Is there a TMAO / Atherosclerosis risk with supplemental choline / carnitine?

[apod]

Does your diet exclude a lot of the mentioned foods?

http://blog.radiantlifecatalog.com/bid/ ... ant-Living

I've cut back from eating 4 scrambled eggs a few times a week with lots of grass-fed butter to 2x boiled eggs 2x a week sans the butter. Usually, when I would eat beef liver once a week or so, I would eat it blended in with grass-fed ground beef or a food-processed ribeye. Since tweaking my diet, I've pretty much eliminated ground beef and fatty cuts of beef and haven't been eating much beef liver or chicken liver as a result. In the past, I would go through several blocks of cheese in a week, where I've cut out full-fat dairy and moved toward non-fat and low-fat fermented dairy, primarily to push calcium intake up around 800mg/d (I wouldn't mind ditching dairy all together for a calcium supplement or other foods, but I haven't found anything ideal.) I eat plenty of nuts and cruciferous vegetables, but the choline supplied there is minimal. I still need to get in for a new NMR to see which way my diet changes have budged the numbers. Lately, I am eating a lot of fructose (avg. ~110g of sugar a day), where I believe extra choline, or at least an "adequate intake" of choline, might help there with whatever potential there might be for a fatty liver. I also eat a lot of protein high in methionine, where choline might help there as well with homocysteine (which I've never measured), although perhaps a diet high in animal protein sets my gut bacteria up for producing ample TMAO.

I see Dr Sinatra, a respected cardiologist, mentioning that he himself takes L-carnitine at 200mg twice a day, with ALCAR 500mg twice a day, with free-range lamb (one of the highest animal sources of carnitine) / beef / bison 2-3x a week.

This is an interesting article:
http://perfecthealthdiet.com/2013/04/le ... eat-scare/

If the risks from TMAO is just the suppression of bile acid creation leading to higher LDL levels, that doesn't sound like too much of an issue when keeping an eye on LDL-P (possibly with foods / supplements that raise bile acid creation?)

[circular]

Re: choline … might want to check your PEMT rs7946 gene. I am T,T (normal is C), which is 16.8872% of people. Nutrahacker says "converts phosphatidylethanolamine to phosphatidylcholine" and the consequence for me is "fatty liver due to low choline". I'm not aware if I have it, but I suppose I should look up how to find out. I wonder if the same SNP has any impact on choline in the brain, or if that's controlled by another PEMT SNP.

Promethease says:

"rs7946, a SNP in the phosphatidylethanolamine N-methyltransferase PEMT gene and also known as +5465G-A, leads to a V175M (valine to methionine at amino acid position 175) substitution in the PEMT protein, and is a loss of function mutation. Caucasians with nonalcoholic fatty liver are more likely to carry the rs7946 (A), with the effect being most pronounced for rs7946(A;A) genotypes. [PMID 16051693OA-icon.png]
However, rs7946(A) carriers are not more likely to have fatty liver, based on a study of many more patients, including ones of Hispanic and African-American descent. [PMID 17012264]

"How can this be? One explanation [doi: 10.1096/fj.06-1005ufm] concludes the following:

"Caucasians have a different distribution of this SNP than do Hispanics and African Americans;
Having this SNP may be necessary, but is not sufficient, to cause fatty liver, as many individuals with the SNP have normal liver fat;
Probably this SNP does slow the export of fat from liver, but only rs7946 carrying individuals who also take in too many calories too quickly (i.e. overeat) will wind up with fatty livers."

Nutrahacker says "encourage phosphatidylcholine". I'm taking 500 Cognizen CDP per day (for about 15 days now). I wonder if I should up that to 1000 per Bredesen's upper limit, or add in a different type. I guess I need one that is downstream of my genetic glitch, phosphatidylcholine or further. Harrison, you say, "CDP-choline is broken down into choline" … I wonder if CDP is upstream of my genetic glitch, such that I should be sticking with Bredesen's alternative recommendation of alpha-GPC, which you say is "a breakdown product of phosphatidylcholine". Thanks in advance for any thoughts anyone has on this.

