Creatine
Creatine is possibly the most promising anti-aging supplement available in the industry today.  A tremendous amount of research has been published between 1998 and now that has helped us to understand this very important nutrient and how it functions in the human body.  Creatine supplementation, in a stabilized, alkaline form so it does not raise creatinine, does so much more than simply help athletic performance and  muscle building. Creatine supplementation has numerous physiological effects, which have the potential to substantially reduce morbidity and mortality.

What is creatine?
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.

CREATINE SUPPLEMENTATION MAY HELP SUPPORT:

• •Athletes
• •Muscle building
• •Sarcopenia
• •Strength
• •Increasing exercise intensity
• •Recovery from exercise
• •Physical performance recovery after rapid weight loss
• •Reduce cell damage and inflammation from ultra-endurance exercise
• •Reduce athletes' cramping, heat illness, dehydration, muscle strains and tightness
• •Brain health
• •Depression
• •Neurological problems
• •Parkinson's Disease
• •Huntington's Disease
• •ALS
• •Sleep Deprivation
• •Memory/Cognitive Function
• •Vegetarians
• •Atherosclerosis
• •High homocysteine
• •Post-stroke
• •Ischemia
• •Traumatic brain injury
• •Rehabilitation from bed rest or immobilization
• •Recovery from nerve injury
• •Bone loss
• •Glucose-insulin metabolism
• •Posttraumatic stress disorder
• •Congestive heart failure
• •COPD
• •Muscular dystrophies
• •Cramping associated with dialysis
• •Muscle breakdown from corticosteroids
• •Unexplained mental retardation, developmental arrest, neurological deterioration, speech delay, seizures, movement disorders, and autistic-like behavior

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, phosphocrea tine is involved primarily in the first ten seconds of very high intensity contraction.

The benefits one derives from creatine supplementation depends upon how much his or her tissue crea-tine 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. 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 compound alpha lipoic acid 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 (T3), and norepinephrine.

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 to produce gains in strength, energy and muscle mass in people with various conditions and diseases.  It also results in quicker restoration of energy after exertion and therefore improves performance  in repetitive bouts of very high intensity exercise. 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 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.

How is creatine good for the heart? Metabolic Syndrome?
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. Creatine has a positive effect on lipids. 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. In one study, creatine even lowered homocysteine when taken (at a dose of two times their creatinine levels) along with a multivitamin, more effectively than multivitamin alone.

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 fast- ing 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. When combined with supplemental protein and resistance training, creatine resulted in improved glucose tolerance test results.

How is creatine anti-aging?
Creatine affects many of the top ten markers of biological aging including loss of muscle mass, drop in resting metabolic rate, 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.

The number one biomarker of aging 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. 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.  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.

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. Creatine uses a sodium transporter. It is important for athletes to maintain normal electrolyte levels. Athletes should consider using Electrolyte Synergy from Designs for Health along with KreAlk-Alert to prevent electrolyte depletion and inability to transport creatine.

How is creatine good for the brain?
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 supplemen-
tation 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. In animal models of traumatic brain injury, creatine supplementation appeared to protect neurons by maintaining
mitochondrial bioenergetics. Intramitochondrial oxidative stress and calcium levels 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, 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. (3) With regard to animal models of Alzheimer's disease, creatine protects hippocampal neurons from ?-amyloid toxicity, and therefore could potentially reduce the formation of plaques. (3)

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 supple-
mentation 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.

Oxidative stress is another fundamental mechanism of biological aging. 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. (6)

How do we know creatine is safe? 
Researchers have tested creatine in doses as high as 20 g per day in humans with no ill-effects.  Virtually all of the published research has been done with 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 supplementationdoes 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 foot- ball 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.

This is the conclusion of a study published in the British Journal of Sports Medicine after giving 48 subjects 20 g of creatine for 5 days followed by 3 g creatine for 9 weeks: "Interpretation: These data provide evidence that there are no obvious adverse effects of acute or more chronic creatine supplementation on the haematological indices measured, nor on hepatic, muscle, and renal function. Therefore there is no apparent health risk associated with creatine supplementation to healthy people when it is ingested in quantities that have been scientifically proven to increase muscle creatine stores."

Another factor that makes creatine supplementation likely to be well accepted by patients is the improvement in physique, which most will experience, often within a few days. 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.