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 (B9):
- 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”.
- COMT is the enzyme that methylates dopamine.
- 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.
- Short-term: you would expect to see impact in body tissues “damaged” under normal conditions (skin, gut).
- 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