#46 - Chris Masterjohn, Ph.D.: Navigating the many pathways to health and disease - NAD and sirtuins, methylation, MTHFR and COMT, choline deficiency and NAFLD, TMAO, creatine, and more
Chris Masterjohn, PhD in nutrition science, discusses NAD supplements, choline deficiency's role in NAFLD, and the importance of methylation, including MTHFR and COMT genes. He also covers creatine's benefits and dietary strategies for methylation.
Deep Dive Analysis
17 Topic Outline
Chris Masterjohn's Background and Path to Research
Choline: Its Importance and Role in Fatty Liver Disease
Non-Alcoholic Fatty Liver Disease (NAFLD): Prevalence and Causes
TMAO: Understanding its Role and Concerns with Choline
Impact of Different Fatty Acids on Liver Health
The Challenge of Measuring Flux in Biochemical Pathways
NAD Precursors: Physiology, Supplements, and Liver's Central Role
Intravenous NAD and Extracellular NAD as a Signaling Molecule
Oral NR and NMN: Absorption, Metabolism, and Clinical Data
The MTHFR Gene and its Impact on Methylation
The Methylation Pathway and Homocysteine Regulation
The COMT Gene: Dopamine Methylation and Personality Traits
Creatine: Synthesis, Benefits, and Role in Methylation
Dietary Strategies for MTHFR and Methylation Support
Potential Harms of NAD Precursors and Methyl Group Depletion
Decision Making with Inconclusive Data and Personal Experimentation
Chris Masterjohn's Unconventional Beliefs
9 Key Concepts
Methyl Group
A one-carbon unit that is essential for synthesizing and modifying molecules in the body. The process of adding a methyl group is called methylation, also known as one-carbon metabolism.
Choline
An essential nutrient that acts as a methyl donor, is a component of the neurotransmitter acetylcholine, and is crucial for forming phosphatidylcholine, a phospholipid in cell membranes and lipoproteins. Deficiency can lead to fatty liver disease.
Non-Alcoholic Fatty Liver Disease (NAFLD)
A condition where fat accumulates in the liver, not due to alcohol consumption. It is often linked to obesity and can progress to more severe inflammation (NASH) if not managed.
TMAO (Trimethylamine N-oxide)
A compound produced when gut bacteria metabolize choline or carnitine into trimethylamine, which the liver then converts to TMAO. It has been controversially linked to cardiovascular disease risk.
Flux (Biochemistry)
Refers to the movement and turnover rate of molecules within biochemical pathways, rather than just their static concentration. Understanding flux requires dynamic measurements, analogous to watching a video instead of a snapshot.
NAD (Nicotinamide Adenine Dinucleotide)
A coenzyme vital for cellular energy production (oxidative phosphorylation) and consumed by enzymes like sirtuins and PARPs for DNA repair and cellular protection. Its levels are thought to decline with age.
MTHFR Gene
A gene that encodes the methylenetetrahydrofolate reductase enzyme, which is involved in constructing methyl groups from amino acid metabolism for the folate pathway. Common genetic variants (polymorphisms) can reduce its activity, affecting methylation efficiency.
COMT Gene
A gene that encodes catechol-O-methyltransferase, an enzyme that methylates dopamine. Genetic variations in COMT activity can influence mental flexibility versus stability, affecting traits like focus, worry, and impulsivity.
Creatine Synthesis
The process of creating creatine in the body, which is a significant consumer of methyl groups (45% of total demand). Creatine is crucial for energy buffering in cells, muscle strength, and various other physiological functions.
10 Questions Answered
Choline is an essential nutrient that serves as a methyl donor, a component of the neurotransmitter acetylcholine, and a crucial part of phosphatidylcholine, a phospholipid vital for cell membranes and for transporting fat out of the liver.
Without sufficient choline, the liver cannot produce enough VLDL (very-low-density lipoprotein) particles, which are necessary to export triglycerides (fat) out of the liver, leading to fat accumulation and NAFLD.
While choline can be metabolized to TMAO by gut bacteria, the overall story linking dietary choline from eggs and meat to heart disease via TMAO is likely oversimplified and not strongly supported by evidence, especially when considering the high TMAO content naturally found in fish.
Polyunsaturated fatty acids (PUFAs) may lead to less liver fat in the short term, but if steatosis is present, they significantly increase the risk of progressing to steatohepatitis (NASH) due to their vulnerability to oxidative damage.
Oral NR is primarily absorbed and converted to NAD in the liver, which then releases nicotinamide into the bloodstream. Other tissues take up this nicotinamide to synthesize their own NAD, as direct NAD transport in the blood is not a primary physiological mechanism.
