Some are effective in increasing depleted energy stores. Adenosine, adenine, inosine, 5-amino-imida-zoicarboximide riboside (AICAR) are some of the ATP precursors that have been marginally useful in increasing ATP regeneration following energy depletion. In fact, my company has a patent on the use of ribose plus adenine for energy production.

Most studies involving these compounds have been of short duration, and only partial ATP recovery occurred. Furthermore, ATP precursors that are relatively distant in terms of the enzymatic steps required to re-form ATP may be less efficient in inducing ATP recovery, while structurally related precursors like adenosine exhibit undesirable side effects, such as vasoconstriction (tightening of blood

  1. Ronald Teijung and his colleagues showed that single doses as low as 2.2 grams were sufficient to increase nucleotide salvage after energy depletion by 177 percent over baseline. Single doses of 6.4 grams increase salvage by 536 percent of baseline.
  2. and slowed atrioventricular conduction (a disturbance in normal heart rhythm).

Q: Since ribose is a sugar, wouldn 't taking an oral ribose supple -ment result in its being metabolized directly to glucose?

A: The direct answer is no. Research conducted with 3H-labeled ribose has determined its metabolic route in the body. As quickly as five minutes to one hour following the appearance of ribose in the blood, it begins to appear in the cell nuclei of several tissues, including the liver, kidney, heart, skeletal muscle, smooth muscle and several others. Most of this ribose is directly metabolized to purines and pyrimidines, which are used for nucleic acid synthesis (mostly RNA) and nucleotides, such as ATP. RNA, of course, is required for protein synthesis, and the adenine nucleotides are used to build energy stores via ATP.

Some ribose is metabolized to glycogen in the cell cytoplasm (the space between the cell membrane and the cell nucleus). That's due to a flux of ribose up the pentose phosphate pathway (PPP) to glucose. The amount of ribose directed to this pathway is regulated by the requirements of the purine and pyrimidine pathways. Free ribose is first directed toward nucleotide and nucleotide biosynthesis, or nucleotide salvage, with flux up the PPP if an abundance of ribose is present.

A small amount of ribose is also metabolized to glycoproteins, which exist in many cellular secretions formed in the Golgi apparatus of cells. Those secretions may include pancreatic secretions, mucous and certain lipids, or fats; however, the glycoprotein secretions aren't relevant to the role of ribose in heart and skeletal muscle.

Q: What's the suggested optimum daily dose of ribose for athletic or exercise purposes, and what's that dose based on?

A: Scientists have worked out the dose-response kinetics describing the role of ribose in adenine nucleotide salvage. For example, research conducted by Dr. Ronald Terjung and his colleagues showed that single doses as low as 2.2 grams were sufficient to increase nucleotide salvage after energy depletion by 177 percent over baseline. Single doses of 6.4 grams increase salvage by 536 percent of baseline. In another study, Terjung's group determined that a single dose of 6.4 grams increased the synthesis of new adenine nucleotides in skeletal muscle by 340 to 430 percent, depending on muscle fiber type.

In a pilot study conducted at Ball State University in Indiana, researchers found that doses of 30 grams daily, taken as three doses of 10 grams each, increased total power output, peak power output and mean power output by 9.5 to 9.9 percent. That study also showed two additional and interesting findings. First, total adenine nucleotide levels— that is, the sum of ATP, ADP and AMP—in athletes decreased by up to 39 percent after high-intensity exercise. In short, energy levels dropped significantly following hard training. Second, after 48 hours of rest the athletes given ribose showed an increase in both ATP and adenine nucleotides, and they recovered to 85 percent of preexercise baseline. Athletes not taking the ribose continued to lose both ATP and total ade-

nine nucleotides and, therefore, showed no recovery at all. That result is consistent with the findings of other researchers, who also found little or no recovery in adenine nucleotide pools even after three days of rest following intense exercise.

What, then, is the proper dose of ribose? At this point we don't know More research is required, and Bioenergy is contracting with universities to continue those studies. We do know, however, that doses as low as 2.2 grams per day can provide beneficial effects, and higher doses may provide additional benefits.

