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Four powerhouse nutrients

L-carnitine shuttles fuel into cells to be burned as energy; coenzyme Q10 sparks the energy within the cells; ribose is a component of adenosine triphosphate (ATP); and alpha-lipoic acid increases ATP levels. TODD RUNESTAD delves into the evidence behind these energy-producing ingredients

Energy is the capacity to produce changes in matter or the ability to move something — to do work. Although energy cannot be created or destroyed, it can be converted from one form to another. So touching a lit match to a log, for instance, breaks molecular bonds and energy escapes from the wood as heat and light. The trick is to provide consumers with energy sources that make the wood burn more efficiently, or add more wood to the fire, rather than the equivalent of pouring gasoline on the wood — that would make it burn faster, but shorter.

In human terms, what is of interest to nutritional ingredients suppliers and product developers is to create lasting energy as opposed to a jolt in insulin response. Calories provide energy, of course, yet consumers are not exactly clamouring for 2,000-calorie energy bars. Glucose is the best energy source, but it can spike the insulin response in an unhealthy manner. Stimulants like caffeine or ephedra provoke a state of temporary excitement. Both glucose and stimulants, however, lead to the inevitable crash.

Like a piece of wood, glucose molecules are burned — oxidised — during respiration. The energy released by glucose oxidation is used to promote cellular metabolism. The early, anaerobic phase of cellular respiration involves a partial breakdown of energy-supplying molecules such as glucose and results in a gain of only a few molecules of the energy-carrying substance adenosine triphosphate (ATP).

The complete aerobic breakdown of glucose occurs in the mitochondria. During this process, the pyruvic acid that was converted from glucose in the anaerobic phase is converted into acetyl coenzyme A. These molecules enter a complex series of reactions of the Kreb?s cycle that produces a relatively large number of ATP molecules. ATP in turn is used to provide energy for most of the immediate work that the cell does. The cell gets energy from ATP by using a chemical process to cleave off one of the three phosphate molecules to create ADP — adenosine diphosphate.

The issue is one of improving the efficiency and effectiveness of energy production, as opposed to a temporary metabolic kick or glucose response. For product developers, the search is on for nutrients that improve the conversion of fatty acids and other compounds into energy, a transfer from chemical to mechanical energy — mitochondrial ingredients, if you will.

Carnitine fuels the fire
Humans have two primary sources of fuel: sugar and fatty acids. The metabolism of fat produces roughly twice as much energy as carbohydrates. Fatty acids are the primary energy substrate for the production of ATP by oxidation.

In order to be used for bioenergetic production via mitochondrial fatty acid oxidation, long-chain fatty acids need to be effectively transported into the mitochondria. A breakthrough discovery occurred in the 1960s when the vitaminlike compound carnitine was found to act as a shuttle for lipids into the mitochondria.1 This process requires several transport proteins including the carnitine shuttle — carnitine acyltransferase and two carnitine palmitoyl transferases, as well as carnitine.2 Supplemental L-carnitine can significantly increase fatty acid oxidation in healthy adults.3

Carnitine?s energy applications have been shown in endogenous carnitine content in active elderly people, in chronic fatigue syndrome patients, in certain vascular conditions, in end-stage kidney failure and for athletes. The evidence base is sometimes equivocal but there remains much promise in the nutrient. Notably, doses of several grams cause no toxicity.

In a study that demonstrated the value of carnitine to energy and quality of life, centenarians (mean age 102) had higher mean serum carnitine levels (8.99mg/L) than elderly (mean age 66) control individuals (7.71mg/L). This was associated with improved physical and mental activity. The centenarians did not receive supplemental carnitine.4

In a study that showed carnitine?s energy utility for older people, a placebo-controlled, randomised, double-blind trial investigated 84 elderly subjects with onset of fatigue following slight physical activity. The supplementing group received oral 2g L-carnitine twice daily. Their physical and mental fatigue was measured using the Wessely and Powell scale. After 30 days, these scores decreased significantly by 40 per cent (physical fatigue) and 45 per cent (mental fatigue), compared to 11 per cent and 8 per cent, respectively, in the placebo group. The supplementing group also experienced increased total muscle mass, reduction of total fat mass and an improved serum lipid profile.5 When taken orally, carnitine has a systemic bioavailability of 5-15 per cent.6,7

The debilitating fatigue inherent in chronic fatigue syndrome can be ameliorated with L-carnitine. In a two-month comparison study against amantadine, carnitine was better tolerated and demonstrated significantly better clinical parameters among 30 patients with chronic fatigue syndrome.8

