Creatine: Genes, Cognitive Function, and Strength | 23andMe

Genetic Lifehacks Weekly Newsletter

Hi everyone -

I've been getting a lot of questions about 23andMe this week and wanted to give a little background on the situation. Some of the headlines are pretty scary, as click-bait headlines tend to be.

Background:
23andMe became a public company in 2021 with lots of investment money, and it expanded rapidly with spinoff offerings, including a full telehealth company.

Last year, they made headlines with falling stock prices and poor financials. The board resigned, and then in November, their SEC filing stated that they were in financial trouble. The CEO, Anne Wojcicki, tried to buy the company back as a private company. Her offer was rejected, and over the weekend, the committee that makes financial decisions decided to put the company into Chapter 11. The CEO resigned on Sunday (but is still on the Board) and released a statement saying: "I have resigned as CEO of the company so I can be in the best position to pursue the company as an independent bidder."

What does this mean for 23andMe in the future?
It depends on who buys the company. Importantly, 23andMe's Privacy Policy says that in the event of a bankruptcy, merger, or acquisition that their current privacy statement and TOS will continue to apply to your personal information. Their statement on the bankruptcy and continuing services also reiterated that the privacy policy remains even when the company is sold.

Should you delete your data?
That's up to you. If you're not using the features on 23andMe -- or any other genetic testing or report platform -- I've always advocated for downloading your genetic data, storing it safely (including a backup copy), and deleting your genetic data so that it isn't stored online. This keeps your data safer and prevents you from forgetting that your genetic data is out there somewhere.

However, if you're using the features on a genetic service, then it may be worth keeping it. For 23andMe, if you are keeping your account, be sure to keep an eye on the news or read their emails to know what is happening.

Reminder of the Genetic Lifehacks model:
For members, the genotypes that you see in the articles and summary reports are generated by connecting to your data on your storage drive. Your genetic data is not stored on my server.

I created Genetic Lifehacks this way because I believe your genetic data is safest when you store it and don't share it. However, this means that I can't help you if you lose your raw data file... Keep it safe and back it up.

Things change:
Several genetics companies have changed hands or gone out of business in the past couple of years. I love what I'm doing and plan on sticking around for a long while.

This is a good reminder that "nothing can be said to be certain, except death and taxes". If you want to join me in putting off death, subscribe to Longevity Lifehacks. There's no getting around taxes.

Gratefully yours,
Debbie

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Creatine: Boosting Muscles and Increasing Brain Power

Key takeaways:
~ Creatine acts as a backup energy source for muscles and the brain to use in times of stress.
~ Genetic variants in the genes related to creatine synthesis can impact muscle pain, athletic performance, and cognitive ability.
~ Creatine supplements are inexpensive and readily available. Studies show that creatine monohydrate supplementation effectively boosts muscle power and brain creatine levels under certain conditions.

What is creatine?

Creatine is an amino acid that plays an important role in energy production within both brain tissue and muscles. The body can synthesize creatine from other amino acids, and you can get it from your diet.

Let's first take a look at how creatine is used in cellular energy:

Adenosine triphosphate (ATP) is at the heart of cellular energy. ATP is primarily produced in mitochondria — you know, the powerhouse of the cell.

ATP stores energy in the bonds between the phosphates, which store and then can release energy within the cell.

The ‘triphosphate’ part of ATP means it has three phosphates bound together. When ATP releases energy, it sheds one of its phosphates and becomes adenosine diphosphate (ADP) with only two phosphates remaining. This is where creatine comes in. In specific cell types, creatine helps recycle ADP back into ATP by donating a phosphate group. Thus, creatine can help replenish cellular energy when it's running low.

How does the body make creatine?

While creatine supplements are typically associated with bodybuilders, it is actually utilized in all types of muscles and in the brain.

Creatine is synthesized from the amino acids glycine and arginine, along with a methyl group donated by SAMe.

The biosynthesis of creatine is a multi-step process.

First, glycine and arginine, two common amino acids, combine to form guanidinoacetate. Then, creatine is formed from guanidinoacetate with the addition of a methyl group. This process occurs primarily in the liver and kidneys. Once synthesized, creatine then enters the bloodstream and can be used throughout the body.[ref]

Within cells, creatine can be further converted to phosphocreatine with the help of the enzyme creatine kinase (CK). Phosphocreatine, also known as creatine phosphate, stands ready, available for converting ADP to ATP when more energy is needed.

Muscle cells and the brain both need a lot of ATP for energy. When a lot of energy is required, such as lifting something heavy or sprinting, phosphocreatine rapidly replenishes ATP from ADP. In normal, lower-energy situations, ATP is produced directly from glucose or fatty acids.

In addition to being synthesized in the liver, creatine can be obtained from the diet as well as from supplements. Creatine is naturally found in animal protein-rich foods, such as muscle meats. Supplemental creatine, which bodybuilders commonly use, is also a source of creatine for creating the phosphocreatine used when repairing and building muscles.

