Creatine

Creatine is a well-known dietary supplement, popular among athletes for its ability to enhance physical performance in high-intensity, short-duration activities. Apart from its performance-enhancing benefits, recent studies and analysis also hint at creatine's potential advantages concerning longevity and aging.

Forms of Creatine

Creatine supplements come in various forms, each with its own set of properties and purported benefits. Here are the most common forms:

• Creatine Monohydrate: This is the most common and well-researched form of creatine. It consists of creatine molecules and a water molecule. Numerous studies have confirmed its safety and efficacy in improving physical performance.

• Creatine Ethyl Ester (CEE): This form is claimed to have better absorption rates and a longer half-life in the body compared to Creatine Monohydrate. However, some studies suggest that it may not be as effective.

• Creatine Hydrochloride (HCL): Creatine HCL is known for its solubility in water. It is believed to require a smaller dosage and to have better absorption compared to Creatine Monohydrate.

• Creatine Malate: This is creatine bound with malic acid, which is supposed to help with energy production. The malic acid is believed to help in the Krebs Cycle, a pathway that produces ATP.

• Creatine Citrate: Creatine Citrate is creatine bound with citric acid, making it more water-soluble than Creatine Monohydrate but requiring a larger dosage.

• Buffered Creatine (Kre-Alkalyn): This form has a higher pH level, which is claimed to allow for better absorption and less stomach discomfort compared to other forms.

• Creatine Nitrate: This is creatine bound with nitrate molecules. It is supposed to have better solubility in water and higher absorption rates.

• Creatine Magnesium Chelate: This form is chemically bound to magnesium, which is supposed to enhance water solubility and improve muscle contraction.

Each form of creatine has its unique characteristics, and individuals may choose a particular form based on personal preferences, tolerance, and the intended benefits they wish to achieve from supplementation. Creatine Monohydrate remains the most recommended form due to its extensive research backing and proven safety and efficacy. Other forms may also be effective, but more research is needed to confirm their benefits and safety.

Despite claims of increased solubility, bioavailability, and superior uptake mechanisms, there is currently no evidence supporting the use of any alternative form of creatine over creatine monohydrate. Although all forms of creatine (except reatine ethyl ester) were shown to be safe in existing studies, further research is necessary to determine whether alternative forms of creatine are potentially more effective or worth the higher cost. Creatine monohydrate remains as the most studied and cost-effective form of creatine.

Bioavailability

Pharmacokinetic profile of creatine monohydrate (CrM), tri-creatine citrate (CrC), or creatine pyruvate (CrPyr)

In the effects of ingesting isomolar amounts of creatine (4.4 g) in the form of the monohydrate (5 g), tri-creatine citrate (6.7 g) and creatine pyruvate (7.3 g) on creatine concentrations in plasma was compared. The dosage per from were isomolar, meaning every form had the same amount of active molecules. Since the molar mass per form is different, that results in different doses. The findings suggest that different forms of creatine result in slightly altered kinetics of plasma creatine absorption following ingestion. Differences in bioavailability are thought to be unlikely since absorption of creatine monohydrate is already close to 100%. The small differences in kinetics are unlikely to have any effect on muscle creatine elevation during periods of creatine loading.

Potential Longevity Benefits

Lifespan

Survival rate of wild type mice after starting 1% creatine submission beginning in the age of 365 days

In animal studies, creatine supplementation has been associated with a 9% increase in lifespan. Creatine-fed mice also demonstrated significantly better performance on neurobehavioral testing. While human trials are needed to confirm these findings, they suggest a potential benefit of creatine supplementation for longevity.

The average daily food intake for an adult female C57BL/6 mouse ranges from approximately 2.5 to 5 grams, with a typical weight of 20-25 grams. If we take the average food intake to be 3.75 grams, then a 1% inclusion of creatine in this diet corresponds to a creatine intake of 0.035 grams per day. To calculate the creatine dose in mg/kg, divide the creatine intake by the average weight of the mouse (assuming 22.5 grams), resulting in a dose of approximately 1555 mg/kg. Converting this mouse dose to a human equivalent dose (HED) using allometric scaling with a conversion factor of 12.3, the HED is around 126 mg/kg. For a 75 kg human, this dose translates to about 9450 mg/day.

