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

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

Postby apod » Mon Jul 13, 2015 8:48 pm

Is there an ideal form of choline / carnitine that doesn't carry as much of a risk of TMAO / atherosclerosis?

https://en.wikipedia.org/wiki/Choline#Recent_research
https://en.wikipedia.org/wiki/Carnitine#Atherosclerosis

The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that Alzheimer's disease is caused by reduced synthesis of the neurotransmitter acetylcholine. ApoE4 plays a crucial role in the cholinergic dysfunction associated with Alzheimer's disease. An isoform-dependent impaired regulation of the transport of phospholipids in the brain of apoE4 carriers could explain the reduced levels of phosphatidylcholine, phosphatidylethanolamine and choline reported in Alzheimer's disease. This, in turn, may lead to decreased acetylcholine synthetic capacities. http://www.ncbi.nlm.nih.gov/pubmed/8618881

Studies on a number of different populations have found that the average intake of choline was below the adequate intake. Looking at cronometer, my intake averages out around 350-400mg. The recommended adequate intake (AI) for choline is 550mg for men.

With choline, I'm seeing different forms like citicholine, alpha-gpc, phosphatidlcholine, choline citrate, and choline bitartrate, and carnitine in forms like L-carnitine, L-carnitine Fumarate, ALCAR, GPLC, and LCLT. Are these cardioprotective or proatherogenic? Are any of these forms better for APOE4? Is it best to get it from diet? (It seems like I've read that vegetarians don't have as much of an issue with TMAO?)

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

Postby circular » Mon Jul 13, 2015 11:10 pm

Hi apod,

In his Feb 2015 Revision Letter Dr. Bredesen recommends:

"Citicoline (Cognizin) 500 or 1000 ("alternatively one can substitute alpha-GPC 500 mg)"

and

"Acetyl-L-carnitine (ALCAR) 500mg per day"

I just went ahead and got those and didn't worry about the details.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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

Postby Gilgamesh » Tue Jul 14, 2015 12:58 am

Hey apod,

I've raised this issue before here. Most people in the CR community have quit all forms of carnitine, as well as choline (citicoline appears to be particularly risky). In healthy rodents, carnitine appears to shorten lifespan (see first link below).

The question is whether ε4s might react differently. Dr. Bredesen clearly thinks they will, and as anyone who read his ground-breaking paper knows, he's got a good mechanistic explanation for why. But I'd love to know what he thinks about the TMAO research. Did he mention anything about it at the get-together in S.F.?

http://arc.crsociety.org/read.php?2,215 ... msg-215593

http://arc.crsociety.org/read.php?2,215 ... msg-215688

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

Postby Harrison » Tue Jul 14, 2015 8:07 am

I can't speak too much to the cardiovascular risk of choline, but I am skeptical of the link. Here is a recent study suggesting no link: http://www.ncbi.nlm.nih.gov/pubmed/26063062. Choline should reduce inflammation, so it should be useful from that standpoint. I think staying on top of lipids and getting a cardiac calcium scan (which I still need to do!) are are good strategies for moderating risk. Here are my 2 cents on the different forms of choline around (modified from the original time I posted it in the long Bredeson thread).

Taking various forms of choline can come down to two questions: Bioavailability and price. Choline bitartrate are horse pills, but you end up with a lot of choline on the cheap (about 45% useable choline). When Citicoline (aka CDP-choline) is broken down into its constituent molecules, it results in about 20% choline, as well as cytidine (which is converted to uridine and people claim has some cognition boosting effects). 500 or 1000 mg of Citicoline as recommended by Bredeson might be 100mg or 200 mg of usable choline. Another option is GPC choline, which in the body is a breakdown product of phosphatidylcholine. That is about 40% choline. Bredeson recommends 500 mg of that, which would be about 200mg useable choline.

Also, phosphatidylserine may eventually be converted into phosphatidylcholine, which can then be broken down into choline. If the benefit of taking choline is to strengthen cell membranes, phosphatidylserine or perhaps GPC choline are closer to that biochemically. If the benefit is to make acetylcholine, or even betaine, Choline and CDP-choline are closer to that biochemically.

In addition, choline is an activator of alpha7 nicotinic acetylcholine receptors. Tropisetron, the drug that the Bredesen study in Australia is using, is also an alpha7 activator, although it's primary activity is serotonin-3.

I am taking choline and hope my body can figure out the best place for it via methylation, phosphorylation, or acetylation.

I use Country Life Choline (650 mg Choline Bitartrate, which contains 293 mg of useable choline according to the label, or 45%) twice a day. It is under $12 from amazon for 100 pills. Cognizin CDP-choline (800 mg x 60 pills) is about $35, and that is one of the cheaper ones (never tried). GPC choline (600 mg x 60 pills) is also about $35 (also never tried).

