21 replies to this topic

[GreenTea]

I've become confused over conflicting information about methionine and health. I have seen studies saying that methionine restriction is what is responsible for the effects of CR and that it reduced ROS and doubled glutathione. I've also seen studies that say that methionine, cysteine is responsible for increasing glutathione two-fold. These are two totally conflicting points of view that have very serious ramifications such as whether protein is good or bad. I also wonder what this means to supplements like S-Adenosyl-L-Methionine and NAC (heard someone on this forum say that if you were restricting methionine you should not take it but I can't find any reason why).

Edited by GreenTea, 01 February 2011 - 10:59 PM.

[JKDC]

It confuses me also. I believe researchers also restrict methionine to give mice fatty livers.

[leha]

I think they restrict choline to get the fatty livers--or at least, choline deficiency is what triggers that problem.

Regarding methionine, I have been following this whole thing as well, and I don't think the reports are necessarily conflicting. Here's why: Restricting methionine in the diet is not the same as starving cells of methionine. In the study you cited, GreenTea, where GSH increased in response to treatment with methionine and cysteine, the treatment was made to cultured cells. In the studies that showed benefits from restricting methionine, the restriction was applied to the diet of living rats/mice.

What happens when you restrict methionine in a living organism is that it causes the organism to perform some level of biosynthesis, and/or protein scavenging to supply the needed methionine to cells. Cultured cells don't have access to these pathways by virtue of their isolation from the larger organism. It might very well be that the adult body, when starved of methionine, produces more cell-available methionine than it would normally, causing an increase in GSH by the very same mechanisms produced in the cell culture experiment.

It also may be that the process of producing methionine internally (in the absence of dietary methionine) is itself beneficial to the organism, since methionine production involves the recycling of homocysteine back to methionine; and also since it may be that some amount of autophagy of long-lived, but damaged proteins is required to produce new proteins when they are in short supply from diet.

So the way I see it, there are at least three separate paths by which dietary methionine restriction may afford the positive effects of CR: 1) by kicking the organism into a kind of "overdrive," where it produces more cell-available methionine than it was previously getting from diet; 2) by forcing the organism to recycle homocysteine; and 3) by forcing the organism to recycle damaged, but marginally-usable long-lived proteins to get the building blocks for methylation, thus promoting the generation of new proteins to replace the old.

In all of these cases, the organism would need optimal levels of choline and B vitamins to do this work, and for at least some populations, NAC might also be a factor (needed, though; not avoided). I haven't seen enough research on the NAC connection, but I do recall seeing one study that indicated that some people are missing some gene necessary to produce GSH optimally, and I'm speculating that NAC could help in those cases.

I am currently experimenting with trying to keep my dietary methionine under 1 g per day, which is, admittedly, not as low a percentage as what the rats were getting. I'm also taking choline, because I don't get enough of it in my diet. I have only been doing this for a couple of months, so it's too soon to know anything except that it is really hard to avoid methionine in your diet!

I'm definitely interested in hearing others' opinions on this subject. There's obviously a lot of research that has not yet been done but should be...

[smithx]

I am currently experimenting with trying to keep my dietary methionine under 1 g per day

What are you eating on this diet?

Can you give an example of a typical day's or week's balance of foods?

[leha]

I don't really have typical days, in that I'm getting a lot of variety, but the breakdown is mostly veggies, with some fish and occasional meat used more as a flavor enhancer than a main course. I get a little bit of milk, maybe an egg a week, I make home made bread, veggie chili, various "garden" curries, and a eat some fruit.

I'm also using CRON-o-meter, so keeping close track of everything. And some days are "meatier" than others, but my 21 day average for recorded methionine is .9 g (which means my real average, if you factor in the items that the database doesn't list amino acids for, is probably closer to double that). My total calories are around 1300, and my total protein is around 66 g, which is higher than I'd like it to be, and obviously, I am still over a gram on methionine, but it's a work in progress.

If we assume I'm getting 2 g methionine average per day, that is roughly 3% of my total protein. Even estimating higher than that would produce a fairly low amount. But I'm worried that the total protein is too high. I'm shooting for 55 g/day.

Obviously this isn't a perfect system, because you have to rely on the USDA database to monitor something that they often leave out, but it's better than I was doing just winging it.

[capsun]

I've done the math on all of the methionine restriction studies in mice, and it seems to me that the amount of MET(+CYS) they were receiving (translated to humans) was around 800-1,000mg/day. I know that Michael calculated this to be differently awhile ago (263mg), however, his calculation was based on the US RDA for MET+CYS (1330mg at 80% restriction), rather than mice-to-human caloric/protein equivalents. This 800-1,000mg/day also coincides with quite a few studies finding the total sulfur amino acid (MET+CYS) requirement in humans to range from around 550-1,330mg per day (depending on the study). Anyway, I wouldn't go too low (especially in high periods of stress) because of course that would mean... death.