Muscle Mass, Strength, Bone and Body Composition

Sarcopenia, an age-related condition, leads to reduced muscle mass, strength, and functionality. Aging also generally causes loss of muscle mass, bone mass, and balance while increasing body fat. Various interventions like creatine supplementation alongside resistance training have been proposed to counteract these issues. Some studies have shown that creatine supplementation during resistance training can significantly improve muscle mass, strength, and even bone density in older individuals. For instance, creatine has been observed to enhance muscle mass and strength in older men and postmenopausal women during resistance training, and improve balance in individuals after sleep deprivation. Creatine's effect extends to promoting muscle endurance, functional task performance, and even fat loss, which could be beneficial in managing adult-onset obesity while preserving muscle mass during weight loss interventions. These findings suggest that creatine supplementation, especially when combined with resistance training, could be a promising strategy to combat age-related muscle and bone deterioration, and help in managing adult-onset obesity. Further studies are required to solidify these findings and understand the long-term implications of creatine supplementation in older individuals.

Cognitive Function

Creatine supplementation is associated with a 5-15% increase in brain PCr (Phosphocreatine) content, which is believed to enhance brain bioenergetics. Research has delved into its potential impacts on cognition, memory, and executive function, especially among older individuals or those with mild cognitive impairment. Several studies have highlighted that creatine supplementation can reduce mental fatigue and potentially improve cognitive abilities including memory and executive function. For instance, certain studies have shown that creatine supplementation can increase oxygen utilization in the brain, thereby reducing mental fatigue during repetitive mental tasks, enhance working memory and processing speed, and even improve certain cognitive tasks under sleep deprivation. Moreover, creatine supplementation has been found to maintain or enhance performance in various cognitive and memory tasks in both young and elderly participants. For example, it's shown to improve muscular endurance and sustain cognitive performance during a simulated soccer match. While there are promising findings, not all studies agree on the benefits of creatine supplementation for cognitive function, and more research is needed to solidify these claims. Nonetheless, current evidence suggests that creatine supplementation may hold potential in supporting cognitive function, especially as one ages.

In aging adults (68–85 years), creatine supplementation of 20 g/day for 7 days improved memory measures such as forward number recall, backward and forward spatial recall, and long-term memory. Further, vegetarians saw working memory improvements after creatine supplementation of 5 g/day for 6 weeks. A direct comparison between omnivores and vegetarians revealed better memory post creatine supplementation in vegetarians than meat-eaters. However, some studies did not observe any beneficial effects of creatine on memory measures in children, adults, and older adults.

Moreover, sleep deprivation, which is known to impact brain bioenergetics, seems to be another area where creatine supplementation shows promise. Preliminary evidence suggests that combining creatine supplementation with sleep deprivation can enhance cognitive function, especially when coupled with mild to moderate exercise. For instance, after 24 hours of sleep deprivation, those supplemented with creatine saw less change in performance from baseline in random movement generation, choice reaction time, balance, and mood state. Additionally, another experiment from the same group indicated that creatine supplementation counteracted the loss of complex central executive function due to sleep deprivation.

Overall, there is mounting evidence suggesting that creatine supplementation can enhance certain cognitive functions, especially when brain bioenergetics are under stress, such as during sleep deprivation.

Glucose Management and Diabetes

Creatine supplementation has been associated with influencing glucose management, especially in the context of exercise and dietary practices. The uptake of creatine into tissues is influenced by glucose and insulin levels. Moreover, creatine supplementation has shown potential in preventing declines in the GLUT-4 transporter, which is essential for glucose uptake into cells, during immobilization and even increasing GLUT-4 by 40% during rehabilitation after muscle atrophy. The co-ingestion of creatine with carbohydrates or a combination of carbohydrates and protein has been reported to increase creatine uptake and/or muscle glycogen levels, which could be beneficial for glycogen storage and overall glucose management.