Another important function of L-carnitine is the ability to shuttle short chain fatty acids from inside the mitochondria to the cytosol — the protein-rich watery pool in which the cell organelles are suspended. Because of this detoxification action, L-carnitine is responsible for maintaining energy metabolism of the whole body.9

Muscular metabolism is based on a complex network that involves energy-producing enzymes and fatty acids. It is within the mitochondria that the first step of their utilisation takes place, and carnitine plays a fundamental role in their metabolism. Carnitine plays a positive role in improving muscle function and physical performance in patients with peripheral vascular disease10 or end-stage renal disease11,12 — although a 2005 review by a researcher at Harvard Medical School asserts an ?unproven benefit? to carnitine in dialysis patients.13

A deficiency of carnitine results in a decrease in fatty acid concentrations in the mitochondria, thereby reducing energy production. Carnitine deficiency in humans is therefore associated with myopathy and impaired fatty acid oxidation.14 Because of L-carnitine?s function as a regulator in the fat-burning process, it follows that it plays an important role in regulating weight and increasing energy levels.

Perhaps the best way researchers have explored carnitine?s effects is to test its results in exercise situations. Impairment of muscle contractility due to fatigue may play a role in determining human performance. Through unclear mechanisms, high carnitine concentrations were shown to delay muscle fatigue and permit improved maintenance of contractile force in studies using in vitro animal systems.15,16 Data suggests L-carnitine supplementation can speed up recovery from exercise stress by reducing lactate production, which decreases muscle soreness post-exercise.17

In continuing debate over L-carnitine?s energy efficacy, it has been noted that skeletal muscles are the main reservoir of L-carnitine in the body and possess carnitine concentrations at least 50-200 times higher than in blood plasma.18 At rest, the skeletal muscle carnitine pool is distributed as 80-90 per cent carnitine, 10-20 per cent short-chain acylcarnitine and less than 5 per cent long-chain acylcarnitine.19 Exercise for 60 minutes at low intensity has no effect on the skeletal muscle carnitine pool. However, after only 10 minutes of high-intensity exercise, the muscle carnitine pool is redistributed to 40 per cent carnitine and 60 per cent short-chain acylcarnitine.19,20 This redistribution is accentuated over a further 20 minutes of exercise and does not fully normalise over a 60-minute recovery period.19

The question remains over whether supplementing with carnitine would alter the muscle carnitine pool. A 2000 review by Eric Brass, MD, PhD, at Harbor-UCLA Medical Center of short-term (less than one month) carnitine supplementation concluded that while trials of up to one month in duration increase plasma carnitine levels, carnitine has no effect on muscle carnitine concentrations, and thus is questionable in its effect on athletic performance.21

Brass, who has published widely on carnitine research including with Italian carnitine supplier Sigma-Tau, reports that carnitine is effective in end-stage renal disease patients for whom reduced exercise tolerance is a symptom.22,23 His most recent review reports ?Several, but not all, studies suggest that subjects on carnitine supplementation have altered regulation of fuel homeostasis.?24 He notes further that small changes, which may be very important to the athlete, are seen with carnitine supplementation. As for the armchair athlete, he concludes, ?While data do not allow a conclusion to be drawn that carnitine is beneficial, the negative has not been proven either.?

Co-Q10 fuels mitochondria
When sugars and fatty acids are ferried by carnitine into the mitochondria, electrons extracted from the raw materials are processed by enzymes to produce ATP. Often the protein portion of an enzyme is inactive until it is combined with an additional substance. This part is needed to complete the active form of the enzyme molecule or bind the enzyme to its substrate. Such a substance is called a coenzyme. Coenzyme Q10 is an essential component of the mitochondria, where it plays a major role in energy production.25 The extracted electrons are shuttled back and forth between enzymes by co-Q10.26

In addition, co-Q10 has antioxidant effects inside the critical mitochondrial membranes where bioenergetics take place. Oxidative damage within the mitochondria leads to impaired ATP production. During ageing and some neurodegenerative diseases, oxidatively damaged mitochondria are unable to maintain the energy demands of the cell, leading to an increased production of free radicals and may induce premature apoptosis.27 The so-called mitochondrial theory of ageing — a takeoff of Denham Harmon?s famed antioxidant theory of ageing — considers mutations of mitochondrial DNA induced by free radicals as the primary cause of energy decline.28 Co-Q10 is lauded as a primary antioxidant on this front because it is the only endogenous lipophilic antioxidant.29 While co-Q10 does not alter genetic defects in mitochondria, it likely benefits the sequence of mitochondrial impairment from such defects.26