[tornpie]

It's speculation, but I don't believe in methionine restriction. I believe that methionine is doing its job methylating parts of the body and it's really up to supplementation or diet to make sure homocysteine is remethylated by B6, B12, folic acid, and trimethylglycine to keep methionine going back to remethylate. I take 100 mg P5P, 2 mg folic acid, 2 mg methyl B12, and 6 g TMG a day. People say I look a hell of a lot better so it's possible my skin, hair, etc. is getting hardcore methylating action.

[capsun]

The research is really showing otherwise.

Our findings suggest that moderate increases in methionine intake are atherogenic in susceptible mice. Although homocysteine may contribute to the effect of methionine, high plasma homocysteine was not independently atherogenic in this model. Some product of excess methionine metabolism rather than high plasma homocysteine per se may underlie the association of homocysteine with vascular disease.

The effect of the four dietary regimens on the aortic plaque area. Fourteen-week-old ApoE-deficient mice fed control diets develop spontaneous lesions as shown by the white bar. The lesion area increased significantly in mice fed methionine-enriched diets (light and dark gray) in comparison with controls. The highest lesion area was attained in mice that were fed the high-methionine, vitamin-deficient M+B- diet, with a mean lesion area that was nearly twice that seen in the control group (dark gray). The mean aortic lesion area in mice fed the vitamin-deficient normal-methionine B- diet was not significantly different from the mean basal lesion area in controls (white vs. black), despite the fact that the B- group had the highest plasma homocysteine levels (see Table 2). In contrast, the lesion area was significantly higher in mice fed the high-methionine, vitamin-supplemented “M+B+” diet than in controls, despite the fact that homocysteine levels in this group were normal.

[capsun]

Ateromatous plaques in the aortic arch of ApoE-deficient mice. Hematoxylin/eosin staining of the aortic arch of an ApoE-null mouse fed the B vitamin-deficient diet (B-, Upper) and the methionine-rich and B vitamin-deficient diet (M+B-, Lower). Although both lesions (P) are classified as fatty streak (initial) lesions, lesions in the M+B- group were significantly larger. L, lumen; M, media; P, plaque. (Scale bar = 100 μm.)

[tornpie]

I'm not sure how much the findings with mice translate to humans. Mice are herbivores in nature and likely consume very little methionine. Perhaps they don't really the same methionine/homocysteine cycle that humans do or at least not as effective.

[capsun]

It seems to be applicable to humans. The only question is whether certain B-vitamins (such as the methionine-depleting niacin) can curb excess methionine intake or whether dietary methionine intake must be low to begin. Though it seems this particular study already adjusted for nicotine metabolites, so the latter is probably the case. Whatever the case, I don't think it's related to homocysteine status. Having normal homocysteine could be giving a false sense of security.

High dietary methionine intake increases the risk of acute coronary events in middle-aged men.

Virtanen JK, Voutilainen S, Rissanen TH, Happonen P, Mursu J, Laukkanen JA, Poulsen H, Lakka TA, Salonen JT.

Research Institute of Public Health, University of Kuopio, PO Box 1627, 70211 Kuopio, Finland. jyrki.virtanen@uku.fi
Abstract

BACKGROUND AND AIM: Homocysteine, a methionine metabolite, is suggested to be a risk factor for cardiovascular diseases (CVD). To date, the effects of dietary intake of methionine, the key amino acid in homocysteine metabolism, on CVD have not been studied. Our aim was to examine the effects of dietary methionine intake on the risk of acute coronary events.

METHODS AND RESULTS: We examined the effects of dietary methionine intake, assessed with 4-d food record, on acute coronary events in a prospective cohort study consisting of 1981 coronary disease free men from eastern Finland, aged 42-60 years at baseline in 1984-89, in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. During an average follow-up time of 14.0 years, 292 subjects experienced an acute coronary event. In a Cox proportional hazards model adjusting for age, examination years, BMI, urinary nicotine metabolites and protein intake (excluding methionine) the relative risks of acute coronary event in the three highest quarters of dietary methionine intake were 1.31 (95% CI: 0.92, 1.86), 1.31 (95% CI: 0.88, 1.96) and 2.08 (95% CI: 1.31, 3.29) as compared with the lowest quarter. Further adjustments did not change the results. However, opposite association was observed with total protein intake, which tended to decrease the risk.

CONCLUSIONS: The main finding of this study is that long-term, moderately high dietary methionine intake may increase the risk of acute coronary events in middle-aged Finnish men free of prior CHD. More prospective research is needed to confirm the role of dietary methionine in the development of CVD, and whether its effects are independent of homocysteine.

