by Dr. Joseph Debé
Creatine monohydrate is primarily known as an ergogenic aid used by power athletes and bodybuilders to increase strength and muscle mass. However, it has also been successfully used to treat a variety of health conditions and is continually finding new applications. Creatine supplementation has numerous physiological effects, which have the potential to substantially reduce morbidity and mortality.
Creatine (methylguanidine-acetic acid) is formed in the liver, kidneys, and pancreas from arginine, glycine and methionine and is transported through the bloodstream to various tissues. Plasma creatine is taken up into the cell by a creatine transporter protein, which is also used to transfer creatine across the blood-brain barrier. Once inside the cell, creatine is readily phosphorylated to produce phosphocreatine, which is the form that acts like a battery recharger for ATP. Creatine's most important role in human physiology is to contribute to maintenance of ATP levels. When ATP dissociates into ADP and phosphate to produce energy for muscle contraction and other metabolic functions, phosphocreatine donates its phosphate group to ADP to regenerate ATP. This is a reversible reaction, catalyzed by creatine kinase enzymes. At rest, when ATP levels are being replenished via oxidative phosphorylation, ATP will donate a phosphate group to creatine to regenerate phosphocreatine stores.
About 95% of the body's creatine is found in the skeletal muscles, particularly type 2 fibers. Creatine is also found in other tissues, including the brain, heart, endothelial cells, macrophages, kidneys, liver, smooth muscles and testes. The body has a limited capacity for creatine synthesis and those individuals who consume creatine-rich foods have higher creatine tissue levels. Dietary creatine is most concentrated in herring, pork, beef, salmon and tuna. Consistent with this fact, vegetarians appear to have lower tissue creatine concentrations. Low phosphocreatine levels result in lower levels of ATP. Greater phosphocreatine levels translate into greater cellular energy production. With regard to skeletal muscle, phosphocreatine is involved primarily in the first ten seconds of very high intensity contraction.
The benefit one derives from creatine supplementation depends upon how much his or her tissue creatine levels increase. This depends upon several factors, including the starting level of tissue creatine. Creatine supplementation can increase tissue concentrations to a level that is unobtainable through diet alone. There is, however, a limit as to how much creatine a cell can contain (about 160 mmol/kg dry muscle). The activity of the creatine transporter plays an important role in the ultimate response to creatine supplementation. It is one thing to raise plasma creatine levels through supplementation but the benefits from creatine come only through transport into the cell, by the creatine transporter. Insulin has clearly been demonstrated to stimulate cellular creatine uptake. Accordingly, concomitant supplementation of large doses of carbohydrate and protein has been found to increase cellular creatine accumulation. There is also evidence that the insulin sensitizing compounds alpha lipoic acid and D-pinitol can facilitate cellular creatine accretion. High intensity exercise promotes creatine transport into the muscles that are worked. In vitro studies have also shown stimulation of the creatine transporter by IGF-1, triiodothyronine, and norepinephrine. Beta-adrenergic receptor antagonists, on the other hand, reduce creatine concentrations. Aging is associated with lower skeletal muscle creatine and phosphocreatine levels. After age 30, phosphocreatine resynthesis rates after exercise fall 8% per decade.
Supplementation of creatine can raise skeletal muscle creatine levels 10-30% and phosphocreatine levels 10-40%. Creatine supplementation has been found in numerous studies to increase short-term power and muscular strength, as well as muscle mass. It also results in quicker restoration of energy after exertion and therefore improves performance in repetitive bouts of very high intensity exercise. About 70 to 80% of studies have shown positive results. Typical responses to creatine supplementation are an additional 10 to 15 % increase in strength and an additional 1 to 3 % increase in muscle mass over one to three months of resistance exercise training. In Biomarkers - The 10 Keys to Prolonging Vitality, Evans and Rosenberg rank the top ten modifiable biomarkers associated with biological aging. The number one biomarker is muscle mass. From age 20 to 80, the average person loses 20 to 30 % of their muscle mass. Loss of muscle mass, also known as Sarcopenia, produces a multitude of negative metabolic changes, which are incompatible with good health. The number two biomarker is strength. The importance of strength in the elderly is exemplified by simple, yet critical, actions such as being able to arise from a chair or avoid a fall. Inability to carry on activities of daily living due to muscular weakness is a major cause for loss of independence. Additionally, a study of 8,762 men examined the relationship between strength and longevity. The men were assessed for strength at the beginning of the study. Nineteen years later, it was determined that the death rate was highest in the one-third of men who were weakest. Creatine monohydrate is, by far, the most effective nutritional supplement for improving these top two biomarkers of aging: muscle mass and strength.
