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Peter Attia MD#46–Chris Masterjohn, Ph.D.: Pathways to health and disease (NAD, sirtuins, methylation, choline...
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CHAPTERS
- 0:04 – 11:59
Chris's Background and Why History Shapes His Science
After the show's intro and the no-ads explanation, Peter welcomes Chris Masterjohn. Chris describes growing up in Massachusetts, studying history, and moving into nutrition research. He explains how a historical perspective helps him find fresh angles on science.
- •Chris studied history and originally planned to be a social studies teacher
- •Health experiences and a love of biochemistry led him toward research instead of medicine
- •Peter argues that studying something different in undergrad can bring fresh enthusiasm to graduate school
- •Chris asks where an idea came from, because forgotten details can later make sense
- 11:59 – 17:00
What Choline and Methyl Groups Are
Peter raises the TMAO controversy that first connected him with Chris, then asks what choline is. Chris defines choline's roles and explains methyl groups as one-carbon units. They cover the main food sources of choline.
- •Choline is a methyl donor and part of acetylcholine and phosphatidylcholine
- •A methyl group is a one-carbon unit, and methylation is also called one-carbon metabolism
- •Liver and egg yolks are very rich in choline; meats, nuts and cruciferous vegetables supply moderate amounts
- •Choline's essentiality was missed until patients were fed total parenteral nutrition without it
- 17:00 – 25:10
Choline Deficiency and Fatty Liver
Chris explains that people on choline-free TPN developed fatty liver because phosphatidylcholine is needed to build the VLDL that exports triglycerides. They discuss animal data showing choline or its precursors clear fat however it was caused. They also cover the dose Chris would guess is needed.
- •Without choline the liver can't make VLDL to export triglycerides
- •Century-old rodent experiments showed choline, methionine or extra protein prevented fatty liver from sucrose, alcohol or fat
- •In controlled human studies, removing choline from the diet caused fatty liver in nine of ten people
- •Chris's wild guess is about 1,200 mg of choline, versus roughly 130 mg per egg
- •Steatosis is likened to kindling that a second hit can ignite into NASH
- 25:10 – 39:37
NAFLD Epidemic, Visceral Fat and Confounded Diet Studies
Peter shares the history of NAFLD and NASH and the projection that it will become the leading cause of liver transplant. Chris discusses the roles of obesity and visceral fat, and why human diet studies change many variables at once. His own rat study with a methionine-rich diet illustrates the point, and they discuss the recent fructose trial in boys.
- •NASH was coined in 1980 for fatty liver patients who denied drinking alcohol
- •Chris attributes rising NAFLD mainly to obesity and visceral fat feeding the liver through the portal vein
- •Diet changes alter many nutrients at once, so animal data with precise controls help interpret human data
- •Chris's 60% fructose rats did not get fatty liver, probably because his diet had about six times more methionine than casein diets
- •The fructose-removal study in boys cut liver fat by 50%, but other nutrients likely changed too
- 39:37 – 53:36
TMAO, Fish, and Choline Forms
They return to the Cleveland Clinic TMAO papers and the argument that choline and carnitine harm arteries. Chris and Peter explain why fish, which is far richer in TMAO, undercuts the story. Chris explains why he prefers phosphatidylcholine to choline salts and why absorption limits matter.
- •Gut bacteria convert choline and carnitine to trimethylamine, which the liver turns into TMAO
- •Fish contains far more TMAO than eggs or red meat
- •Chris puts the odds that eggs and meat harm via TMAO close to zero but is open to TMAO as a biomarker
- •Phosphatidylcholine is better absorbed and less likely to generate TMAO than choline bitartrate
- •TMAO response to eggs varies widely between people and depends on how many are eaten at one sitting
- 53:36 – 59:48
Fatty Acids, Oxidation and Liver Fat
Peter and Chris define saturated, monounsaturated and polyunsaturated fats. Chris explains how polyunsaturated fats are vulnerable to lipid peroxidation. He explains why PUFAs might reduce liver fat in short studies yet raise the risk of progression to NASH.
- •Double bonds create kinks, making unsaturated fats more liquid
- •Fat between two double bonds is vulnerable to peroxidation, though omega-3 and omega-6 fats are essential
- •A two-week human study found PUFAs gave less liver fat than saturated fat
- •Oxidative stress can damage ApoB particles and cause steatosis, as in alcohol models
- •With existing steatosis, PUFA-rich membranes raise the risk of progressing to steatohepatitis
- 59:48 – 1:09:40
Flux Versus Snapshots in Biomarkers
Discussing VLDL, ApoC3 and insulin resistance, Peter and Chris arrive at the problem of inferring flux from static measurements. They use analogies such as the car-accident photograph and fasting free fatty acids. Chris points out that tracer studies show the true kinetics.
- •Peter explains that insulin resistance raises ApoC3, so VLDL linger and blood levels may not reflect export
- •Concentration is not flux, and a snapshot can mislead
- •Peter's fasting free fatty acids look diabetic but reflect high turnover
- •Serial measurements or many metabolites in a pathway can reconstruct kinetics
- •Labeled tracers show a 75% drop in ApoB secretion in NASH
- 1:09:40 – 1:33:12
NAD Precursors: How NR Is Handled by the Body
Peter introduces NAD, sirtuins and the NR supplements Basis and Tru Niagen. Chris explains how dietary niacin forms are processed, with the liver converting them and releasing nicotinamide as the transport form. They go through the Rabinowitz tracer findings on why NR beats nicotinamide and how the liver acts as an NAD reservoir.
