homocysteine, CBS, autoimmunity - very brief notes

 I don't even have time today to post links to references and  hope I can find them again at some point in future ... {update 2021-07-18 - I'm working on it}

A commenter on YT that I had previously discussed how methionine restriction can actually cause an increase in homocysteine levels asked me what I thought about the apparent paradox - since methionine restriction (MR) lengthens lifespan, but high homocysteine / hyperhomocysteinemia (HHcy) should cause an increase in mortality from CVD (and other things). In lab animals HHcy is induced by feeding excess met and restricting B12, folate and B6. But low met decreases CBS activity, which can also cause HHcy.

Chronic HHcy can cause hypermethylation of the CBS gene, reducing its expression. I'm guessing that's why clinical trials to lower Hcy with vitamin B6 etc. don't necessarily result in improvement in cardiovascular health - CBS is still not working and H2S signalling is still impaired. Maybe not the case, though, if Hcy is successfully lowered in blood, but perhaps cells in stem cell niche in bone marrow are still 'stuck' with CBS 'off'? Or perhaps cystathionine gamma-lyase (responsible for most endothelial H2S production) also gets stuck off?

H2S is needed for bone marrow  endothelial progenitor cells to function properly (BM EPCs) and the mechanism of H2S has something to do with p38 MAPK, which I had read about just a couple of days ago in relation to autoimmune disease.

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Then I started thinking about CoQ10 and statin side effects. The muscle problems related to statin use may be the result of autoimmunity, not due to CoQ10 depletion. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266943/

"Although generally well tolerated, statin users frequently report muscle-related side effects, ranging from self-limiting myalgias to rhabdomyolysis or the rare clinical entity of statin-associated immune-mediated necrotizing myopathy (IMNM). Statin-associated IMNM is based on the development of autoantibodies against 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis and the pharmacologic target of statins, and leads to a necrotizing myopathy requiring immunosuppressive therapy.  ...

Statins can cause myopathy/myositis either as a noninflammatory, toxic effect12 or as a trigger of an autoimmune process have quite similar initial presentation. The difference between the two conditions though is the effect that has the discontinuation of the offending toxic agent (Table 1). While in the first case, the weakness resolves within weeks or months, in the latter case, the statins have triggered a self-sustained inflammatory cycle requiring the addition of immunosuppression in order to reverse the myopathy, as we see in idiopathic inflammatory myopathies (IIM)."

However, CoQ10 depletion could theoretically contribute to the development of autoimmunity. Open access review: 

'Therapeutic Potential and Immunomodulatory Role of Coenzyme Q10 and Its Analogues in Systemic Autoimmune Diseases' - https://www.mdpi.com/2076-3921/10/4/600/htm

This review cites many papers by a JY Jhun, et al.; I was dismayed by the choice of cotton seed oil as placebo in at least one of the Jhun et al.'s studies: https://pubmed.ncbi.nlm.nih.gov/26045320/ 

Cottonseed oil was shown to lower LDL cholesterol; the mechanism is not known: https://pubmed.ncbi.nlm.nih.gov/22852052/

I was also dismayed by this video on statins by 'Medlife Crisis' and the study reviewed therein https://www.youtube.com/watch?v=R6FGaR7vOHk and the study reviewed therein since side effects can  persist after discontinuation.

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There was a case report of CoQ10 causing autoimmunity, which resolved after discontinuation - only one report so this appears to be quite rare.

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Somehow or other I wound up reading about l-canavanine and lupus; alfalfa sprouts might not be so healthful after all. Arginine supplementation might help to ameliorate. 

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Hcy neurological harm depends on glycine levels:

https://pubmed.ncbi.nlm.nih.gov/30626145/

"The mechanism of damage evoked for Hcy excitatory role has been found [65,66]: Hcy is anagonist of the endogenous glutamate receptors, NMDA receptors [67,68].Through Hcy-NMDA binding, Hcy indirectly enhances calcium influx [69]. This is not a constant reaction, and it largely depends in the Glycine concentration; when glycine is in normal concentration(10μmol/L), Hcy acts as a partial antagonist of the glycine site of the NMDA receptor, and it inhibits the receptor-mediated activity, acting as a neuroprotective factor [23,65]. Therefore, it can be easily demonstrated that when glycine levels are normal, only HHcy could exert a toxic effect(i.e., Hcy = 100μmol/L).On the contrary, when glycine levels are higher inside the brain, more than 10μmol/L, (and this occurs in clinical conditions in different scenario: brain ischemia, head trauma, or even protracted migraine cluster), even a low concentration of Hcy (i.e., Hcy = 10μmol/L) could be an agonist on NMDA [70,71], exerting an excitatory action, and enhancing calcium influx."

So don't take glycine when you have a migraine? What are homocysteine levels like in typical mouse models for neurodegenerative diseases? Are they comparable to those in elderly humans? Seems like mouse studies on glycine should be run at different Hcy levels; I imagine high gly and HHcy would be very bad.