Some people have problems taking a lot of choline (GI issues), and CDP or GPC choline will likely be better for them.

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

Postby Gilgamesh » Tue Jul 14, 2015 9:35 am

Harrison,

Thanks for the link. I, too, am not overly worried about choline (I'm more worried about ALCAR), but even with choline, the TMAO studies gave me cause for concern. Have you read the Nagata et al paper (the one you link to)? The abstract says they controlled for covariates but I'd like to know which covariates.

BTW, nice background article for those who want to dig into this further:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453578/

Much more here, too:

http://www.ncbi.nlm.nih.gov/pmc/?term=choline+tmao

GB

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

Postby apod » Tue Jul 14, 2015 9:42 am

It's interesting looking at Uridine. I wonder if supplementing that instead would be a decent strategy to work around the choline gut-bacteria byproducts. (This seems like a plus for CDP-Choline, which is only ~18% choline and predominately uridine/choline-precursors.) "Oral intake of uridine does appear to increase brain phospholipid precursors in otherwise healthy persons." "Uridine is thought to benefit synaptic functions due to increasing levels of brain phosphatidylcholine." http://examine.com/supplements/Uridine/

It looks like betaine has a similar risk profile. http://www.ncbi.nlm.nih.gov/pubmed/21475195 http://www.nature.com/nature/journal/v4 ... 22_F3.html

If TMAO is the main issue with carnitine, I would be curious how the levels produced from something like ALCAR would compare with eating seafood (which I believe supplies a hefty dose of pre-formed TMAO, but is otherwise usually associated with a decreased risk of heart disease / mortality.) If these risks are gut-related, I would be curious if there are dietary factors or supplements that can improve those issues. It looks like Firmicutes generate much of the TMAO, where in this article, the ratio of Firmicutes to Bacteroidetes in a glutamine-fed group decreased from 0.85 to 0.57. http://www.ncbi.nlm.nih.gov/pubmed/25023447

For the mice with decreased lifespan, how much carnitine were they eating? In this study with rats, the study group had decreased mortality compared with the control group and the article speculated that it may increase longevity. "Acetyl-L-Carnitine supplementation is associated with an attenuated decline in mitochondrial count during aging. Mechanically, ALCAR supplementation has the ability to reduce the correlates of aging seen in lab animals, regardless of deficiency state. Whether this translates to a pro-longevity effect in humans is not known for sure, but highly plausible." http://examine.com/supplements/L-Carnitine/

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

Postby Harrison » Tue Jul 14, 2015 11:39 am

Unfortunately I can't get the full text for the Nagata et al paper. The food consumption aspect of it is based on surveys, so it has some pretty substantial limitations, but I think it is an interesting counterpoint to all the in vitro work that suggests the link between choline and TMAO.

Another study worth considering is a pilot study in 6 men: http://www.ncbi.nlm.nih.gov/pubmed/10456680. There is one particularly interesting paragraph to me:

From the present data it emerges that the major dietary precursor of trimethylamine and its N-oxide in man is trimethylamine N-oxide itself, with little additional contribution from choline or carnitine. It appears, therefore, that the only foods which should present problems to ‘fish-odour syndrome’ patients would be seafoods. Clearly, in clinical practice, the issue is more complicated than this ( Ayesh et al., 1993; Mitchell, 1996). It is appreciated that the number of subjects examined in this present study was small, and that differences in gut microflora between individuals, and even within the same individual over time, may vastly influence enterobacterial liberation of these amines from their precursors ( Hill, 1995). The large inter-individual differences found within the significant increases of trimethylamine and N-oxide output following fish ingestion (mean coefficient of variation=0.17, range=0.03 to 0.42) are presumably testimony to this. It is possible that certain individuals with overt ‘fish-odour syndrome’ may possess gut microflora which are able to readily liberate trimethylamine from these other potential precursors (choline and carnitine), thereby widening the list of potentially problematic foods. Indeed, modulation of the gut microflora, with the selective ablation of such culpable microbes, may lend itself as a means of maintenance therapy within these patients.


I think it's also interesting in the Romano et al, 2015 paper that they screened 79 strains of gut fauna and 9 were capable of producing TMA from choline in vitro. It's possible that more of the strains could produce TMAO in vivo, but it could also be less. To take the paper at face value, 11% of gut fauna may be capable of producing TMAO. Then each individual would need to know how much of the problematic strain they had, if any.

All of this to me that says if you have "Fish-odor" syndrome, you may have the problematic gut fauna and that you if you are worried about TMAO, you probably don't want to supplement with choline. I would probably go with phosphatidylcholine in that case.