At this point I'd suggest doses of three to five grams a day to maintain high levels of nucleotides in muscle. Higher doses may be taken to boost energy before and after high-intensity workouts or for competition. As a practical matter, though, I don't think it's necessary to take in more than 10 grams per dose. For best results I'd suggest taking a dose an hour or so before training and again 30 minutes after the workout. For maintaining ATP stores, it's best to take a single dose after a workout. More information on this will likely emerge with continuing re-

I don't think it's necessary to take in more than 10 grams per dose. For best results I'd suggest taking a dose an hour or so before training and again 30 minutes after the workout. For maintaining ATP stores, it's best to take a single dose after a workout.

After 48 hours of rest the athletes given ribose showed an increase in both ATP and adenine jcleotides, and they recovered ) 85 percent of preexercise baseline. Athletes not taking the ribose continued to lose both ATP and total adenine jcleotides and, therefore, showed no recovery at all.

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0: What's the maximum safe (lose of oral ribose supplements?

A: Research shows that up to 60-gram doses are safe. No one has yet examined doses higher than that. Such doses of ribose are not recommended, however. Dose levels greater than 20 grams may cause gastrointestinal discomfort and possibly diarrhea. That can happen with any carbohydrate consumed in single large doses.

In addition, high-dose ribose can lead to a slight, asymptomatic decrease in blood glucose levels. Some speculate that this is due to a mild insulin reaction that drives glucose out of the blood into tissues. The effect has occurred in studies involving dogs, but the human-based research isn't as clear at this point. Since athletes taking ribose will also likely get other carbohydrates, this effect should be of no particular consequence, since the carb ingestion will maintain blood glucose levels.

My company, Bioenergy, has obtained premarket clearance for sale of ribose as a supplement in doses of up to 20 grams. That would certainly be considered a safe dose.

O: Are there any long-term studies examining the effects of ingest -ing oral ribose supplements?

A: Several studies have examined the safety of ribose supplementation and infusion. One involved giving 60 grams a day to a single subject for one year without incident. Bioenergy has conducted laboratory-animal safety studies and found ribose to be safe; however, there aren't any studies that have investigated very long-term ribose ingestion at any dose level.

Bioenergy is engaged in clinical trials using ribose as an injectable drug. They're being conducted under an Investigational New Drug submission with f *

the Food and Drug Administration (FDA) and are about to move into phase-three, or multicenter trials. That means ribose has passed the first two safety hurdles required by FDA standards.

Q: How long should people take supplemental ribose without a break?

A: Again, to maintain adenine nucleotide levels at their peak, I'd suggest taking at least a maintenance dose daily. Clearly, that can be lower with less strenuous activity and increased as exercise intensity goes up.

Q: Recent creatine studies indicate that creatine should be taken in cyclical fashion, due to possible decreased creatine absorption follow ■ ing a downgrade of a creatine-carrier system in the body. Does the same hold true for ribose; that is, should it also be cycled for best re ■ suits?

A: Since uptake of ribose into cells occurs through facilitated diffusion and thus doesn't require any type of cellular carrier system, it need not be cycled. When a cell needs ribose, it will readily take it up. What must be adjusted is doses, which should be based on level of exercise intensity and frequency.

Q: Since ribose works by helping to preserve vital adenine nu ■ cleotides—that is, ATP precursors—why not just supplement them?

A: As I noted earlier in my explanation of why ATP itself isn't a useful supplement, various ATP precursors have been tested and found to be not as effective in helping to regenerate ATP as ribose supplements. The reason is simple: The limiting factor in salvage or synthesis of adenine nucleotides is a ribose compound called 5-phosphoribosyl-1-pyrophosphate, or PRPP, which must be present in sufficient amounts to drive the salvage and synthesis reactions. PRPP is essentially a ribose molecule with three phosphate groups attached. Supplemental ribose is the most direct route to production of PRPP in the cell.

Q: Are there any known medical contraindications to using oral ri -hose supplements, such as possible allergies or worsening of existing diseases? In short, are there some people who should not use this sup -plement?

A: Again, the only known side effects that have appeared thus far involved gastrointestinal problems such as diarrhea when large single doses of ribose were taken. However, anyone with hypoglycemia or a tendency to rapid changes in blood glucose levels should consult a physician before using ribose supplements.

Q: Some articles have warned against combining ribose with pro -tein supplements. Is that correct?