[apod]

Re: choline … might want to check your PEMT rs7946 gene. I am T,T (normal is C)

Very interesting, I'm a CT there. It looks to me like CDP-choline is primarily a cytidine supplement, which is converted to uridine, then choline (and may offer some benefits beyond simply supplementing choline?) A 500mg dose contains less choline than eating 1 small 59 calorie egg. I'm leaning toward trying citicholine at 250mg if I do supplement.

[Julie G]

FWIW, I'm CT there as well. I've settled on 250mg of citicholine a day plus about 10 very high (660mg) Omega-3 eggs a week. I initially played with 500mg of citicholine and found it to be like rocket fuel Definately take it in the AM...

I recall a study in which choline, uridine and Omega-3s improved cognitive decline in E4 mice. (It's buried in the fish oil thread.) These are essentially the ingredients in Souvenaid- an AD medical food not yet available in the US.

Souvenaid info:
http://www.souvenaid-us.com
Research on Souvenaid:
http://www.ncbi.nlm.nih.gov/pubmed/?term=Souvenaid
http://www.ncbi.nlm.nih.gov/pubmed/?ter ... yn+connect

[circular]

apod, do you know if cytidine > uridine > choline pathway is outside the phosphatidylethanolamine > phosphatidylcholine pathway, such that CDP-choline would then be useful to me? However, geez, I wonder if 1000 mg of Cognizen CDP-choline would provide enough to make a difference?

There's a great chart here listing the free choline content of foods, which I assume is already downstream of my PEMT glitch? (as well as the other forms) http://www.ars.usda.gov/SP2UserFiles/Pl ... holn02.pdf

I also need to sort out the difference between PEMT genes that affect fatty liver and genes that may affect choline in the brain. Are they the same or different? I haven't had time to get into this enough yet.

Nutrahacker also calls attention to CHRNA5 (normal T, I'm A,G) which is 48.4664% so common. "Neuronal acetylcholine receptor subunit alpha-5 … increased nicotine uptake … avoid nicotine". That's easy, but he doesn't say how this could affect acetylcholine activity itself - seems to increase it, which absent nicotine would be a good thing, no?

Now, see this:

"Diminished folate availability increases demand for choline as a methyl donor while decreased choline availability increases demand for folate methyl groups" http://www.ars.usda.gov/SP2UserFiles/Pl ... holn02.pdf

Good gravy, I also have potential decreased enzyme function for dihydrofolate > tetrahydrofolate on DHRF. At least I'm a heteroz there.

This an example of why I'm beginning to believe that our individual ApoE4 protocols can't be designed without going down a lot more genetic rabbit holes, including the confusing methylation maze. Nutrihacker has helped me appreciate this more.

This is also why many won't endorse or fund Bredesen's work … the complexities are quite mind-boggling and quite possibly incalculable.

This may be a main study Dr. Bredesen relies on in his protocol. Note it only had 30 participants, but it does point to benefit specifically for E4, so the CDP-choline might provide marginal reassurance in the context of E4:

"As compared to placebo, citicoline [Cytidine 5'-diphosphocholine = CDP-choline] improved cognitive performance in Alzheimer's disease patients with APOE E4 (ADAS: difference between groups = -3.2 +/- 1.8 scores, p < 0.05; ADAS-cog: difference between groups = -2.3 +/- 1.5, ns); and this improvement on cognition was more pronounced (ADAS, p < 0.01; ADAS-cog: difference between groups = -2.8 +/- 1.3, p < 0.06) in patients with mild dementia (GDS < 5). Citicoline also increased cerebral blood flow velocities in comparison with placebo (p < 0.05)… In addition, neither adverse side effects nor alterations in biological and hematological parameters were induced by citicoline. The present data indicate that citicoline (1,000 mg/day) is well tolerated and improves cognitive performance, cerebral blood perfusion and the brain bioelectrical activity pattern in AD patients. According to our results, it seems that citicoline might be a useful treatment in Alzheimer's disease, and that the efficacy of this compound is greater in patients with mild mental deterioration and/or bearing the epsilon 4 allele of the APOE."

http://www.ncbi.nlm.nih.gov/pubmed/10669911

I'm getting less worried about TMAO when taking citicholine in the context of a lower fat and lower carb diet and otherwise healthy biomarkers. What's less clear is how much I should take in the context of my PEMT gene. For all I know my body is compensating somehow?