Intravenous NAD is unlikely to be an effective transport mechanism for increasing intracellular NAD; extracellular NAD primarily functions as a signaling molecule, and injecting it may cause an inflammatory response rather than directly boosting cellular NAD.
MTHFR is an enzyme crucial for the folate-dependent methylation pathway. Common genetic variations (polymorphisms) can reduce its activity, potentially increasing choline requirements and affecting overall methylation capacity, though its impact is often oversimplified.
The COMT enzyme methylates dopamine. Variations in COMT activity influence dopamine metabolism, with higher activity linked to mental flexibility (e.g., 'warrior' phenotype) and lower activity linked to mental stability but also a tendency for thoughts to 'get stuck' (e.g., 'worrier' phenotype).
Creatine synthesis consumes a large portion (45%) of the body's methyl groups. It's a crucial energy buffer in cells, important for muscle function, and has been linked to mental health benefits, with supplementation potentially reducing the demand on the methylation cycle.
High doses of NAD precursors might deplete the body's methyl group supply because the liver methylates and excretes excess nicotinamide (a byproduct of NAD metabolism), potentially impacting other methylation-dependent processes like creatine synthesis.
28 Actionable Insights
1. Increase Choline for Fatty Liver
Consume enough choline (or precursors like methionine/protein) to clear triglycerides from the liver, as this has been shown in animal studies to prevent or resolve fatty liver disease regardless of the cause.
2. Aim for 1200mg Choline Daily
Strive for approximately 1200 milligrams of choline daily, which can be challenging to achieve through diet alone (e.g., one egg contains ~130mg), to support liver health and prevent fatty liver.
3. Prioritize Food-Based Choline
Opt for phosphatidylcholine from food sources (like eggs and liver) over choline salts in supplements, as it is better absorbed and less likely to generate TMAO in the gut.
4. Increase Choline for MTHFR
Individuals with MTHFR gene variants that reduce methylfolate activity may have a higher choline requirement (e.g., 900-1200mg daily) because they use more choline to compensate for methylation, impacting various bodily functions.
5. Supplement Creatine to Reduce Methyl Demand
Supplementing with creatine (e.g., 5 grams daily) can significantly reduce the body’s overall methyl group demand, as creatine synthesis accounts for a large portion (45%) of methyl group utilization, which can be beneficial for those with compromised methylation capacity.
6. Take Creatine Daily
If supplementing with creatine, take 5 grams daily, regardless of exercise schedule, to maintain steady body stores and support various physiological functions beyond just exercise performance.
7. Optimize Riboflavin for MTHFR
If you have MTHFR gene variants, ensure optimal riboflavin (Vitamin B2) status, as MTHFR is a riboflavin-dependent enzyme and a lower affinity for riboflavin can reduce its activity.
8. Increase Glycine Intake
If you have low methylfolate levels, consider increasing glycine intake (e.g., through bone broth, collagen, gelatin, or glycine powder) as your body may be losing glycine in the urine due to perceived methyl abundance.
9. Glycine for Sleep and Blood Sugar
To potentially improve sleep, take 3 to 6 grams of glycine powder before bed; for better blood sugar control, take 3 to 5 grams of glycine powder with a meal.
10. Use TMG for Methylation Support
If you have difficulty lowering homocysteine despite other interventions, supplementing with trimethylglycine (TMG) can be highly effective, as it supports the choline-dependent pathway for remethylating homocysteine back to methionine.
11. Consider B6 for High Homocysteine
If you have high homocysteine levels that respond to B6 supplementation, it suggests a need for more B6 to support the breakdown of homocysteine, particularly in the fed state.
12. Oral NR for NAD Increase
If aiming to increase NAD levels, oral nicotinamide riboside (NR) may be a superior precursor to nicotinamide, as NR is less prone to immediate detoxification in the liver and more effectively increases hepatic NAD.
13. Consider Methyl Donors with NR
If supplementing with high doses of nicotinamide riboside (NR), consider supplementing with a methyl donor like trimethylglycine (TMG) to counteract the potential depletion of your body’s methyl group supply due to the detoxification of excess nicotinamide.
14. Space Out Choline Intake
When consuming choline-rich foods like eggs, consider spacing out your intake throughout the day rather than eating a large quantity at one sitting, due to a potential absorption cap that could lead to TMAO generation.
15. Eat Eggs for Choline
Consume eggs as a primary source of choline, as they provide choline in a form that is less likely to generate high levels of TMAO in the blood compared to choline tartrate supplements.
16. Limit PUFAs with Fatty Liver
If you have fatty liver (steatosis), be cautious with a high intake of polyunsaturated fatty acids (PUFAs), as they increase vulnerability to progression to steatohepatitis due to more oxidative targets.
