#46–Chris Masterjohn, Ph.D.: Pathways to health and disease (NAD, sirtuins, methylation, choline...

Choline is essential for making VLDL particles, which transport triglycerides out of the liver. Without enough choline, fat accumulates in the liver, leading to NAFLD. This has been consistently observed in TPN patients and animal studies where choline is withdrawn from the diet. (Timestamp: 1025 seconds)

Animal studies consistently show that sufficient choline can prevent or reverse fatty liver, regardless of the cause (sugar, alcohol, fat). While human studies directly testing choline supplementation for NAFLD resolution are lacking, the physiological evidence suggests a strong potential. (Timestamp: 1345 seconds)

TMAO (trimethylamine N-oxide) is a compound produced in the gut from choline and carnitine. While some studies by the Cleveland Clinic linked high TMAO levels to atherosclerosis, the overall evidence is mixed. Critical analysis points out that fish, a heart-healthy food, naturally contains hundreds of times more TMAO, complicating the direct link. (Timestamp: 2388 seconds)

Saturated fats have no double bonds, making them straight and solid. Monounsaturated fats have one double bond, and polyunsaturated fats have two or more, introducing kinks and making them more liquid. Polyunsaturated fats, while essential, are more vulnerable to lipid peroxidation when oxidative stress or inflammation is present, which can worsen NAFLD progression from steatosis to steatohepatitis. (Timestamp: 3242 seconds)

NAD+ is a crucial coenzyme involved in mitochondrial energy production and serves as a substrate for sirtuins and PARPs, enzymes involved in DNA repair and cellular protection. NR and NMN are precursors that the body converts into NAD+ to potentially boost its levels, particularly in the liver. (Timestamp: 4213 seconds)

Mouse studies suggest that while oral NR and NMN can increase overall NAD+ levels, the liver plays a central role, converting most into nicotinamide. This nicotinamide then circulates and is taken up by other tissues to synthesize their own NAD+. The amount of intact NR or NMN reaching non-hepatic cells and being converted directly to NAD+ is physiologically minimal. (Timestamp: 4566 seconds)

A primary concern is that taking high doses of NR or NMN might excessively consume methyl groups as the body detoxifies the resulting nicotinamide. This increased demand for methyl groups could potentially impact other critical methylation-dependent processes, though human studies on this are still emerging. (Timestamp: 6461 seconds)

MTHFR is an enzyme central to the methylation cycle, synthesizing the methyl group used by folate to recycle homocysteine into methionine. Common genetic variants in MTHFR lead to a gradient of enzyme activity, affecting the efficiency of folate utilization and increasing the body's choline requirement as a compensatory mechanism. (Timestamp: 6707 seconds)

COMT is an enzyme that methylates dopamine. Variations in COMT activity influence dopamine metabolism, affecting mental flexibility, focus, and stability. The 'warrior' phenotype (high activity) is associated with mental flexibility and higher impulsivity, while the 'worrier' phenotype (low activity) is linked to sustained focus but also potentially more rumination and anxiety. (Timestamp: 7477 seconds)

For those with lower MTHFR activity, strategies include consuming 900-1200 mg/day of choline (preferably from food), supplementing with creatine to reduce methyl group demand, ensuring adequate riboflavin intake for MTHFR function, and potentially supplementing with glycine to buffer methyl groups and support sleep/blood sugar. (Timestamp: 7840 seconds)

Creatine synthesis accounts for a large portion of methyl group demand and is highly sensitive to methionine availability. It acts as a buffer for methyl groups. Beyond exercise performance, creatine is vital for sperm motility, stomach acid production, muscle hydration, and can improve depression in women. (Timestamp: 7953 seconds)

Peter Attia emphasizes that the level of evidence needed to take action is subjective, depending on personal values and risk tolerance. He values assuming an historical default (things with a long proven track record) over a 'nothing is default' or 'status quo is default' approach, especially for complex health interventions. (Timestamp: 9144 seconds)