A review of creatine supplementation in age-related diseases: more than a supplement for athletes

General benefits

Aging is associated with lower levels of creatine and phosphocreatine, specifically in the skeletal muscle. Phosphocreatine regeneration rates following exercise fall approximately 8% each decade after age 30⁵⁰. Creatine supplementation increases both creatine and phosphocreatine from 10–40% in athletes⁵⁰. Furthermore, a recent review described a meta-analysis of the role creatine supplementation and resistance training plays on muscle health in an aging population. Based on the analysis of 13 published, creatine had an overall beneficial effect on aged individuals muscle mass⁵¹. Since the creatine transporter can readily transport creatine from the bloodstream across the BBB, it is reasonable to suggest that exogenous supplementation of creatine would increase concentrations in the brain, where endogenous creatine levels may be diminished as a person ages. In neurodegenerative disorders (as outlined below), creatine may help slow the progression of each condition.

Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder resulting from the loss of dopamine neurons in the midbrain with symptoms becoming apparent when approximately 60% of these neurons are lost⁵². Notable symptoms of PD include resting tremor, postural instability, bradykinesia, loss of muscle mass, strength, and increased ability to fatigue. The treatment measures for PD involve early detection of the disease and understanding how to slow PD progression once symptoms have been reported. Rodent models often used for the study of PD are induced by toxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to mimic the pathogenesis and progression of the disease marked by dopaminergic neuron loss, mitochondrial dysfunction, and oxidative stress^53,54. In particular, complex I of the electron transport chain within the mitochondria is deficient in patients with Parkinson’s disease. The fact that postural instability, loss of muscle mass, and strength all occur in the progression of PD, and are coupled with creatine’s ability to alter cellular energetics, has led to the hypothesis that the creatine dietary supplementation could minimize the associated symptoms with Parkinson’s disease.

An early study testing the benefit of creatine in MPTP-induced Parkinson’s disease mice showed significant neuroprotection with 1% creatine supplementation in diet⁵⁵. In 2006, a group of investigators at the National Institute of Neurological Disorders and Stroke (NINDS) began a phase III clinical trial for creatine in 200 patients affected by Parkinson’s disease after second phase preliminary data showed that creatine was able to slow down the progression of the disease⁵⁶. A year later, a double-blind study compared the control group (no creatine supplementation) to the test group (20 Parkinson’s disease patients), which received a creatine loading dose of 20 grams per day for 5 days and a creatine maintenance dose of 5 grams per day thereafter⁵⁷. The purpose of this study was to specifically explore if creatine could help increase muscle strength in idiopathic Parkinson’s disease patients. Both groups received resistance training during the study. A difference was observed in the creatine supplemented group with some of the strength exercises used versus the control group⁵⁷. In September 2013, the NINDS announced that the phase III clinical trial for creatine use in Parkinson’s disease was halted because the study would result in an observable significant difference⁵⁸. The test subjects tolerance for creatine or creatine associated side effects were not the cause for stopping the trial. The patients in this creatine clinical trial received 10 grams creatine daily for up to 5 years. Although this outcome is disappointing, the ability for creatine to alter energy dysfunction in addition to muscle strength may still have a combinatory effect with other Parkinson’s disease drug treatments. The possibility remains that creatine may be beneficial for Parkinson’s disease patients, but more work needs to be done to demonstrate the dietary supplements efficacy.

Huntington’s disease

Huntington’s disease (HD) is a neurodegenerative disease where the onset of symptoms occurs in midlife. Once the symptoms begin, a patient can expect to live, on average, 20 more years⁵⁹. Those that develop Huntington’s disease possess genetically inherited mutations in the number of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene responsible for producing the huntingtin protein^60–63. The huntingtin protein is expressed throughout the central and peripheral nervous systems. Upon the onset of HD symptoms, the patient begins to exhibit changes in mood, cognition, and motor coordination^60–63. In addition to contributing to an abnormal gait, resting tremor and even epileptic seizures associated with Huntington’s disease, the mutant huntingtin protein product leads to impaired energy metabolism⁶⁴. Without a cure for Huntington’s disease, the impairment of energy metabolism offers an avenue and target for new therapies. Furthermore, there is an observed reduction in the phosphocreatine and inorganic phosphate ratio in Huntington’s disease patients’ muscle tissue, which may indicate the Huntington mutation’s involvement in dysregulating the phosphocreatine/creatine ratio⁶⁵. In a mitochondrial toxin Huntington’s disease mutant mouse model, R6/2, creatine is hypothesized to act as a means of buffering, or providing a larger phosphocreatine pool for rapid conversion of ADP to ATP, energy within the cell^5,66–68. Furthermore, as an extension of the work done by Matthews and colleagues⁶⁸, the Ferrante group⁶⁹ showed that lifespan was extended by 9.4, 17.7 and 4.4% when supplemented with 1, 2, or 3% creatine in the diet, respectively⁶⁹.