A: There's confusion on that point. In a short book recently published about ribose, Edmund Burke, Ph.D., suggests that ribose not be taken with protein-containing compounds, such as various types of supplements. The reason Burke suggests that is simple: Ribose is known as a reducing sugar, which means that when it mixes with certain other compounds, it creates reactions that convert it into something else.

For example, when ribose is mixed with protein and heated, it forms

Since uptake of ribose into cells occurs through facilitated diffusion and thus doesn't require any type of cellular carrier system, it need not be cycled. What must be adjusted is doses, which should be based on level of exercise intensity and frequency.

Cardiac research involving ribose shows that it improves performance when taken before and after stress. For long-term aerobic events, though, it may also be beneficial to use ribose during the event.

what's called the Milliard reaction with amino acids contained in the protein. That's the same process that turns meat brown when cooked and provides the typical aroma of cooked beef. In this case the functional benefits of ribose are lost. If the protein isn't heated or cooked, however, the Milliard reaction doesn't occur.

So, if you keep a protein mixture cold, no problems occur in reaction to ribose. If, however, ribose is mixed with protein and warmed up, such as what happens when you leave a protein drink in the hot sun or a hot car, a Milliard reaction may occur, and the functional benefit of ribose may be lost.

Q: What's the best way to take ribose supplements? With carbs, with meals or on an empty stomach ?

A: The best way to take ribose is probably with other carbohydrates or alone on an empty stomach. That would ensure maximum absorption. However, I'd suggest taking ribose an hour or so before and/or about 30 minutes after exercise. Cardiac research involving ribose shows that it improves performance when taken before and after stress. For long-term aerobic events, though, it may also be beneficial to use ribose during the event. Note that if used in this manner, a low dose is advisable to avoid an embarrassing side effect, such as diarrhea.

Q: How long does it take to feel the effects of a ribose supplement?

A: In our experience about 60 percent of the people who've taken ribose supplements actually feel an effect. Some say they just have more energy. Others believe they can train harder and longer. It usually takes about three or four days to get those feelings. I would emphasize, however, that the research suggests that everyone taking ribose will get a beneficial effect if he or she exercises hard enough to deplete adenine nucleotide pools. Users may not feel it, but ribose is still working to enhance their energy and recovery.

The biochemistry about this is quite clear. Adenine nucleotides decrease in all strenuous exercise under both aerobic and anaerobic conditions. If an athlete exercises hard enough to lower cellular energy charge, then ribose will assist in recovery. It's like a rapid recharge on a rechargeable battery.

Q: What beneficial effects can a person using ribose supplements expect? Do they include increased energy? Added strength? In -creased exercise recovery?

A: There's absolutely no question that ribose supplementation will positively affect heart and muscle cell recovery following high-intensity exercise, and in most cases users will feel more energetic.

The body requires ribose to form adenine nucleotides, such as adenosine triphosphate (ATP). Research has shown, however, that the metabolic pathway leading to ribose production in heart and skeletal muscle isn't efficient, due to a lack of a specific enzyme called glucose-6-phosphate dehydrogenase (G-6-PDH) that regulates the pentose phosphate pathway in cells. In other tissues, such as liver and kidneys, the pathway isn't rate-limited by the enzyme. Consequently, the kid-

There is absolutely no question that ribose will positively affect heart and muscle cell recovery following high-intensity exercise, and in most cases the user will feel more energetic.

neys and liver can make as much ribose as they need, although that source of ribose isn't available to other organs and tissues. Each cell must maintain its own supply of ribose for nucleotide and RNA production. As energy-producing substrates are used up and lost, they must be replenished. That's where ribose comes in.

Does it add up to increased strength levels? I don't know. It's often suggested, however, that the key to increased muscle strength is increased muscle recovery. Muscles—including the heart—must have the highest amount of energy possible to perform at maximum load. To the extent that ribose improves recovery, it's reasonable to expect that it will help increase strength over time. That's evidenced by the Ball State study discussed above, in which subjects taking ribose were able to perform more work, as measured by higher total, peak and mean power

To the extent that ribose improves recovery, it's reasonable to expect that it will help increase strength over time. Energy is the key to performance, and without question ribose maintains energy in stressed cells.

outputs. Energy is the key to performance, and without question ribose maintains energy in stressed cells.

