Addressing Hypometabolism

nanobug

Member
This post is based on a published study entitled "Metabolic features of chronic fatigue syndrome" by Naviaux et al. There is also an appendix with additional info. In particular, this appendix contains a nice detailed metabolic map (Figure S6).

The main conclusion of the paper is that CFS is consistent with a state of hypometabolism resulting from physiological stress to the cells (a cell danger response mechanism.) Based on this information, I am going to try to develop a strategy to get the system (in this particular case called me) out of this funky state.

In this first post I'm not going to address mitochondrial oxidative phosphorylation impairment, which I believe is also a major problem. I'll do that in a later post.

From the paper: "All of the metabolic abnormalities that we identified in CFS were either directly regulated by redox or the availability of NADPH. [...] When reduced (NADPH) and total (NADPH plus NADP+) pools are low, sterol, fatty acid, protein, and nucleotide synthesis fall to baseline survival levels. When NADPH levels are higher, metabolism is shifted from persistence to normal cell function and growth, anabolic pathways are stimulated, biomass is created, and carbons and electrons are stored as biopolymers for cell growth and repair in the form of lipids, protein, glycogen, glycans, and nucleic acids."

From this, one is tempted to conclude that increasing NADPH ad hoc is a winning strategy but the authors caution: "NADPH cannot be simply added as a nutritional supplement to produce the tidal change in metabolism needed to shift the dauer state of CFS to normal health." However, they hypothesize that "incremental improvements in NADPH production could theoretically be supported by interventions directed at folate, B12, glycine, and serine pools, and B6 metabolism (SI Appendix, Fig. S6)."

I spent a few hours looking at the metabolic map in Figure S6 (in the Appendix) and came up with the following conclusions:
  • Methylenetetrahydrofolate is an important metabolic substrate for the production of NADPH both in and outside the mitochondria. In particular, it is a substrate for the production of methyltetrahydrofolate (aka, methylfolate) and this process is subject to those pesky genetic variations in the MTHFR gene many of us are already acquainted with;
  • Tetrahydrofolate, the demethylated version of methylfolate, is an important cofactor in the production of methylenetetrahydrofolate via several pathways;
  • Outside the mitochondria, tetrahydrofolate is created when it cedes its methyl group to cobalamin (B12) resulting in methylcobalamin, which in turn is used in the methylation cycle we all know and love. It may also be created from dietary folate via a sequence of reactions.
  • Inside the mitochondria, tetrahydrofolate may also be obtained from folinic acid.
  • Trimethylglycine is an important component in the methylation cycle and, as part of this cycle, it gets demethylated into dimethylglycine. Dimethylglycine is an important component for the production of methylenetetrahydrofolate.
Although there are a few more details (quite a few!) that I am not going to bother enumerating, I've settled on a "NADPH protocol" that relies on supplementing (potentially heavily) with:
  • Methylcobalamin
  • Methylfolate
  • Pyridoxal phosphate
  • L-glycine
  • Trimethylglycine
  • N-Acetylcysteine
I already supplement with the first three at close to RDA levels so I'll be adding extra for good effect.

Supplementing with these is far from a new or big revelation for many with CFS, considering that "methylation" has been for quite some time a hallmark of "treatment." But this is clearly not enough and addressing another variable in the hypometabolism equation is required. That variable is mitochondrial oxidative phosphorylation. I'll attempt to do so in a subsequent post. In any case, @Remy already addressed this in several of his posts.
 

Not dead yet!

Well-Known Member
My mind may have grabbed onto an obsession, but I thought it worth mentioning that 2 million people in the USA is around 0.7% of the population....

and 1% of the population has Celiac disease, except 83% are undiagnosed... so my math may be bad,but it might be right around 0.7% that are undiagnosed.

My mind finds these patterns based on current obsessions, but it's interesting because of the description of fatigue and long term pain. Both of those were very much reduced when I gave up gluten properly. I'm not saying try it because it works, I'm saying it's a pattern match that may or may not be valid.

Or I'm too tired to notice the logic error right now. :D

Although there are a few more details (quite a few!) that I am not going to bother enumerating, I've settled on a "NADPH protocol" that relies on supplementing (potentially heavily) with:
  • Methylcobalamin
  • Methylfolate
  • Pyridoxal phosphate
  • L-glycine
  • Trimethylglycine
  • N-Acetylcysteine
I already supplement with the first three at close to RDA levels so I'll be adding extra for good effect.
I think these are reasonable, but you might want to consider whether glycine is really what you're looking for. Compare with taurine. Maybe I'm missing something, but I thought glycine and taurine were used the same way, except glycine was used instead of taurine if you didn't have a source of taurine in your diet. (ie. vegans will use glycine like others use taurine, but the result for me was profound pain and fatigue)

If the map you're looking at is based on a vegan animal, like a rabbit or a cow, you might want to take a look at a map of a cat or a dog or a pig's metabolism, each of which should be using taurine.

I had trouble finding the map itself so sorry if I'm misinterpreting that. The use of glycine in this case may be unrelated to what I'm thinking about. I'm thinking about the cycling between methionine-taurine-cysteine in the liver.
 

Meirav

Member
@nanobug =
Hi! how did your approach go?

I have been 'concocting' my own approach, through trial and error based on my biochemistry (per lab tests) and researching a little bit of biochemistry. At some point I read an interview with Naviaux and his recommendation was similar to what I have come up with - more or less. I haven't yet implemented all of it. Still a work in progress.

I'm not really sure what he means by B6 metabolism concretely
My PLP is wonky, a bit high and supplementing that doesn't work.
I'm not quite sure what he is referring to by B6 metabolism.
 

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