Aging is associated with a reduction in skeletal muscle protein synthesis. Several studies have provided different lines of evidence that creatine supplementation increases muscle protein synthesis and satellite cell activity. Most, although not all, studies have found creatine supplementation to benefit elderly subjects. One study found five days of creatine monohydrate supplementation to restore youthful levels of phosphocreatine and phosphocreatine resynthesis rates. A double-blind, placebo-controlled study of thirty men, average age 70.4 years, who underwent a weight training program, found greater increase in fat-free mass, knee extension strength and endurance, leg press endurance and overall power in the creatine group. Another double-blind placebo-controlled study of 7 days of creatine supplementation in elderly subjects found increases in body weight, fat-free mass, and strength. Importantly, this study also included two assessments of lower-extremity functional capacity, including a timed repetitive sit-stand test, which simulates arising from a chair. On this measure too, creatine-supplemented subjects outperformed those given placebo. The authors of this study concluded, "Creatine supplementation may be a useful therapeutic strategy for older adults to attenuate loss in muscle strength and performance of functional living tasks."
Creatine supplementation has been found to produce gains in strength, energy and muscle mass in people with various conditions and diseases. Congestive heart failure patients supplemented with creatine have exhibited signs of enhanced skeletal muscle metabolism with reduced lactate and ammonia accumulation. Creatine improved both strength and endurance in this patient population.
In a double-blind placebo-controlled study, in which subjects had a leg immobilized for two weeks then underwent an exercise rehabilitation program, creatine supplementation resulted in more rapid restoration of strength and muscle mass. Creatine should therefore benefit older individuals who are recovering from bed-rest or immobilization of a limb due to injury, surgery or illness.
Creatine has other physiological effects that are consistent with healthy aging. Creatine supplementation has been found to lower elevated serum cholesterol and triglyceride levels. One study found a 6% reduction in total cholesterol and a 23% reduction in triglycerides and VLDL cholesterol after eight weeks of creatine supplementation. Combining creatine with exercise appears to be synergistic in lowering cholesterol.
Many of creatine’s effects are enhanced when combined with exercise. A combination of creatine supplementation and resistance training was found to increase peripheral blood flow. A double-blind placebo-controlled study divided subjects into three groups. One was given creatine and underwent a resistance-training program, the second exercised but received a placebo. The third group was given creatine but did not exercise. At the end of this 28-day trial, only the group that exercised and took creatine had a significant increase in calf and forearm limb blood flow. Both creatine groups had a significant increase in resting metabolic rate, which is the number three biomarker of aging according to Evans and Rosenberg. There is some evidence that creatine favorably alters other "top ten" biomarkers, including body fat percentage, aerobic capacity, the body's ability to regulate its internal temperature, glucose tolerance, and bone density. Creatine supplementation has been found to reduce n-telopeptide levels (a biochemical marker for bone loss), and, when combined with resistance training, creatine increased bone mineral content.
There are several lines of evidence to suggest creatine supplementation improves insulin sensitivity. Insulin resistance appears to be a central metabolic aberration contributing to unhealthy aging and reduced lifespan. This was illustrated by a study involving 208 healthy men who were evaluated for their insulin sensitivity and then followed for an average of six years. They were divided into three groups, according to insulin sensitivity. After the study period, one out of every three men in the tertile with the poorest insulin sensitivity had developed hypertension, type 2 diabetes, cancer, heart disease or stroke. All of the men in the group with the best insulin sensitivity remained healthy. The effects of creatine supplementation that point toward improved insulin sensitivity include lowering of elevated plasma triglyceride and VLDL and total cholesterol levels, increasing muscle glycogen stores, and a trend toward lower fasting blood glucose levels. Additionally, levels of Glut 4 protein were found to increase by 40% in response to creatine supplementation compared to placebo. Glut 4 protein is involved in insulin-stimulated muscle glucose uptake.
Oxidative stress is another fundamental mechanism of biological aging. Antioxidants defuse free radicals and reduce the damage they inflict upon biological systems. Creatine has been found in several studies to possess antioxidant properties. In animal studies it demonstrated protection against superoxide anions, peroxynitrite and hydroxyl radicals.
Another “anti-aging” effect of creatine supplementation is to increase intracellular water content. Aging is associated with loss of intracellular water. Phosphocreatine has also been found to reduce leakage of cytoplasmic contents, such as intracellular enzymes. This may be attributed, in part, to phosphocreatine's ability to stabilize cellular membranes and prevent tissue damage.
A number of animal studies have found creatine supplementation to protect neurological tissue against ischemic, traumatic, and toxic insults. Protection against ischemic brain damage has obvious implications for defense against stroke.