Co-Q10 is primarily known for its cardiovascular benefit because of the high co-Q10 content of the heart muscle. Patients with heart failure have reduced myocardial tissue content of co-Q10, and the greater the deficiency correlates to severity of heart failure.30 In addition to improvements in New York Heart Association classification of condition severity and reduced hospitalisation frequency, co-Q10 supplementation in heart patients also improves exercise capacity. Because cardiac and skeletal muscles have common physiological and bioenergetic features, it is proposed that co-Q10 can similarly help with physical performance. (Statin drugs, used to keep cholesterol levels in check, ironically also deplete the body of co-Q10 because the inhibition of cholesterol biosynthesis also inhibits the synthesis of co-Q10.)31

To further this theory, the peak co-Q10 value in humans in most organs is reached at 20 years of age, and is followed by a continuous decline, with hearts 77-81 years old containing only 43 per cent of the content as from hearts in patients 19-21 years old.32

In a comparison of rats either given co-Q10 for life compared to controls, the supplemented group lived significantly longer with the ?most spectacular? difference being the greater activity level in the supplemented group.33

One of the most lauded of human studies with co-Q10 and exercise performance, a 1997 Finnish study of 25 top-level cross-country skiers who took 90mg/day demonstrated significant performance improvements in aerobic, anaerobic and VO2 max indices. Fully 94 per cent of skiers felt that the supplement had improved their performance and recovery time vs 33 per cent in the placebo group.34

In the same year, a month-long Australian study using similar quantities of supplemental co-Q10 in male road cyclists and triathletes found significant increases in plasma co-Q10 levels, but no correlating improvements in aerobic, anaerobic, oxygen uptake, blood lactate, heart rate, lipids or blood pressure.35

Indeed, in a recent review of 11 studies in which co-Q10 was tested for an effect on exercise capacity, six showed a modest improvement, yet five showed no effect.36 The review did find, however, significant benefit in hypertension and in heart-failure studies.

A study of middle-aged, post-polio and healthy subjects supplementing with 100mg/day for six months found co-Q10 positively affected muscle energy metabolism in the post-polio individuals to a greater extent than in the controls.37

In a real-life study of 15 middle-aged untrained men who took 150mg/day for two months, they experienced plasma co-Q10 increases, as well as increases in their subjective perception of vigour. However, VO2 max was unchanged in this uncontrolled non-blinded trial, and while lactate release during handgrip testing tended to decrease, it was not to a significant degree.38

The conclusion at this point may be that while co-Q10 certainly acts as an antioxidant (and thus may have long-term effects on health and ageing), and supplementation increases blood levels of the nutrient, supplementation may only benefit those who are compromised with specific cardiovascular issues, rather than healthy individuals.

D-ribose comprises ATP
The difference between the aforementioned duo and D-ribose is that ribose can actually replace the energy pool within cells. D-ribose is a structural component of ATP, along with adenine and phosphate. Energy is created when the last phosphate of ATP cleaves off. De novo synthesis of ATP is a relatively slow process, requiring the body to convert glucose to ribose and then ATP. Supplemental ribose forms the precursor to ATP directly upon entering the muscle cell and can thus bypass the pathway.39 Ribose passes through cellular membranes efficiently and can increase ATP levels.40

Supplemental ribose forms the precursor to ATP directly upon entering the muscle cell
In particular, once ATP levels have been depleted because of physiological stress or exercise, it takes as much as three days to restore levels. Following ischaemia, it may require as long as 10 days for recovery. 41 In a rat study using intravenous ribose, the repletion time was cut to 12 hours. 42 Indeed, ribose was originally developed for pharmaceutical applications to speed up heart patient recovery after surgery. Research frontiers became expanded after ribose?s demonstrated efficacy on the heart (the body?s largest muscle, after all) to touch on skeletal muscle improvement and overall energy.

In a human study of 20 patients with documented severe coronary artery disease, 60g/day ribose in four oral doses significantly improved the time they were able to exercise comfortably, by 30 per cent. The control group showed no improvement.43

A double-blind, placebo-controlled trial of ribose supplementation (10g/day) assessed exercise performance and body composition in young, male recreational bodybuilders. After four weeks, the ribose group experienced significant pre-treatment to post-treatment increases in total work performed and bench press strength, though there was no difference noted in measures of body composition.44

In two in vivo rat models with heart infarct that were given intravenous ribose, the cardiac adenine nucleotide pool was normalised by ribose, which also resulted in an improvement of global heart function.45 Of note, a combination of ribose with adenine or inosine was more effective in completely restoring cardiac ATP levels than either intervention alone.