17. Avoid Oral NMN Supplements
Oral nicotinamide mononucleotide (NMN) supplements are likely not absorbed intact due to their charged phosphate group, suggesting they may be less effective than NR or other precursors for increasing NAD.
18. Avoid IV NAD Infusions
Intravenous NAD infusions are not recommended as a physiological means of increasing intracellular NAD, and may trigger an inflammatory response or amplify negative signaling.
19. Start Low with NR Supplementation
If experimenting with nicotinamide riboside (NR) supplementation, consider starting with lower doses (e.g., 75mg twice daily) than typically found in commercial products, as a cautious approach to assess individual response.
20. Gelatin for Tendon Health
To increase collagen synthesis in tendons, consider consuming 15 grams of gelatin with a little vitamin C before exercise, as the increased blood flow during activity can help deliver collagen peptides to connective tissues.
21. Optimize Methyl Donors for COMT
Understand that your COMT genotype influences your potential rate of dopamine methylation, but nutritional intake of methyl donors directly impacts actual methylation, suggesting that optimizing these nutrients can influence mental flexibility or stability.
22. Distinguish Concentration from Flux
When interpreting scientific data, especially blood tests or metabolic markers, remember that a static concentration measurement does not fully represent the dynamic ‘flux’ (movement and turnover) of a molecule, which can lead to misinterpretations.
23. Evaluate Evidence for Action
When making health decisions, consider the level of evidence required to take a specific action, but also critically evaluate the level of evidence (or lack thereof) needed to justify inaction or maintaining the status quo.
24. Study Historical Scientific Foundations
To gain a fresher perspective and uncover overlooked details in scientific understanding, delve into the historical foundations and origins of ideas, rather than solely focusing on the latest research.
25. Respect Conventional Science
Avoid dismissing conventional scientific beliefs or established guidelines outright, as understanding their core rationale is crucial, even when exploring progressive or alternative health approaches.
26. Diversify Undergraduate Studies
When planning for graduate school (e.g., medical school), consider studying a completely different subject in undergraduate to gain a fresh perspective and enthusiasm for your chosen graduate field.
27. Leverage Positive Placebo Effects
If a health intervention makes you feel great, even if it’s potentially a placebo effect, leverage that positive feeling, but also be prepared to stop if an intervention makes you feel unwell, regardless of its purported benefits.
28. Prioritize Objective Biochemical Proxies
When self-experimenting with health compounds, prioritize interventions that can be evaluated with objective biochemical proxies rather than solely relying on subjective feelings, as the latter can be influenced by the placebo effect.
6 Key Quotes
If you don't have enough choline, you can't make the VLDL particle to get triglycerides out of the liver.
Chris Masterjohn
The idea that mistaking a concentration for flux is one of the overwhelming interpretive problems in science and in popular science in both.
Chris Masterjohn
Overwhelmingly, if you're talking about a tissue other than the liver, what's happening is that supplement gets converted into nicotinamide, reaches the other tissues as nicotinamide, and increases tissue NAD by that tissue taking the nicotinamide and making the NAD.
Chris Masterjohn
The liver doesn't just have NAD that's immediately being used in respiration and is immediately being used in sirtuins and parps. It has a reserve pool of NAD that it holds onto for the specific purpose of a slow release of nicotinamide to the rest of the tissues that they will take up.
Chris Masterjohn
COMT is not a gene for a mental state, right? It's a gene that has a partial influence on the stickiness of your mind.
Chris Masterjohn
Creatine is the ideal thing to vary with the methyl group supply because you can eat a steak, you can do all your creatine synthesis when you were—when you had enough methyl groups. Then five hours later, you're in the fasted state, and you—you don't synthesize creatine anymore.
Chris Masterjohn
2 Protocols
Dietary Strategies for MTHFR Support
Chris Masterjohn- Consume 900-1200 milligrams of choline daily, preferably from food sources like eggs and liver.
- Supplement with 5 grams of creatine daily to reduce overall methyl group demand.
- Ensure adequate methylfolate intake (e.g., 400 micrograms of methylfolate and 800 micrograms of methyl B12) to support the folate pathway.
- Increase glycine intake (e.g., 3-6 grams daily from bone broth, collagen, or powder) to buffer methyl groups and support various physiological functions.
Mitigating Potential Negative Effects of NAD Precursors
Chris Masterjohn- Take a lower dose of NAD precursors (e.g., 75mg NR twice daily instead of 500-1000mg).
- Match NAD precursor intake milligram for milligram with a methyl donor like TMG (trimethylglycine) to support methylation capacity.