Q: Are any existing food supplements synergistic with ribose, and, conversely, should some supplements be avoided when people take ri -bose?

A: The metabolic actions of common food supplements are unique. Creatine, for example, increases energy by providing an increased pool of creatine phosphate to drive the passing of a donated phosphate in the recycling of ADP (adenosine diphosphate) to ATP. Carnitine helps to ferry fatty acids across the mitochondrial membrane, which enhances energy production from fatty acid metabolism. Pyruvate enhances the TCA, or Krebs, cycle that drives the electron transport system in cells, leading to enhanced ATP cycling from ADP. Those nutrients are all unique, but they're all interrelated. They do have one thing in common though: They don't work well without a sufficiently high pool of adenine nucleotides to recycle.

Strenuous, high-intensity exercise decreases the pool of adenine nucleotides in heart and skeletal muscle. That point is beyond debate; it's an established fact. Ribose effectively increases those pools, and as such, it's synergistic with all the compounds that increase the available pool of adenine nucleotides for the above compounds to work with. Thus, while the metabolic mechanisms of the different nutrients are unique, they're also interrelated.

Q: Does ribose also interact with creatine supplements in terms of increasing the effectiveness of creatine in the body?

A: While ribose doesn't directly interact with creatine supplements, it does directly affect the adenine nucleotide pool and so enables creatine to work more effectively. In that sense, ribose does increase the effectiveness of most creatine supplements.

Q: Can people take ribose and creatine at the same time, or should the supplements be used at different times?

A: Ribose is definitely compatible with creatine and can be used at the same time.

Q: Since the average single dose of creatine is five grams, or one teaspoon, what would constitute an average dose of ribose?

A: Ribose is a fairly expensive supplement, due to relatively high production costs, so users may want to experiment with ribose doses. I suggest taking 2.2 grams before and after your workout. That's consistent with the research.

Q: I understand that ribose hasn't been commercially available until now because in the past it was prohibitively expensive to manu -facture. Why is the current process more economical?

A: That's a complicated question. There are two basic ways to produce ribose. The expensive technique involves growing yeast cells to high biomass, breaking them apart, collecting the contained nucleic acids (DNA and RNA) and, finally, breaking apart the nucleic acids to collect the ribose. Plenty of steps and expense are involved.

We make ribose by direct fermentation from corn sugar (glucose), a process that's similar to making cheese or other fermented foods. Bacteria in the fermentation eat glucose and produce ribose through their metabolism. We collect, purify and crystallize the ribose. Since the process contains fewer steps, it's less expensive.

Q: What specific adenine nucleotides are lost during intense exer -cise?

A: An excellent question! The adenine nucleotides include adenosine triphosphate, adenosine diphosphate and adenosine monophosphate (AMP), which collectively supply the vast majority of cellular energy and fuel such activities as muscle contraction. Energy is provided to the cell each time one phosphate group is broken down into another (ATP to ADP to AMP). Under normal conditions, with abundant oxygen available, the recycling of ADP to ATP occurs instantaneously and energy is recycled. When oxygen is depleted, as occurs during high-inten-sity exercise, though, the recycling process cannot keep up.

When there isn't sufficient oxygen, ADP further degrades. Two molecules of ADP combine to form one molecule of ATP and one molecule of AMP, and the ATP helps the cell perform work. As the process continues, however, the cell suffers an increase in AMP concentration, which it cannot tolerate. Cells need to maintain a careful balance between ATP, ADP and AMP concentrations to maintain normal work and stay healthy. When AMP levels rise, the ratio is pushed out of whack, and the cell must do something to decrease the rising AMP levels.

Skeletal muscles have a few options to correct the imbalance. Notable among them is a process for releasing AMP metabolites from the cell to lower overall AMP concentration; however, that leads to a reduced total adenine nucleotide pool, and it can be a significant reduction. For instance, 50 percent decreases in adenine nucleotide pools have been observed in the heart, and published reports show that the pool can drop 32 percent or more in skeletal muscles. Again, fewer adenine nucleotides mean less ATP, which equals less cellular energy.

Q: Since some rare cases of hypoglycemia, or low blood sugar, can occur with higher doses of ribose, should people who have a tendency to blood sugar fluctuations or diabetes be wary of using ribose?