ALA increases ATP
Alpha-lipoic acid (ALA) plays an important link in cell respiration, in particular glycolosis and the Kreb?s cycle. Most of the metabolic reactions in which ALA participates occur in mitochondria. Supplemental dihydrolipoic acid (DHLA) — the reduced form of alpha-lipoic acid — has been shown to increase ATP synthesis in the mitochondria of heart cells in a rat model.46

It is believed that increased ATP production occurs because of ALA?s role in the oxidation of pyruvate and the alpha-ketoglutarate in the mitochondria.47 For energy metabolism to progress to the Kreb?s cycle, pyruvate must be converted into acetyl-CoA. Alpha-lipoic acid is one of four coenzymes required by the body in order to create acetyl-CoA. Oxidative phosphorylation completes the complex procedure of capturing energy and ultimately enhancing energy production.48

Alpha-lipoic acid also houses antioxidant properties in both lipid and water regions of the cell. Advanced glycation end products (AGEs), which accumulate on long-lived proteins including in Alzheimer?s disease, are suggested to contribute to apoptosis, decreased cellular ATP levels, and increased glucose consumption and lactate production. Researchers in Germany recently discovered that these AGE-induced metabolic changes can be attenuated by ALA.49 The researchers postulated that ALA may be useful against AGE-influenced effects in neurodegeneration through their positive effects on cellular energy metabolism.

Alpha-lipoic acid has also been seen to be a useful partner with L-carnitine in ameliorating mitochondrial decay in the ageing heart. Mitochondria from aged tissue use oxygen inefficiently, decreasing activities of mitochondrial enzymes, impairing ATP synthesis and increasing oxidant production.50 Because the heart may be susceptible to mitochondrial dysfunction due to myocardial dependency on beta-oxidation of fatty acids for energy, researchers at the Linus Pauling Institute in Oregon studied mitochondrial beta-oxidation with L-carnitine in rats.51 While mitochondrial beta-oxidation improved, the carnitine did not reverse the age-related decline in antioxidant status. The researchers then added alpha-lipoic acid as a co-supplement both because of its major role in cellular metabolism as a cofactor for mitochondrial enzyme complexes as well as due to its antioxidant properties.47,52 Adding alpha-lipoic acid to the mix positively addressed the deficiency in carnitine?s overall performance.

Better than improving markers of energy improvement, the same researchers then assessed actual ambulatory activity in young and old rats with the carnitine and lipoic acid supplementation regime. They found that the metabolic rate and oxidative stress as well as mobility of old rats were restored to that of unsupplemented young rats.53

Interestingly, the reduced form of alpha-lipoic acid, dihydrolipoic acid, has been shown to be a more efficient scavenger of free radicals in reducing both vitamins C and E radicals.54

In a rat study, ATP levels were significantly higher with hearts perfused with DHLA than those without.55

While most of these studies are in rat models, one human study found that supplemental ALA both reduced ALA deficiencies with liver disease and increased ATP content.56 Additional human studies are likely required to assess the effectiveness of ALA — as well as DHLA — in increasing human energy.

Whether incorporated into bars, beverages or other delivery systems, harnessing nutrients to increase overall human energy capacity and day-to-day activities is the next great frontier in functional foods development. The energy drinks category has greatly expanded even as the ephedra market has disappeared, yet ingredients that are essentially stimulants buoyed the category. Developing products using ingredients that naturally increase energy in healthful ways will pave the way to these next-generation consumer products.

Todd Runestad is science editor of Functional Foods & Nutraceuticals. Respond: [email protected]

Table 1

Potential mechanisms for a beneficial effect of carnitine supplementation on exercise performance in healthy humans

  1. Enhance muscle fatty acid oxidation
  2. Decrease muscle glycogen depletion rates
  3. Shift substrate used in muscle from fatty acid to glucose
  4. Replace muscle carnitine redistributed into acylcarnitine
  5. Activate pyruvate dehydrogenase via lowering of acetyl-CoA content
  6. Improve muscle fatigue resistance
  7. Replace carnitine lost during training

Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr 2000 Aug; 72(2 Suppl):618S-23S.