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

Postby Julie G » Tue Jul 14, 2015 3:42 pm

ALCAR supplementation is another risk vs. reward dilemma for E4s :? The TMAO connection in humans is "iffy" and many have suggested it may depend on the context of one's overall gut health. For the the vast majority here, who eat a preponderance of cellular plant foods and pay exquisite attention to overall gut health via fermented foods and probiotics; it MAY ultimately prove to be be a wise bet to use ALCAR for our brain health...

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.

Given that the Nature study, that initially raised the alarm with re. to ALCAR and heart health was also done on mice, I tried to find a HUMAN study that examined actual outcome of ALCAR supplementation on heart health. Surprisingly, I found the exact opposite correlation in humans:

L-carnitine significantly improves cardiac health
http://www.elsevier.com/about/press-rel ... art-attack
A comprehensive literature search yielded 153 studies, 13, published from 1989-2007, were deemed eligible. All the trials were comparison trials of L-carnitine compared with placebo or control in the setting of acute myocardial infarction.

This systematic review of the 13 controlled trials in 3,629 patients, involving 250 deaths, 220 cases of new heart failure, and 38 recurrent heart attacks, found that L-carnitine was associated with:

-Significant 27% reduction in all-cause mortality (number needed to treat 38)
-Highly significant 65% reduction in ventricular arrhythmias (number needed to treat 4)
-Significant 40% reduction in the development of angina (number needed to treat 3)
-Reduction in infarct size

The authors here also speculate that it is the enhancement of mitochondrial function that conferred the protection. Since E4 carriers exhibit mitochondrial deficits as early as our 20-30s, it may be even MORE important for us to begin ALCAR supplementation early to help protect against mitochondrial deficiencies. :?:

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

Postby apod » Tue Jul 14, 2015 4:30 pm

This article is somewhat reassuring for a 250-500mg dose of carnitine:
http://www.ncbi.nlm.nih.gov/pubmed/16988205
A significant increase in the plasma concentrations of trimethylamine-N-oxide from baseline was evident only for the 2-g dose of L-carnitine (from 34.5 +/- 2.0 to 149 +/- 145 microM)
Although, this is an interesting article on carnitine that points to another metabolite (gamma-butyrobetaine) that could be atherogenic: http://www.cell.com/cell-metabolism/abstract/S1550-4131(14)00453-7

In the past, I tried Sodium R-Alpha-lipoic acid and found it to be sort of a blood sugar crash in a pill. In reading more about Uridine, I've come across discussions on potential carcinogenic / viral concerns. Tricky!

For the article "Plasma levels of choline, TMAO and betaine are associated with atherosclerosis risks in humans and promote atherosclerosis in mice", I wonder if the plasma level of choline is directly producing atherosclerosis, or if it's correlated with the digestion of choline (and production of TMAO), or some other factor. (This old clip with kurzweil comes to mind.) It looks like CDP-Choline causes a lower rise in plasma choline than alpha-GPC with a 5hr 23% increase at 500mg (I'd be curious to compare with lecithin / liposomal phosphatidylcholine). I've come across other discussions that mention rises in cortisol / stress hormones / insulin / dopamine with CDP-choline or growth-hormone with alpha-gpc.

Maybe for now I'm cool with the 350-400mg of dietary choline and whatever carnitine is being provided from my omnivorous whole foods diet.

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

Postby GenePoole0304 » Wed Jul 15, 2015 11:52 am

apod wrote:Is there an ideal form of choline / carnitine that doesn't carry as much of a risk of TMAO / atherosclerosis?

https://en.wikipedia.org/wiki/Choline#Recent_research
https://en.wikipedia.org/wiki/Carnitine#Atherosclerosis

The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that Alzheimer's disease is caused by reduced synthesis of the neurotransmitter acetylcholine. ApoE4 plays a crucial role in the cholinergic dysfunction associated with Alzheimer's disease. An isoform-dependent impaired regulation of the transport of phospholipids in the brain of apoE4 carriers could explain the reduced levels of phosphatidylcholine, phosphatidylethanolamine and choline reported in Alzheimer's disease. This, in turn, may lead to decreased acetylcholine synthetic capacities. http://www.ncbi.nlm.nih.gov/pubmed/8618881

Studies on a number of different populations have found that the average intake of choline was below the adequate intake. Looking at cronometer, my intake averages out around 350-400mg. The recommended adequate intake (AI) for choline is 550mg for men.

With choline, I'm seeing different forms like citicholine, alpha-gpc, phosphatidlcholine, choline citrate, and choline bitartrate, and carnitine in forms like L-carnitine, L-carnitine Fumarate, ALCAR, GPLC, and LCLT. Are these cardioprotective or proatherogenic? Are any of these forms better for APOE4? Is it best to get it from diet? (It seems like I've read that vegetarians don't have as much of an issue with TMAO?)



Does your diet exclude a lot of the mentioned foods?

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


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