- •NAD levels fall from consumption by sirtuins and PARPs, while the NAD/NADH ratio reflects overfeeding
- •Nearly all NAD in non-liver tissues derives from circulating nicotinamide made by the liver
- •Only a trace of intact NR reaches muscle in mouse tracer studies
- •Nicotinamide inhibits sirtuins and PARPs, so it must be quickly converted or methylated and excreted
- •Chris suggests NR is better at raising hepatic NAD because it can't be detoxified before becoming NAD
- •Peter likens the liver's NAD reserve to glycogen
- 1:33:12 – 1:50:00
IV NAD, NMN, and Human NR Trials
Peter asks about IV NAD clinics, and Chris explains that extracellular NAD acts as a signaling molecule that triggers inflammatory responses. Chris doubts that oral NMN is absorbed intact. They review the ChromaDex human studies, which found no metabolic benefits, and why tissue turnover suggests where benefits would show.
- •Chris says extracellular NAD seems to be a signal, not a transport form, and activates granulocytes
- •Chris bets that NMN's charged phosphate is cleaved in the gut and not absorbed intact
- •Human NR trials showed no benefit on glucose or lipids, and the studies were short
- •NAD turnover is far higher in skin and gut, where benefits might appear first
- •Chris sees the main risk as the drain on methyl groups from methylating nicotinamide
- 1:50:00 – 2:04:35
MTHFR, Homocysteine and the Methylation Cycle
Peter asks what MTHFR is and whether anyone should care. Chris explains the methylation cycle, in which S-adenosylmethionine donates methyl groups and homocysteine is recycled via folate/B12 or choline/betaine. He covers MTHFR polymorphisms as a spectrum, the riboflavin link, and why B6 works on homocysteine through a different pathway.
- •Everyone has MTHFR; its activity is spread fairly evenly across the population
- •Low MTHFR activity makes people burn through more choline, raising their requirement
- •MTHFR variants raise homocysteine mainly in people with poor riboflavin status
- •After a protein-rich meal MTHFR shuts down and B6-dependent breakdown of homocysteine switches on
- •B6-responsive homocysteine points to a fed-state disposal problem, not an MTHFR problem
- 2:04:35 – 2:10:31
COMT, Dopamine and Warrior vs. Worrier
Peter asks where COMT fits. Chris explains that COMT methylates dopamine and shapes mental flexibility versus stickiness. He describes the associations with psychiatric traits and cautions that genotype only sets potential given the methyl donor supply.
- •COMT methylates dopamine; higher activity brings mental flexibility, lower activity brings stability
- •COMT activity is roughly 25% at each extreme and 50% in the middle
- •Low-methylation types may do better at sustained focus, such as academics, competitive swimming and sticking to exercise
- •OCD is linked to low methylation, and substance abuse and ADHD to high methylation
- •Chris sees little diagnostic utility; nutrition affects actual methylation rate
- 2:10:31 – 2:23:55
Dietary Strategies: Choline, Creatine and Glycine
Chris outlines strategies for low MTHFR activity, starting with 900–1,200 mg of choline from food. He explains why creatine supplementation reduces methyl demand, and why people may need more glycine. They discuss collagen versus glycine powder, bone broth and Peter's homocysteine case that responded to TMG.
- •About 45% of methyl demand goes to creatine synthesis, so supplementing creatine lowers it
- •Creatine helps muscle hydration and strength, and has been linked to depression and other roles
- •Low methylfolate leads to methylated glycine being lost in urine, so more glycine may be needed
- •Glycine studies show better sleep at 3–6 g and better blood sugar at 3–5 g, but collagen benefits are less clear
- •Peter's patient's homocysteine fell 50% with TMG, which Chris reads as a fasted-state recycling problem
- 2:23:55 – 2:43:20
NR Methyl Drain, Personal Use and Evidence Standards
Chris returns to NR, estimating how much methyl supply nicotinamide detoxification could consume and recommending matching NR with TMG. They debate whether fixing homocysteine matters and what level of evidence justifies action. Chris shares his low-dose NR experiment, and Peter shares an anecdote about rosacea and IV NAD.
- •Detoxifying 1,000 mg of nicotinamide could cut creatine synthesis by about 500 mg
- •Chris recommends matching NR milligram for milligram with TMG, and says the methyl drain is a theoretical concern
- •The skeptic's case against treating homocysteine or MTHFR is acknowledged, and action thresholds depend on subjective values
- •Chris took about 150 mg of NR daily as a self-experiment
- •Peter reports rosacea improvement in patients taking NR products, and both note the difficulty of separating placebo from effect
- 2:43:20 – 2:51:59
Contrarian Views and Closing
Peter poses Peter Thiel's question about important truths few people agree with. Chris answers with his libertarianism, his respect for RDAs and conventional nutrition science, and his belief that obesity causes metabolic dysfunction. Peter disagrees on obesity, and they wrap up with where to find Chris.
- •Chris calls himself twice the libertarian of your libertarian uncle
- •He considers the RDAs good though sometimes outdated science and criticizes dismissing them
- •He agrees with conventional theory that obesity causes metabolic dysfunction, a view some in his community dislike
- •Peter sees obesity as largely a compensatory response to something metabolic
- •Chris's website is chrismasterjohnphd.com, and he is @chrismasterjohn on social media
