On: Navigating the many pathways to health and disease

Episode: 46

Date: March 2019

Key Subjects:

• Entrepreneur, independent researcher and doctorate in nutrition.
• Methylation.
  • See Methylation write-up for more details.
  • Methylation cycle: 
    • From methionine to homocysteine.
    • Homocysteine either gets broken down or converted back to methionine.
  • Two pathways to convert homocysteine back to methionine:
    • Folate (B9):
      • Folate+ amino acid metabolism + MTHFR => methyl donation to B12 => methyl donation to homocysteine to become methionine.
    • Choline (B4): choline => betaine => methyl donation to homocysteine to become methionine.
  • Folate pathway may not be efficient due to genetic (MTHFR) issues.
    • Creates too much homocysteine, which is bad (causes oxidative stress).
    • Fix: improve MTHFR function by supplementing with vitamin B2 (riboflavin: MTHFR is a riboflavin-dependent enzyme).
  • The other solution is to increase the importance of the choline pathway:
    • Requires that you increase choline intake (through diet or supplements).
  • Or, you can remove homocysteine by breaking it down more aggressively:
    • The presence of metyl folate (ie, methylated folate present) signals that there is enough methyl available.
    • Since there is no need for homocysteine conversion, the removal pathway is activated: glycine is methylated and peed out.
    • Requires B6 vitamin.
    • Increase this pathway by supplementing with metyl folate or B6.
  • Methylation cycle and fasting vs. feeding:
    • Feeding: no need to recycle homocysteine (you have enough methionine from food), so homocysteine conversion is inactive (MTHFR is inactive) and homocysteine breakdown is active (requiring B6).
    • Fasting: need to recycle homocysteine, so conversion / MTHFR is active and breakdown path is inactive.
    • If you have high homocysteine in a fed state, it means you have insufficient B6 for homocysteine clearance.
  • Purpose of methylation – creatine:
    • Almost half of supply of methyl groups are to synthesize creatine.
  • Purpose of methylation — dopamine:
    • COMT is the enzyme that methylates dopamine.
      • Determines the rate of methylation given the methylation supply available (ie, subject to efficiency of your methylation cycle).
    • If you methylate dopamine, it becomes less active.
      • Higher rate of methylation of dopamine = more flexible = “warrior”.
      • Lower rate of methylation of dopamine = more stable = “worrier”.
  • If you have high homocysteine, feel like you worry too much:
    • Increase choline intake (methyl donor for homocysteine conversion).
    • Increase creatine (lower methylation demands).
    • Increase metyl folate (methyl donor for homocysteine conversion).
    • Increase glycine (metyl folate signals homocysteine breakdown and glycine methylation, glycine gets peed out, you may need more).
      • Glycine promotes better sleep.
      • Bone broth. 
• NAD+ supplements.
  • See Sirtuins and NAD write-ups for details.
  • NAD+: 
    • Respiratory process: NAD+ is used over and over again, cycling back and forth from NAD+ to NADH during during ATP creation.
    • Sirtuins (and PARPs): sirtuins, involved in DNA repair, consume and use up NAD+ (leaving behind NAM).
  • As we age, we seem to have less NAD+.
    • Perhaps we don’t produce enough or we use too much.
  • NAD supplements have become very popular.
    • Supplements have to be in the form of precursors to NAD+.
    • NR or NAM ->  NMN -> NAD+.
  • These supplements are first stored in the liver and trickled out when needed.
    • The liver makes NAD+ for its own use and stores a reserve pool for the rest of the body.
    • The reserve NAD+ is carried to other cells when needed through the blood stream in the form of NAM (NAD+ only travels in NAM form).
    • At the cell, the NAM is either used converted to NAD+ and used or detoxified (methylyated and removed).
  • No strong support yet on positive impact of NAD supplements.
    • Short-term: you would expect to see impact in body tissues “damaged” under normal conditions (skin, gut).
      • Hard to measure impact.
    • Longer term: genomic stability, less DNA damage accumulation.
      • No evidence yet.
  • May be some negative side-effect to NAD supplements.
    • When sirtuins use up NAD+, they release NAM.
    • The NAM so created switches off sirtuins.
      • Negative feedback loop.
    • Either use NAM (to make NAD+ again) or get rid of it.
    • Supplements may result in too much NAM being created.
    • To remove NAM, you need to methylate it.
    • If many methyl groups are used to remove NAM, there is less methyl available for other key methylation processes.
  • NR (rather than NAM) may be the better supplement.
    • NR mostly first gets absorbed in the liver, where it gets converted and stored as NAD+ (NR -> NMN -> NAD+).
    • At no point are sirtuins blocked (NR, NMN, or NAD+), 
    • If you take NAM, there may be an immediate threat to sirtuin activity.
    • If you take NMN, unclear if it is efficiently absorbed.
  • NAD+ is a signaling molecule:
    • If you inject NAD+, you trigger an inflammatory response.
    • In the body, NAD+ outside of cells seems to be a signal of some sort, but unclear what (perhaps a change in a cell’s energy status).
    • So it’s unclear what type of response you are soliciting by injecting NAD+.

Key Takeaways:

• Understand if and how methylation not working:
  • For instance, if in a fasted state, homocysteine is high and not converted, increase methyl donors by supplementing with choline / betaine / TMG.
  • Or, if in a fed state, homocysteine breakdown not working, supplement with B6.
• Supplement glycine.
  • May be low if overly glycine is overly methylated and peed out during homocysteine breakdown.
  • Helps with sleep.
• Supplement creatine.
  • May help to reduce demands for methylation. 
  • Supports wide variety of bodily functions.
• NAD+ supplements:
  • Unclear short-term and long-term impact, side and signaling effects.
  • Take it with a methyl donor (to lessen impact of potential reduction in methyl group availability).
• Resource: Chris Masterjohn website.

Worth Listening:

Dense, technical and nuanced episode covering the specifics and interplay of Methylation and NAD.

• 8/10