Several Huntington’s disease transgenic mice strains have been developed to study the dysfunction in energy metabolism, the electron transport enzymes in the mitochondria, and excessive excitotoxicity associated with the disease^53,70–74. Supplementation with exogenous creatine in one transgenic mouse model showed improved motor performance, reduced atrophy of neurons, and huntingtin protein aggregates, and an observed increased survival rate or life-span^17,69,75. Following these studies, a phase II clinical trial ensued to assess creatine tolerability given at a dosage of 8 grams per day to Huntington’s disease patients⁷⁶. From these studies, Hersch and colleagues determined that 8-hydroxy-2’-deoxyguanosine (8OH2’dG), a marker for damaged DNA, was abnormally high in patients with HD, but was reduced after creatine treatment⁷⁶. In an interview regarding the phase III clinical trial of creatine usage in Huntington’s disease patients, the CREST-E (Creatine Safety, Tolerability, and Efficacy) clinical trial, Hersch reported that 8OH2’dG had returned to normal levels. Subsequently, there was an observed reduction in brain deterioration rate when patients were supplemented with creatine and that creatine kinase is a potential biomarker for HD⁷⁷. The potential of creatine as a viable therapy for HD remains to be seen and the results from CREST-E clinical trial will provide some indication to the dietary supplement’s utility. Thus, creatine supplementation remains a potential therapy for Huntington’s disease, however further studies are needed.

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is marked by the loss of voluntary muscle control from the progressive degeneration of motor neurons^78,79 with subsequent neuronal loss resulting in paralysis^80,81. The cause and cure for ALS remain elusive. The most promising treatment is the drug riluzole, which only increases the lifespan of those with the disease by 6 months⁸². To complicate the search for effective treatments, as many as 50% of ALS patients experience cognitive impairment that is revealed when they undergo specialized testing for neuropsychological deficits⁸³. In addition to motor neuron loss observed in ALS patients, cognitive impairment most often associated with the frontotemporal region of the brain is not always present⁸³. Furthermore, despite identifying a genetic overlap in ALS and other neurodegenerative disease mechanisms, the sporadic occurrence of cognitive impairment in ALS patients obscures understanding a clear etiology of the disease⁸³.

At a molecular level, ALS is characterized by altered glutamate homeostasis, oxidative damage, elevated intracellular calcium concentrations, mitochondrial swelling, and electron transport chain complex I deficiencies leading to reduced energy intake^84–87. Generally, mutations in the gene responsible for the production of the enzyme, superoxide dismutase (SOD1) are common in many cases of familial ALS⁸⁰. The loss of function associated with SOD1 mutations reported in ALS translates to the accumulation of toxic free radicals from superoxide generated by the mitochondria^80,88,89. This suggests that the build up of free radicals results in altered energy production. Thus, creatine may serve as an energy alternative that is beneficial for ALS patients.

Klivenyi and colleagues studied transgenic mice with a mutated human SOD1 gene and assessed the neuroprotective effects of creatine. This was in response to the promotion of survival and improved motor coordination they observed with long-term creatine supplementation⁹⁰. Along with the proposed creatine benefits in protecting neurons from insufficient energy production, the results indicated that creatine administration protected neurons from oxidative damage. In contrast, two completed clinical trials in 2003 and 2004 tested oral creatine supplementation and provided little notable improvements in lifespan, muscle strength, or motor unit numbers in patients with ALS^91,92. Although there is an observed trend toward enhanced survival following creatine supplementation, these studies distinguished between large differences (30–50% difference). Due to the high threshold for observing significant differences, there remains a possiblilty that creatine has a subtle effect. Currently, the long-term effects of creatine supplementation are being studied in a phase II clinical trial associated with the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS).

Long-term memory

The ability to encode new memories (working memory), recall previous events (episodic/long-term/declarative memory) and short-term (primary/active) memory declines with age^93,94. Previous reports indicated that phosphocreatine stores are quickly depleted upon brain activation, while ATP concentrations remain constant^95,96. A reduction in creatine levels may have an effect on the immediate recall of knowledge based on the dramatic drop in phosphocreatine levels from brain activation. In 2003, Rae and colleagues questioned if creatine supplementation enhanced intelligence in healthy subjects⁹⁷. For 6 weeks, subjects were given 5 grams of creatine orally per day. Following this protocol, the subjects showed improvements in working memory and intelligence utilizing the backward digit span and Raven’s Advanced Progressive Matrices tasks, respectively. Furthermore, each of the participants were vegetarians, which supported the role that exogenous creatine has on increasing participants’ serum creatine levels. Using magnetic resonance spectroscopy to measure creatine levels, it was determined that creatine levels increased in the brain, solidifying that creatine is not solely distributed in skeletal muscle⁹⁸. Creatine supplementation has been considered for the improvement of memory in the elderly. One such study in the United Kingdom reported that subjects with an average age of 76 saw improvements in long-term memory when supplemented with 20 grams per day of creatine for 1 week⁹⁹. In addition to improvement in the long-term memory task, the elderly subjects improved in both forward and backward spatial recall as well as forward number recall. Based on these results, the investigators concluded that creatine could enhance cognition in elderly subjects, although follow up studies have not elucidated a mechanism by which creatine does this. Currently, there are few studies focused on the role that creatine supplementation plays on cognition and memory. In addition, how creatine improves memory in the aforementioned studies is yet to be understood at the molecular and cellular levels.

Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease marked by neurofibrillary plaques and tangles in the brain. One of the challenging characteristics of AD is the inability to definitively determine if a patient has the disease while alive. Only during the postmortem exam the disease can be definitively diagnosed¹⁰⁰. However, these hallmarks can be observed in the postmortem brains of individuals that did not display dementia or deteriorated cognitive function. As the disease progresses, the symptoms include severe dementia, confusion, and the loss of long-term memory. Although the onset of AD is not entirely understood, studies have shown that high-energy metabolism precedes the onset of AD while there are increased levels of myo-inositol, an important structural component of lipids, in comparison to the relative creatine concentrations. Furthermore, this increase in the ratio of myo-inositol and creatine precedes the onset of dementia in individuals with Down’s syndrome^101–103. Creatine was shown to be protective of rat hippocampal neurons when confronted with beta-amyloid (Aβ) toxicity¹⁰⁴. One possible mechanism to intervene with the progression of Alzheimer’s disease is creatine kinase. Creatine kinase is responsible for the conversion of ATP to ADP and vice versa¹⁰⁵ and tends to be susceptible to high levels of oxidative damage in the brains of Alzheimer’s disease patients¹⁰⁵. In Alzheimer’s disease, creatine kinase activity is reduced by as much as 86% along with a reduction of in creatine kinase protein expression of 14%, which suggests that the Alzheimer’s disease brain has lower levels of phosphocreatine in the beginning stages of the disease^101,106. Although creatine kinase levels were reduced, studies have questioned the involvement of creatine upon finding deposits of the molecule in amyloid precursor protein (APP) in transgenic mice¹⁰⁷. The solubility of creatine in an aqueous solution is 100 mM, however the total creatine concentration in the brain only reaches 20 mM¹⁰. Possible explanations for the origin of these creatine deposits in the transgenic mice models include: (1) spillage from neuronal cell death, (2) excess oligodendrocyte production of creatine, (3) limited creatine uptake by the CRT and (4) the oxidation of creatine kinase that limits the formation of phosphocreatine^108–111. Although each of these possibilities has been studied extensively, it remains unclear to the exact origin of the creatine deposits. This further reiterates that the exact role of creatine in AD is still yet to be understood and may be more complicated than previously thought.

Stroke

Stroke is “defined as an acute neurologic dysfunction of vascular origin with sudden (within seconds) or a least rapid (within hours) occurrence of symptoms and signs corresponding to the involvement of focal areas in the brain”¹¹². In the past decade, stroke has been the second leading cause of death¹¹³. Ischemic stroke, which is more common^114,115, occurs when the brain is deprived of glucose and oxygen due to insufficient blood supply. This causes acidosis, an increase in intracellular calcium, and the formation of reactive oxygen species leading to ischemic cell death¹¹⁶. Symptoms of ischemic stroke include sudden numbness on one side of the body, vision disturbances, difficulty in speaking and understanding, imbalance, and loss of coordination. The available treatments for ischemic stroke consist of the use of tissue plasminogen activator (tPA)¹¹⁷ and/or surgical treatments. The commonly used in vitro model for ischemic stroke involves oxygen-glucose deprivation^118,119 and rodent model for stroke involves mechanical or thromboembolic occlusion of cerebral vessel to mimic cerebral ischemia^120–123.

An early study involving eight stroke patients has demonstrated that creatine and phosphocreatine content is reduced in the ischemic brain¹²⁴. In rat hippocampal slices, pre-incubation with creatine (0.03–3 mmol/L) dose-dependently reduced damage due to anoxia¹²⁵. Another in-vitro study in rat hippocampal slices showed dose dependent increase in phosphocreatine concentration and delay in anoxic depolarization after incubation with 1 mM creatine¹²⁶. Creatine was shown to exert protective antioxidant effect in U937 human promonocytic cells after oxidative damage¹²⁷. Creatine has been shown to be neuroprotective in an experimental model of anoxia in neonatal mice supplemented with creatine^128–130. Also, rats subjected to creatine pretreatment before cerebral hypoxia showed a reduction (25%) in the volume of edematous brain tissue compared when compared to control¹³¹. Zhu et al. showed that mice supplemented with 2% creatine in the diet showed reduced neuronal damage compared to control groups following middle cerebral artery occlusion that causes ischemic stroke. The study indicated that this beneficial effect of creatine is due to the restoration of energy depletion and inhibition of caspase activation along with some other unknown mechanisms¹³². These studies support the fact that creatine could be a potential compound to be used as a prophylactic, or preventative, dietary supplement in patients at high risk for stroke¹³³. Still, more work is needed to demonstrate the efficacy of creatine to prevent stroke and to develop a creatine supplementation regimen to help patients at risk for stroke to avoid the debilitating event.