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

KEYPOINTS

• 01

  Without enough choline, fat gets trapped in the liver

  Choline is needed to make phosphatidylcholine, which coats the VLDL particles that carry triglycerides out of the liver. Patients on intravenous feeding formulas that lacked choline developed fatty liver, mirroring rodent experiments from the early 20th century. Masterjohn's reading of those animal studies is that with enough choline, the liver can clear its fat whether the source is sugar, alcohol or fat.

• 02

  Choline needs may be far above typical intake

  Masterjohn estimates average intake at about 300 mg a day. Some genetically predisposed people need as much as 1,200 mg, and labeling studies show triglyceride export from the liver in NASH (inflamed fatty liver) at about 25% of normal. He uses that to argue some people may need several times typical intake. Liver and egg yolks are the richest sources.

• 03

  Fatty liver has inputs and outputs

  Fructose, alcohol and very high polyunsaturated fat intake drive fat into the liver, while choline governs how fast it leaves. Attia, who considers fructose molecule for molecule perhaps the biggest driver of NAFLD, notes that removing it usually also causes weight loss, which muddies the results. They discuss Miriam Vos's eight-week study in children, in which whole families were given the food, as a chance to separate the two.

• 04

  TMAO as a heart-disease villain fails first principles

  Stan Hazen's Cleveland Clinic work linked TMAO, which gut bacteria and the liver make from choline and carnitine, to atherosclerosis in genetically engineered mice and to heart disease risk in people. Masterjohn and Attia point out that fish contains far more TMAO, perhaps hundreds of times more than you'd get from eggs or red meat, yet fish eating is consistently associated with better heart health. Attia sends patients who bring him the papers to Masterjohn's write-up, though he wouldn't rate the possibility of harm as zero.

• 05

  The liver stores and regulates NAD

  Masterjohn compares the liver's NAD pool to glycogen: the liver keeps blood levels tightly controlled by releasing precursors such as nicotinamide for other tissues, much as it keeps blood glucose near 5 grams. This matters for understanding what NAD-boosting products can actually change in other tissues.

• 06

  IV NAD and oral NMN are unlikely to work as advertised

  Cells can't simply absorb NAD from the blood, so Masterjohn suspects any felt effect of IV NAD is placebo or a nonspecific signal; Attia notes friends describe infusions as 'the worst feeling in the world'. Masterjohn would bet NMN isn't absorbed intact, because enzymes in the small intestine strip phosphate groups off everything we eat, as they do with riboflavin-5-phosphate.

• 07

  High-dose NAD precursors may drain methyl groups

  Excess nicotinamide is cleared by attaching a methyl group (methylation), and studies show large increases in methylated nicotinamide in urine and blood with NR. Typical NR doses of 1,000–2,000 mg dwarf the niacin RDA of about 15 mg. In theory, every 1,000 mg of nicotinamide cleared this way could cut creatine production by up to 500 mg against roughly 2 grams made per day. Masterjohn suggests a lower dose matched milligram for milligram with the methyl donor TMG (trimethylglycine).

• 08

  Methylation centres on SAMe and homocysteine

  Methionine becomes S-adenosylmethionine (SAMe), the universal methyl donor, leaving homocysteine to be recycled through MTHFR or the choline/betaine route, or broken down. Masterjohn says about 90% of methyl groups go to making creatine and phosphatidylcholine; creatine alone accounts for about 45%, and it's the first thing to suffer when methyl groups run short.

• 09

  COMT variants shape dopamine and temperament

  COMT uses methyl groups to break down dopamine. Masterjohn says faster dopamine methylation is linked to mental flexibility and slower methylation to stability, popularly the 'warrior' and 'worrier' types. Normal variation is personality, while the extremes may raise psychiatric risk.