Energy drinks are on the house
Opportunities have never been greater for beverage makers striving to do more than just satisfy thirst. For consumers looking for a pick-me-up, caffeine has never been seen in such a range of beverage delivery systems. Indeed, energy beverages were the fastest-growing US supermarket item in 2003, jumping 56 per cent in mass market sales (while carbonated soft drinks declined), according to Information Resources Inc.

Caffeine- and taurine-containing drinks have been on the European market for about 15 years now. Leading the way in the US is Red Bull, which is commonly used as a drink mixer with alcoholic beverages.

But why use a mixer when you can mix the stimulant right into the alcohol? That seems to be the sentiment with a new round of beers and booze with the kicker brewed right in. Beer king Budweiser recently launched ?B-to-the-E? — a saucy combination of beer and caffeine, including ginseng and guarana, a botanical with natural caffeine content. New Century Brewing, in Massachusetts, just launched Moonshot, a pilsner beer with a shot of caffeine. Engine Energy Gin Energy Drink is a new launch in Russia that combines gin with guarana.

Guarana is being sourced by manufacturers who are trying to get around using ?caffeine? on labels. It is also a way of differentiating a product from the caffeine-based drink mixers (Red Bull) and the salt-replacing sports drinks (Gatorade).

Across Europe, beverage manufacturers are jumping on the bandwagon. In Italy, the Shark company has introduced a beverage with guarana, as well as actives such as taurine, glucuronolactone, choline, caffeine, lysine, inositol and vitamins. In the UK, EJ-10 Liquid Performance Drink contains phosphatidylserine, maltodextrins and isolated proteins, but avoids both caffeine and taurine.

At the other end of the spectrum, Cult Energy Activator, out of Norway, goes whole hog with guarana, ginseng and caffeine.

Other botanical-infused beverages include Jugular Energy Drink, which contains eleutherococcus (also known as Siberian ginseng) and rhodiola, as well as L-carnitine and taurine. Rhodiola has been shown to improve energy levels without the letdown, and help alleviate stress.

Soy has even entered the pitch in sports beverages through soybean peptide, a bonding of multiple amino acids that absorbs in the intestinal tract faster and more efficiently than amino acids and may help produce energy faster than other amino acids. PowerAde, from Coca-Cola Japan, has 4g of soybean peptide — which is different from the PowerAde available in the US, which has B vitamins as its actives.

The branched chain amino acids — isoleucine, leucine and valine — are unique among amino acids in their ability to provide energy during endurance exercise. These are found in whey protein, which will likely find its way out of the protein powder market and into beverages.

Indeed, the beverage delivery system clearly shows no signs of letting up as far as innovative ingredients, formulations and product launches.


Is the secret just in the caffeine?
Studies demonstrate that functional energy drinks, which contain known levels of caffeine as well as other ingredients — notably the amino acid taurine — do indeed keep consumers up longer. Is it all in the caffeine?

Three recent studies by a pair of researchers at Loughborough University Sleep Research Centre in the UK found that caffeine-containing drinks all significantly reduced sleep-related driving incidents and subjective sleepiness for 30-90 minutes among sleep-deprived subjects.1,2,3

Another study went one better and compared Red Bull to placebo for stimulant properties. It found that while placebo drinkers experienced significantly decreased scores regarding vitality, social extrovertedness and well-being, the Red Bull group had no change. Notably, because half of the study cohort was noncaffeine users, the effects cannot be explained in terms of the restoration of plasma caffeine levels following caffeine withdrawal.4

In order to also check the caffeine withdrawal hypothesis, British researchers allowed subjects to drink coffee freely before a short-term study assessing mood, memory and information processing. The placebos were a sugar-free and a sugar-containing drink, in order to examine the effects of sugar. In both studies, the caffeinated, taurine-containing beverage produced improved attention and verbal reasoning, compared to the sugar-free and sugar-containing drinks — meaning something besides a glucose response was going on.5

Finally, German researchers compared the cardiac parameters of 13 trained athletes with Red Bull vs a similar drink (that also contained caffeine) only without taurine and a third drink without either caffeine or taurine.6 Cardiac stroke volume — blood pumped by the heart — improved only in the Red Bull group. Furthermore, in this group the peak late diastolic inflow was significantly higher compared with pre-exercise levels. Notably, this observation was also made in the caffeine group — but without any consequences on ventricular function, which can presumably be attributed to taurine (though a synergistic effect with glucuronolactone cannot be ruled out entirely).


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