In a notable study, Gualano et al. evaluated the effects of creatine supplementation (5 g/day for 12 weeks) during training in participants with type 2 diabetes. The findings indicated that creatine supplementation improved glucose tolerance to a standard meal, increased GLUT-4 translocation, and significantly reduced HbA1c levels, which is a long-term indicator of glucose control. Furthermore, the AMPK-alpha protein content, which is related to cellular energy regulation and possibly glucose uptake, tended to be higher after creatine supplementation. This increase was significantly related to the changes observed in GLUT-4 translocation and HbA1c levels, suggesting that AMPK signaling might play a role in the effects of creatine supplementation on glucose uptake in individuals with type 2 diabetes.

Overall, the evidence suggests that creatine supplementation can enhance glucose uptake and insulin sensitivity, which may help individuals manage their glucose and HbA1c levels, particularly when engaging in an exercise program. Hence, creatine supplementation might offer a supportive role in healthy glucose management, especially in conjunction with exercise and dietary strategies.

Heart Disease

Coronary artery disease, which restricts blood flow to the heart, increases the risk of ischemic events, arrhythmias, and heart failure. Creatine and its derivative, phosphocreatine (PCr), are known to help maintain heart energy levels during these ischemic events. This has led to interest in exploring creatine or PCr administration as a way to reduce heart-related issues in individuals with chronic heart failure.

Studies have shown promising results. For example, administering PCr and phosphocreatinine intravenously in canines prevented harmful substance accumulation in the heart's ischemic zone, reducing arrhythmia prevalence. Similarly, other researchers found that exogenous PCr administration protected against heart ischemia. When PCr was added to solutions used to preserve heart tissue during ischemia, it improved energy availability, reduced arrhythmia incidence, and improved heart function.

Additionally, creatine supplementation has shown potential benefits for heart failure patients engaged in rehabilitation programs, though results vary across studies. While more research is essential, current findings suggest that phosphocreatine administration and possibly creatine supplementation may support heart metabolism and health, especially during ischemic challenges.

Potential Therapeutic Role

Creatine Deficiency Syndrome

Robust evidence highlights the significance of creatine on cognitive function, particularly observed in individuals with creatine deficient syndromes known to deplete brain creatine stores. Creatine deficiency syndrome is marked by mental and developmental disorders, including learning delays and seizures. Notably, these symptoms are, to some extent, reversed by creatine supplementation. Human studies have yielded mixed results. While some studies have discovered benefits on cognitive functioning, others found no such effects, as comprehensively reviewed by Roschel and colleagues in 2022.

Neurodegenerative Diseases and Muscular Dystrophy

Creatine supplementation has been explored for its potential therapeutic benefits in various neuromuscular diseases like Huntington's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS), among others. While some animal studies showed improved exercise tolerance or clinical outcomes, a large clinical trial found no significant benefit in Parkinson's or ALS patients. However, some evidence suggests that creatine might slow brain atrophy in Huntington's patients. In the case of muscular dystrophies, creatine supplementation demonstrated more promise, increasing muscle strength and functional performance. The results hint at creatine's neuroprotective properties and its potential to enhance muscle strength and endurance, although the long-term efficacy in neurodegenerative diseases remains unclear.

Brain and Spinal Cord Neuroprotection

Creatine supplementation is recognized for its ability to enhance brain bioenergetics and provide neuroprotective benefits, especially during injury or ischemic events. Research has explored its impact on cerebral ischemia, stroke, traumatic brain injury (TBI), and spinal cord injury (SCI). For instance, studies in animals have shown that creatine supplementation can significantly reduce brain damage induced by ischemia and may also lessen the severity of TBI and SCI, leading to improved recovery outcomes. In humans, some findings suggest that creatine supplementation could enhance training adaptations in patients recovering from SCI and might aid in improving aerobic exercise capacity and muscle strength. While some human studies didn't report benefits, the compelling evidence from animal models led to recommendations for athletes at risk of TBI or SCI to consider creatine supplementation for potential neuroprotection.