The mitochondrial theory of aging, which is a variant of the free radical theory, maintains that mitochondrial DNA mutations and damage to mitochondria increase oxidative stress and impair energy production. This is another mechanism that appears to be beneficially modulated by creatine supplementation. In animal models of traumatic brain injury, creatine supplementation appeared to protect neurons by maintaining mitochondrial bioenergetics. Intramitochondrial oxidative stress and calciphylaxis were reduced and ATP levels and mitochondrial membrane potential were increased. Brain damage was reduced by 36 % in mice and 50 % in rats.
In an animal model of Parkinson's disease induced by administration of MPTP, animals pre-supplemented with creatine experienced a 10% decrease in brain dopamine levels compared to 70% reduction in non-supplemented animals. In animals, creatine has also been demonstrated to protect against neurotoxicity of malonate, N-methyl-D-aspartate, 3-nitropropionic acid, and glutamate. With regard to animal models of Alzheimer's disease, creatine protects hippocampal neurons from beta-amyloid toxicity, and therefore could potentially reduce the formation of plaques.
In an animal model of amyotrophic lateral sclerosis, creatine supplementation was associated with reduced oxidative damage, better motor performance, preservation of substantia nigra neurons, and longer survival. In one human study, creatine provided a temporary benefit to patients with this disease, increasing their strength and resistance to fatigue. However, after six months, these benefits seemed to diminish. Additional studies are underway.
Finally, animal models of Huntington's disease induced by neurotoxins, have also found creatine supplementation to provide significant benefits. Specifically, creatine feeding was associated with signs of less oxidative damage, lower lactate levels, dramatically smaller lesion volume, reduced brain atrophy and striatal aggregates, improved body weight and motor performance, delay in development of diabetes, and reduced mortality.
Genetic conditions of creatine deficiency are associated with both physical and mental underdevelopment, which are favorably altered by creatine supplementation. Therefore, it is reasonable to expect creatine supplementation in healthy subjects to improve mental performance as it has been shown to dramatically improve physical performance. This area of investigation is in its infancy. In a study of healthy humans, creatine supplementation at 5 grams four times daily for four weeks produced an average 8.7 % increase in brain creatine. Another study, using a double-blind placebo-controlled protocol, examined the effect of supplementing with creatine on mental fatigue. Subjects were asked to perform as many mathematical calculations as possible within a certain time period. Creatine supplementation was found to reduce mental fatigue and improve performance. Additionally, testing by near infrared spectroscopy revealed signs that creatine increased brain oxygen utilization. These effects are of obvious benefit for aging individuals.
Another study found creatine supplementation improves intelligence and working memory. Yet another study examined the effects of creatine supplementation on individuals who were sleep deprived. Creatine supplementation had a beneficial effect on mood, cognitive and psychomotor performance.
Although creatine supplementation has been found in many studies to have no impact on cancer, there are several positive notable exceptions. In vitro, creatine has inhibited both colon and breast adenocarcinoma growth. In vivo, it has been found to inhibit rat mammary tumors, rat sarcoma, and human colon adenocarcinoma and neuroblastoma cell lines implanted in mice.
Virtually all of the published research has been done with pharmaceutical grade creatine monohydrate powder dissolved in liquid. The weight of scientific evidence to this point is that creatine supplementation is extremely safe. The only documented side effect is weight gain (in the form of desirable fat-free mass). A 21 month study by one of the foremost creatine researchers, Richard Kreider, Ph.D., entitled "Long term creatine supplementation does not significantly affect clinical markers of health in athletes," presented at the 6th International Meeting on Guanidino Compounds in Biology & Medicine in 2001, was designed to respond to rumors about creatine's adverse effects. It involved ninety college football players, some of who received creatine and some of who did not. Sixty-nine different blood analytes, including measures of liver function, kidney function, red and white blood cells, muscle and liver enzymes, blood lipids and electrolytes were evaluated. The conclusion was that creatine produced no effect on any of these measures in healthy football players. Another fact supporting safety of creatine monohydrate is that patients with gyrate atrophy have been supplementing with creatine for twenty years without ill effect.
Few supplements produce a noticeable change in health as rapidly as creatine monohydrate. Typically, results are experienced within a few days. Another factor that makes creatine supplementation likely to be well accepted by patients is the improvement in physique, which most will experience. Weight training enhances the muscle and strength building effects of creatine supplementation. Weight training and creatine supplementation should be a cornerstone of every "Anti-Aging" program. The wide-ranging and powerful anti-senescent properties of creatine make it a fundamental nutritional supplement to promote healthy aging.
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