Diving deeper into creatine kinase:

I mentioned above that creatine kinase is the enzyme used to convert creatine to phosphocreatine, which can then be used by cells for energy when needed.

There are two types of creatine kinase - mitochondrial and cytosolic - found in the muscle and brain. The phosphocreatine created in the reaction acts as an energy buffer, readily available when muscle cells are stressed and need a burst of ATP for energy.[ref]

In medical contexts, doctors often measure creatine kinase levels in the blood to assess tissue damage, especially in cases like cardiac muscle damage during a heart attack. When tissues are harmed, creatine kinase can leak into the bloodstream, serving as a valuable indicator.

Lab tests for creatine kinase:

Doctors often measure creatine kinase levels in the blood to assess tissue damage. For example, if cardiac muscle is damaged during a heart attack, creatine kinase levels will usually be elevated.[ref] CK levels increase in response to brain, heart, or muscle damage.[ref]

What else elevates creatine kinase (CK) levels on tests?
Aside from heart attacks, strenuous exercise can elevate CK levels up to 15 times the normal level. For instance, after running a marathon, CK levels peak after 24 hours and remain elevated for a week.[ref]

Additional causes of elevated CK levels:

• Statins can raise CK levels in people who have statin-induced muscle pain.[ref]

• Obesity or African ancestry is associated with higher CK levels.[ref]

Creatine and Brain Function:

The brain, despite its relatively small size, uses up a ton of energy (ATP) in comparison with the rest of the body.

In the brain, creatine serves as an energy buffer to provide energy in times of stress.[ref] Genetic mutations that cause creatine deficiency in the brain result in severe developmental disorders and seizures.

Creatine obtained from diet or supplements can cross the blood-brain barrier, but the amount that reaches the brain is generally less than what is absorbed by muscles. This implies that to positively impact brain function, a higher intake of creatine might be necessary. Alternatively, it could mean that creatine is prioritized by the muscles unless there is an urgent requirement for it to go to the brain.

As one research study puts it: “It could be that the brain relies primarily on endogenous creatine synthesis until there is some sort of challenge to brain creatine status. These challenges, which could cause a decrease in brain creatine, could be acute (e.g., sleep deprivation, intense exercise) or chronic (e.g., aging, traumatic brain injury, depression, Alzheimer’s disease, creatine synthesis enzyme deficiencies).”[ref]

Another study found that “Creatine supplementation enhanced measures of memory performance in healthy individuals, especially in older adults (66–76 years)."[ref]

Creatine and the Methylation Cycle:

The methylation cycle is a cellular process for producing methyl groups (a carbon + 3 hydrogen atoms) for use in many types of biochemical reactions. Both folate and choline are key contributors of methyl groups in the methylation cycle.

I mentioned above that one step in creatine biosynthesis includes a methyl group. A significant portion of the body's methyl groups – about 40% – is dedicated to producing creatine.[ref]

When methyl groups are low, homocysteine levels will often be elevated. High homocysteine is linked to an elevated risk of heart problems.

Related article: Homocysteine, heart health, and more

A placebo-controlled clinical trial involving individuals engaged in resistance training showed that creatine supplementation over eight weeks reduced homocysteine levels. The study used an initial dose of 25 g/d of creatine for the first five days, followed by 5 g/day for the rest of the trial.[ref]

Methyl groups also play a role in detoxification processes, including arsenic detoxification. A study found that in people with suboptimal intake of choline or folate, supplementing with creatine or folic acid helps aid the detox reaction for arsenic.[ref]

What happens if you don’t get creatine in your diet?

Creatine is not considered an essential amino acid, meaning you can make it in your body and don’t always have to get it from food.

However, getting creatine in your diet may prevent problems as you age or in times of physical stress.

A study of people over age 65 found that getting less than 1g of creatine via diet each day resulted in more than double the risk of angina (chest pain) and 2.5x the risk of liver problems.

The authors of the study concluded: “The considerable shortage of dietary creatine is associated with an increased risk of heart and liver conditions, which calls for public measures that foster diets rich in creatine-containing foods, and additional research to investigate the role of creatine in age-related diseases.”[ref]

Another study found that getting over 0.95g of creatine in foods daily was protective against cognitive decline in older adults.[ref]

Clinical trials using creatine supplements:

Creatine supplements have been very well studied, with thousands of clinical trials.