Enhanced Rehabilitation Outcomes

Creatine supplementation, known for augmenting resistance-training adaptations, has been explored for its potential to improve rehabilitation outcomes post musculoskeletal injury. Research suggests that creatine supplementation might enhance muscle fiber area and peak strength during rehabilitation, and potentially improve aerobic capacity in patients with spinal cord injuries. Moreover, studies have found positive outcomes in patients with chronic heart failure, chronic obstructive pulmonary disease, Parkinson's disease, and knee osteoarthritis, showing improved muscle strength, endurance, physical function, and quality of life. Creatine supplementation might also expedite recovery post muscle-damaging exercise. However, not all studies share these positive findings; some showed no significant improvement in recovery post orthopedic surgeries like total knee arthroplasty or anterior cruciate ligament reconstruction. While the evidence points towards creatine's potential in enhancing rehabilitation outcomes, more research is needed to better understand its impact across different populations and conditions.

Anticancer Effects

Creatine supplementation is being explored for potential anticancer properties, stemming from its crucial role in energy maintenance within cells, especially concerning the energy shuttle system involving creatine kinase. Research has shown that certain malignant cells and immune cells combating cancer often have low creatine content, which may impact energy availability crucial for their functions. The expression of the creatine transport gene, SLC6A8, notably increases in tumor-infiltrating immune cells, indicating a possible role of creatine in cancer immunity.

Studies have demonstrated anticancer properties of creatine and its related compound, cyclocreatine. For instance, creatine, when used alongside anticancer medication like methylglyoxal (MG) and ascorbic acid, has shown to significantly enhance the medication's efficacy, even eliminating visible signs of tumor growth in some cases. Creatine supplementation elevated the low creatine and creatine kinase levels in sarcoma tissues, leading to a regression of tumor cells. Further, creatine's administration, either directly or through dietary supplementation, notably suppressed tumor growth in various mouse tumor models, by possibly enhancing the responses of CD8 T cells, which are crucial for tumor immunity. The findings suggest that creatine supplementation could serve as a supportive anticancer therapeutic intervention, especially in enhancing T cell-based cancer immunotherapies, although more research is needed to confirm these effects and understand the underlying mechanisms.

Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS), also known as post-viral fatigue syndrome (PFS) or myalgic encephalomyelitis (ME), is associated with persistent fatigue and other symptoms like muscle pains and cognitive disorders. The exact cause of these conditions is unknown, but recent studies have shown interest in creatine's potential to enhance functional capacity in affected individuals. Some evidence suggests that impaired creatine metabolism may play a role in CFS-related diseases.

Several studies explored creatine or creatine-related compounds' impact on patient outcomes in CFS conditions. For instance, creatine supplementation led to improvements in depression symptoms, pain measures, and quality of life in certain patients. Another study showed significant improvements in severity markers of fibromyalgia, disability, pain, sleep quality, and overall life quality with creatine supplementation, although these improvements reverted after stopping the therapy. Creatine supplementation also showed potential in increasing muscle function in fibromyalgia patients. Additionally, GAA supplementation positively impacted creatine metabolism and work capacity in women with CFS, albeit without significantly affecting general fatigue symptoms.

The findings from these studies suggest that creatine and/or GAA may offer some therapeutic benefits for patients with CFS, ME, or fibromyalgia by improving functional capacity. However, more research is needed to confirm these effects and understand creatine's role better in managing chronic fatigue-related syndromes.

Pregnancy

Creatine, known for boosting cellular energy, has sparked interest for its potential use during pregnancy to aid neural development and lessen complications from birth asphyxia. The fetus depends on the mother for creatine until late pregnancy, making creatine crucial during this period. Animal studies show that maternal creatine supplementation could enhance neonatal survival and organ function post birth asphyxia. While creatine needs do increase in pregnant women, the research on creatine supplementation during pregnancy in humans is still limited. Though creatine has been found safe in many groups, its safety and effectiveness during pregnancy need more investigation. Hence, while creatine might support the nutritional needs and health of both mother and child, recommending its use during pregnancy should be done with caution due to the limited human studies.