A: High doses of ribose do decrease blood glucose levels. That's the bad news. The good news is that the blood sugar drops aren't usually noticed and are often transient, meaning that they don't last too long. Still, people who have hypoglycemia or diabetes should consult with their physician before using ribose supplements.

Q: Is supplemental ribose just aimed at active people engaged in sports or exercise, or can it also be used to advantage by sedentary people seeking increased energy?

A: The answer is a resounding yes. Anyone who feels he or she needs more energy can take ribose. While we haven't yet conducted specific trials to document that, my company has supplied ribose supplements

Strenuous, high-intensity exercise decreases the pool of adenine nucleotides in heart and skeletal muscle. That point is beyond debate; it's an established fact. Ribose effectively increases those pools.

While ribose doesn't directly interact with creatine supplements, it does directly affect the adenine nucleotide pool and so enables creatine to work more effectively. In that sense, ribose does increase the effectiveness of most creatine supplements.

Ribose Users

to several people who are sedentary or who exercise lightly. They have generally reported feeling more energetic while taking ribose. While I admit that's entirely anecdotal, it does point to some benefits from ribose for such people.

O: Is ribose safe for pregnant or lactating women? Is it safe for children ?

A: To my knowledge, there's never been a study that specifically looked at the safety of ribose in pregnant or lactating women. Even so, ribose is an all-natural and easily metabolized simple carbohydrate, so there's no reason to suspect that it wouldn't be safe for pregnant or lactating women—or children—if taken in moderate doses.

O: Are some forms of ribose superior to others?

A: The key to how good ribose is lies with its purity. Several impuri-

ties can be found in ribose. Virtually all of them are other sugars, such as glucose or arabinose, or sugar alcohols such as sorbitol. The impurities may be hard to find with standard analytical techniques because they're hidden by the ribose. By and large, such impurities aren't toxic, but they also aren't ribose.

Bioenergy supplies highly purified ribose manufactured in the United States. Our plant operates under good manufacturing practices (GMP) as defined by the Food and Drug Administration for food production and is available for inspection at any time. Final purification of our product is done at a plant that also makes pharmaceuticals. Such plants must provide the highest purity possible. Other suppliers of ribose import their products from overseas, and those products may come from plants that don't meet GMPs and aren't available for ready inspection. Purity does matter.

Q: Do you anticipate that ribose will be an expensive supplement in comparison to creatine supplements?

A: Unfortunately, I do. The manufacturing process for ribose is much more complicated than that of creatine, which will keep the price higher. As production volume and efficiency increase, however, the possibility exists that ribose prices will become more moderate.

Q: Will ribose work better for a world-class athlete than it will for the average gym jockey?

A: That's a tough question, as there are lots of factors at play. World-class athletes are different from the rest of us. They're often genetically gifted and through years of training have conditioned their muscles to react more efficiently and effectively. Being human, though, they still lose adenine nucleotides after intense athletic or exercise activity.

Anyone who exercises at high intensity will lose those nucleotides and will benefit from using ribose supplements. The degree to which people lose nucleotides and the speed of recovery may vary, but all will benefit. In that respect I don't expect a world-class athlete to react more favorably to ribose than the average gym jockey, assuming that the gym jockey works out to his or her fullest capacity.

Q: How can ribose be used to treat various medical conditions?

A: My company is currently conducting clinical research involving the use of ribose in treating ischemic heart conditions. A large volume of other research from labs in the U.S., Europe and Japan has been conducted over the past several decades and has shown considerable efficacy for ribose in the treatment of energy-deficient hearts.

Ribose is also useful in treating other medical conditions. Any pathology involving a deficiency of ribose-producing enzymes may be improved with supplemental ribose.

Q: Do you anticipate ribose supplements eventually becoming as popular as or even more popular than creatine supplements?

A: I must say that I really do. While ribose is more expensive than creatine, it's an incredibly effective nutrient for energy recovery. Only ribose can maintain the body's adenine nucleotide pools, which are the

Anyone who exercises at high intensity will lose those nucleotides and will benefit from using ribose supplements. The degree to which people lose nucleotides and the speed of recovery may vary, but all will benefit.

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