Here are just a few of the clinical trials:

• A study from 2024 found that creatine monohydrate mediated accelerated recovery after exercise-induced muscular damage (exercise). Study participants used 3g/day of creatine.[ref]

• A double-blind, placebo-controlled safety trial using 0.3g/kg of creatine per day in men found: “creatine monohydrate supplementation is safe for health and no detrimental effects on different organs and physiological systems were observed in our cohort of volunteers.”[ref]

• In healthy older adults (aged 50-71), creatine before resistance training increased lean muscle mass and decreased fat mass. The trial ran for 32 weeks and used 0.1g/kg of creatine, compared to a placebo.[ref]

• Vegetarians have lower creatine levels, on average. A study of supplemental creatine showed vegetarians had even greater increases in bench-press strength, lean tissue, and other biomarkers than did non-vegetarians. (Both groups on creatine had better results from resistance training than the vegetarian and non-vegetarian placebo groups.[ref]

• Creatine supplementation helped both men and women increase peak power in bench presses and back squats.[ref]

• Creatine plus electrolytes increased sprint cycling times in a double-blind, randomized control study.[ref]

• Under hypoxic (low oxygen) conditions, creatine helps with cognitive function. The study included 15 healthy adults who took creatine for seven days before the 90-minute hypoxia session.[ref]

Negative study results are also interesting:

• Creatine supplementation did not significantly improve bone health in menopausal women with osteopenia.[ref]

• In fibromyalgia patients, creatine supplementation increased muscle strength, but it didn’t reduce pain or improve quality of life.[ref]

Creatine in adipose (fat) tissue:

In fat cells (adipose tissue), creatine is important in thermogenic respiration. Loss of creatine can decrease whole-body energy expenditure.[ref]

Brown or beige fat is the type of fat that creates heat in the body, especially in babies. Brown fat is darker in color than white adipose tissue (white fat) because it contains a huge number of mitochondria cranking out heat as a metabolic waste product.

Exposure to cold can trigger brown fat to produce more energy. It is essential in infants who are too young to shiver. The brown fat helps them to maintain their temperature.

In animal studies, creatine has been shown to enhance energy production when ADP is limited. When researchers limit creatine levels, the cells try to compensate by increasing the enzymes to produce more creatine. Animals lacking the creatine kinase enzyme had increased body weight and elevated fasting blood glucose.[ref][ref] The research here is new and evolving, but it looks like creatine plays a role in adaptation to cold, energy expenditure, and metabolic health.

Creatine for post-viral fatigue syndrome and Long Covid:

Post-viral fatigue syndrome is just what it sounds like - overwhelming fatigue that doesn’t end after you’ve gotten over a viral infection. It can refer to long covid or chronic fatigue syndrome (ME/CFS).

In people with post-viral fatigue syndrome (PVFS), muscle fatigue is reached much more rapidly than normal. It is thought that PVFS perturbs energy metabolism in the muscles. Research shows patients with chronic fatigue have reduced levels of hippocampal creatine, also. While there is “not enough evidence to unequivocally endorse supplemental creatine for PVFS”, researchers do think it is possibly effective, as well as being low-risk and inexpensive.[ref]

In long Covid patients, an 8-week trial of creatine, creatine + glucose, or glucose alone as the placebo, showed that creatine+glucose had a large effect on decreasing body aches, headaches, and brain fog. The participants received 8 g of creatine monohydrate and 3 g of glucose per day. [ref]

Sarcopenia and creatine

Sarcopenia is the loss of muscle mass, causing decreased strength in aging or chronic disease.

It is tempting to think creatine could be used to stop the aging effect on muscles, but research shows it isn’t quite that easy.

Studies in older adults show creatine supplementation alone has little effect on muscle function or mass. But... when creatine supplementation is added to weight training, the results show that it enhances the muscle's response to training, potentially increasing capacity for higher intensity exercise and improving the muscle’s response post-exercise.[ref]

Thus, one way that creatine may be beneficial in older adults is by increasing their capacity for exercising a little longer or lifting a little more weight. Even minor increases in exercise capacity can be important in older adults, and increasing muscle mass or grip strength can help with stability and independence.[ref]

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What I've been reading:

1.) Omega-3s (DHA, EPA) plus Exercise

A new meta-analysis that combines the data from 21 studies shows that adding omega-3 supplements along with exercise adds to the benefits.

Compared to exercise alone, exercise + omega-3s:
~ 2lb of fat loss
~ 4 mmHg lower systolic and diastolic BP
~ 9mg/dL lower triglycerides.

2.) Impact of microplastics exposure on liver health: A comprehensive meta-analysis

Unsurprisingly, the overall impact of microplastics in the liver isn't positive. The research shows a "significant increases in liver enzymes ALT and AST, oxidative stress markers MDA, and pro-inflammatory cytokines IL-6 and TNF-α, along with a notable reduction in antioxidative enzymes like SOD, CAT, GSH, and GPx."

3.) Urolithin A as an NLRP3 inhibitor

A new study (in animals) shows that urolithin A can improve schizophrenia-like cognitive impairment by inhibiting the NLRP3 pathway.

Activation of the NLRP3 inflammasome increases the inflammatory response. Part of the problem in schizophrenia is neuroinflammation, which is exacerbated by NLRP3 activation.

Genetic Lifehacks article on NRLP3 SNPs and Chronic Inflammation