Immune Support

One of the more novel potential uses of creatine is its influence on the immune system. A number of in vitro and animal studies indicate that creatine has immunomodulatory effects. In this regard, several studies have reported that creatine supplementation may alter production and/or the expression of molecules involved in recognizing infections like toll-like receptors (TLR). Creatine might also affect cytokine dynamics, possibly reducing pro-inflammatory cytokines, which could explain its observed neuroprotective benefits in certain central nervous system-related diseases. However, its effects on inflammation and immune response are complex, with some studies indicating potential exacerbation of exercise-induced asthma, while others suggest benefits in lung ischemia and certain respiratory conditions. Additional research is needed to understand creatine’s anti-inflammatory and immunomodulating effects, but it is clear that creatine can affect these pathways. Thus, there is evidence to suggest that supplementation may have anti-inflammatory and immunomodulating effects.

Antidepressive Properties

There have been suggestions since the early 1980s that creatine metabolism or availability might have antidepressive effects, based on numerous studies​​. Further investigations have assessed how creatine or its precursors like S-adenosyl-L-methionine (SAMe) and guanidinoacetate (GAA), influence brain phosphagen levels, depression markers, or the effectiveness of antidepressant medications​. For instance, SAMe has been found to be a viable treatment for clinical depression. In one study, SAMe supplementation led to increased brain creatine and phosphocreatine (PCr) levels, with a more pronounced effect in women compared to men​.

Animal studies have also shown potential antidepressive effects of creatine. In one study, female rats displayed an antidepressant-like response when fed creatine diets, and in another, a single treatment of creatine or exercise showed partial antidepressant effects in mice under chronic mild stress, with combined creatine and exercise yielding greater benefits​. Creatine administration also abolished corticosterone-induced depressive-like behaviors in mice in a separate study​.

In human trials, some support has been found for creatine's effect on depression. For instance, a study found a significant negative relationship between dietary creatine intake and depression among adults in the U.S​​. Another study reported improved outcomes in a small sample of patients with unipolar depression following creatine monohydrate supplementation​​. Moreover, creatine supplementation was found to enhance remission rates in bipolar patients in a couple of studies, with one noting improved verbal fluency tests and the other highlighting enhanced remission MADRS scores in participants who completed the study​.

Although more research is needed, there is some evidence suggesting that creatine may help manage some types of depression and/or anxiety disorders, particularly when combined with choline​​. This indicates that creatine supplementation might be a supportive measure for mental health.

Reproductive Health

There's interest in the potential of creatine to improve fertility due to its role in energy production, crucial for sperm motility. Creatine kinase activity has been associated with better sperm quality and function (4 studies). Some fertility treatments have experimented with adding creatine to the medium during intrauterine insemination to boost sperm viability and the success rates of the procedures, as reported in multiple studies (6 studies). While these initial findings are promising, more research is necessary to fully understand creatine's role in fertility and reproductive health.

Skin Health (Direct Application)

Research has shown that creatine can be beneficial for skin health when applied topically. It's believed that creatine's impact on energy availability in skin cells and its antioxidant properties may be the driving factors behind its potential benefits. Studies have found that applying creatine on the skin can protect against various cellular stress conditions such as oxidative and UV damage, which are known to contribute to premature skin aging and damage. Additionally, topical creatine application has been shown to penetrate the skin, stimulate collagen synthesis, and even affect gene expression and protein levels in the skin. Notably, a study observed that applying a creatine-containing formulation on the skin for 6 weeks led to a significant reduction in sagging cheeks, crow's feet wrinkles, and under-eye wrinkles. These findings suggest that creatine could be a valuable ingredient for topical treatments aimed at preventing and addressing skin aging.

Safety and Dosage

Safety

Since creatine monohydrate became a popular dietary supplement in the early 1990s, over 1,000 studies have been conducted and billions of servings of creatine have been ingested. The only consistently reported side effect from creatine supplementation that has been described in the literature has been weight gain. Available short and long-term studies in healthy and diseased populations, from infants to the elderly, at dosages ranging from 0.3 to 0.8 g/kg/day for up to 5 years have consistently shown that creatine supplementation poses no adverse health risks and may provide a number of health and performance benefits.