[apod]

apod, do you know if cytidine > uridine > choline pathway is outside the phosphatidylethanolamine > phosphatidylcholine pathway, such that CDP-choline would then be useful to me?

It's over my head, but it looks to me like a different pathway.

"The PEMT pathway seems redundant because its product, PC, is also synthesized by the CDP-choline pathway in hepatocytes. Therefore, the PEMT pathway is traditionally considered a backup pathway for PC synthesis in hepatocytes." "The biochemical significance of the PEMT pathway in hepatocytes has been of great interest because the CDP-choline pathway is already present in all mammalian cells and is sufficient for PC synthesis. In vivo studies reveal that the PEMT pathway contributes significantly to the survival of rats during complete deficiency of dietary choline, suggesting that up-regulation of PEMT pathway might, at least in part, substitute for the role of the CDP-choline pathway." http://www.jbc.org/content/274/42/29683.long

Interestingly, the CDP-choline pathway seems to favor "medium chain species" of PC molecules, while the PEMT pathway favors "significantly more long chain, polyunsaturated species."

https://en.wikipedia.org/wiki/CDP-choline_pathway

[apod]

Here’s a paper that makes a strong case FOR acetyl-L-Carnitine (and Lipoic acid) supplementation in E4 mice.

The effect of acetyl-L-Carnitine and Lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer’s disease
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713369/

Three groups of mice: wild type (essentially 3/3s,) unsupplemented E4s, and supplemented E4 mice were put through a series of challenges. The supplemented E4 mice performed very similarly (and even better than) the wild type mice on the challenges. The results are actually pretty impressive; check out figures 7-10. The authors make a case that the acetyl-L-Carnitine (and Lipoic acid) enhance mitochondrial function accounting for the improvement.

I found this interesting article on ALA: http://www.ncbi.nlm.nih.gov/pubmed/18486188
"Dietary restriction feeding extends survival in a range of species but a detailed understanding of the underlying mechanism is lacking. Switching from ad libitum feeding a diet supplemented with alpha-lipoic acid to dietary restriction feeding of the non-supplemented diet, blocks the normal effect of DR to extend survival, even after cessation of lipoic acid supplementation."

More discussion here:
http://www.longecity.org/forum/topic/22 ... te]Results highlights:
* DR rats lived longer than ad lib rats (approx. 12% longer) regardless of whether LA was used in either group
* ad lib -> DR at 12 months of age showed essentially the same lifespan as DR rats (i.e. it didn't matter that they didn't start on dietary restriction until 12 months, they got basically the same benefit as if they had been on DR since 2 months old); DR -> ad lib at 12 months of age rats lost most of the benefits of DR (but there was a small residual benefit)
* ad lib + LA -> DR at 12 months rats did not gain the benefits of DR, ad lib + LA -> DR at 6 months did gain some of the benefits of DR
* DR -> ad lib + LA at 12 months had lifespans as if they were always DR, DR -> ad lib + LA at 6 months had lifespans of intermediate length (so partial continuing effects of DR)

They conclude that LA's effect might be described as locking in the survival trajectory of the animal, but they don't know why. They suggest it is not related to the anti-oxidant properties of LA. Possible mechanisms they mention: it has been implicated that LA can modify gene expression, LA regulates a number of transcription factors, LA can bind to DNA directly, and a few others.[/quote]Also, http://www.ncbi.nlm.nih.gov/pubmed/22785389[quote]The mice that received alpha-lipoic acid had significantly increased glutathione and decreased glutathione peroxidase and malondialdehyde indicating reversal of oxidative stress. These results indicate that alpha-lipoic acid improves memory and reverses indices of oxidative stress in extremely old SAMP8 mice, but decreases lifespan.[/quote]I wonder if there are other antioxidants that stack well with ALCAR. Tricky.

[Lia]

This is an old thread but I wanted to add this link for anyone referencing this page in the future:

http://www.lifeextension.com/Magazine/2 ... ne/Page-01

This tells a different story from what some sources would have us believe.

[aiden]

Choline bitartrate is not well absorbed in the gut, and may raise TMAO more than other choline supplements. One study showed a 10 to 14 fold increase in TMAO when subjects supplemented with choline bitartrate.

[adriana268]

is there a reason no one is talking about taking phosphatidyl choline instead of all the other forms ? I haven't seen this mentioned