Moreover, an evidence-based scientific evaluation has confirmed in 2021 that, when ingested at recommended dosages, creatine supplementation does not result in kidney damage and/or renal dysfunction in healthy individuals, does not cause dehydration or muscle cramping, and appears to be generally safe and potentially beneficial for children and adolescents. The followig misconceptions associated with creatine supplementation were adressed:

• Creatine supplementation does not always lead to water retention.
• Creatine is not an anabolic steroid.
• The majority of available evidence does not support a link between creatine supplementation and hair loss/baldness.
• Creatine supplementation does not cause dehydration or muscle cramping.
• Creatine supplementation does not increase fat mass.

Dosage

The optimal dosage of creatine can vary based on individual factors including body weight, activity level, and the specific goals of supplementation. Below are two common dosing protocols for creatine monohydrate :

• Loading Protocol: Creatine ‘loading’ is defined as supplementing with oral creatine for 5–7 days with a dosage of 20–25 g/day, often divided into smaller doses throughout the day (e.g., four to five, 5 g servings/day). Creatine ‘loading’ may also be prescribed relative to body mass, for example, 0.3 g/kg/d for 5-7 days (i.e., 21 g/day for a 70 kg individual). The ‘loading’ phase of creatine supplementation is followed by a daily ‘maintenance’ phase often ranging from daily 3–5 g servings/day. As dosages of greater than 10 grams may potentially lead to gastrointestinal distress (i.e., diarrhea), a 'loading' phase of 10 g/day may be considerd.
• Non-Loading Protocol: Alternatively, some individuals may opt for a "no-loading protocol" where they take 3-5 grams of creatine per day consistently without a loading phase. This method may take longer to saturate the muscles with creatine but is often preferred for its simplicity and ease of adherence. For example, creatine accumulation in muscle was similar (~20% increase) after participants consumed 3 g/day for 28 days or 20 g/day for 6 days.

Determination of which creatine supplementation protocol is preferred may depend on the goal of the individual. For instance, if an individual is hoping to maximize the ergogenic potential in a very short period of time (< 30 days), adopting the creatine ‘loading’ protocol may be advised. However, if an individual is planning to ingest creatine over an extended period of time (> 30 days), or if avoiding potential weight gain which can sometimes occur during creatine ‘loading’, the creatine non-loading protocol would be a viable option.

The recommended dosage may also vary depending on the form of creatine being used. For example, other forms of creatine like Creatine Hydrochloride (HCL) or Creatine Ethyl Ester (CEE) might require different dosages compared to Creatine Monohydrate.

Clearance

Research has shown that once creatine stores in the muscle are elevated, it generally takes 4–6 weeks for creatine stores to return to baseline.

Efficacy

Creatine supplementation, particularly when combined with resistance training, produces the vast majority of musculoskeletal and performance benefits in older adults. Even without exercise, creatine supplementation alone can provide some muscle and performance benefits for older adults. The supplementation has shown to be beneficial for a variety of athletic and sporting activities and provides a variety of benefits for females across their lifespan. It's also established that other forms of creatine are not superior to creatine monohydrate.

Timing of Supplementation

A meta-study conducted in 2021, followed by another in 2022, reviewed the timing of creatine Supplementation around exercise and highlighted that the evidence supporting a specific timing (i.e., pre- versus post- versus during-exercise) remains limited and somewhat contradictory. The discrepancies in the existing data likely stem from differing supplementation protocols, sample populations, and training regimens across studies. Currently, adapting creatine timing specifically according to when training is performed is not backed by solid evidence and should not be a major concern. Both meta-studies emphasize the need for more well-controlled studies to determine whether the timing of creatine supplementation around training significantly influences intramuscular creatine content and its ergogenic effects.

Conclusion

Creatine supplementation presents a promising avenue for enhancing various aspects of health and possibly longevity, particularly concerning cognitive function, cardiovascular health, blood sugar regulation, and muscle retention. While the evidence is growing, further research, especially large-scale human trials, are required to better understand the full spectrum of creatine's benefits on longevity.

See Also

• Wikipedia article

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