[leha]

Capsun, thank you so much for all this great information!

Edited by leha, 06 February 2011 - 04:30 AM.

[stephen_b]

How about a glass of red wine a day? It's my understanding that the body uses methionine to remove alcohol.

[Dorian Grey]

Anyone care to ponder whether the anti-methionine argument applies to SAM-e supplementation?

Is SAM-e "pre-converted" into a safer form before you take it, or is its effect the same as methionine?

I had been on low dose SAM-e for a couple years, and just laid off it a while back due to some strange side effect I had suddenly began having. Hard to describe, but I seemed to sense a funny odor in my breath an hour or so after taking my SAM-e on an empty stomach in the morning.

I'm on PPC (polyenylphosphatidylcholine) and that is supposed to help you make your own SAM-e. Perhaps this is a better way?

Polyenylphosphatidylcholine corrects the alcohol-induced hepatic oxidative stress by restoring s-adenosylmethionine.
Aleynik SI, Lieber CS.

Alcohol Research Center, Section of Liver Disease and Nutrition, Bronx VA Medical Center and Mount Sinai School of Medicine, New York, NY, USA.
Abstract
AIMS: Since the late stages of alcoholic liver injury are associated with decreased activity of methionine adenosyltransferase (MAT), we wondered whether this already occurs at the early stages and what is the mechanism involved.

METHODS: Sprague-Dawley rats (n = 32) were pair-fed ethanol (36% of energy) or isocaloric carbohydrates (control) in Lieber-DeCarli liquid diets, with or without polyenylphosphatidylcholine (PPC).

RESULTS: After 2 months, there was a striking depletion of S-adenosylmethionine (measured by high-performance liquid chromatography) from 68.2 +/- 5.1 to 36.2 +/- 3.4 nmol/g, associated with a reduction in hepatic reduced glutathione (GSH) from 4.95 +/- 0.20 to 4.09 +/- 0.08 micro mol/g, and an increase from 0.24 +/- 0.02 to 0.47 +/- 0.07 nmol/g of 4-hydroxynonenal (4-HNE), a reliable marker of lipid peroxidation. Hepatic S-adenosylmethionine (SAMe) correlated positively with GSH (r = 0.5916) and negatively with 4-HNE (r = -0.6375). Feeding PPC corrected all values and MAT activity did not differ significantly between groups.

CONCLUSIONS: SAMe depletion occurs already after 8 weeks of alcohol feeding and is fully corrected by PPC, in parallel with the prevention by PPC of the alcohol-induced oxidative stress. Since phosphatidylcholines (PCs) are produced in the liver via methylation of phosphatidylethanolamine by SAMe, it is likely that PPC, by providing PCs, decreases the utilization of SAMe and thereby contributes to its restoration, with replenishment of GSH and correction of the alcohol-induced oxidative stress.

PMID: 12711653 [PubMed - indexed for MEDLINE]Free Article

[leha]

Latest on methionine restriction:

Dietary Methionine Restriction Increases Fat Oxidation in Obese Adults with Metabolic Syndrome.

This is useful in part because it provides the reference amounts of methionine they used for the study. Note that the restricted population was allowed only 2mg/kg body weight of methionine, while the non-restricted controls were given 35mg/kg. Big difference there!

[capsun]

Note that the 2mg/kg restricted population did receive normal amounts of cysteine.

[leha]

Right. I don't think any of these methionine restriction studies that I have seen have limited *all* sulfur amino acids. They all just focus on methionine. And this might even be part of where the benefit comes from; for all we know the body is somehow changing its protein synthesis pathways to use the available cysteine for methionine production, and some byproduct of that change in pathway affords the benefits we see.

[Ames]

At the risk of asking a question with an obvious response, Methionine restriction would preclude the consumption of all methyl donors such as:

Methylcobalamin
TMG
DMG
Methylfolate
SAM-e
and
MSM ??

Just to name a few.

Are there any other restrictions, as far as supplementation goes, to be aware of?

Edited by golgi1, 15 March 2011 - 12:06 AM.

[MPB]

@leha: methionine is an essential amino acid, which means the body cannot produce it at all. In some parts of the body it can be "recycled" like you said. But it is also broken down by the enzyme methioninase. I have not read the article, hence I don't know the conditions and whether the claims are to be trusted. But you have to consider anyway, that since many biopathways depend on methionine, the "overall" outcome under certain circumstances for certain species and even individuals may be benefitial as a whole.

Edited by MPB, 01 July 2011 - 03:04 PM.

[MPB]

just as an example: if you had cystinuria, then methionine is bad for you =)

[triplecrown]

This blog talks about how methionine may reduce the incidence of cancer.

http://www.proteinpo...creatic-cancer/

Edited by triplecrown, 02 July 2011 - 01:11 AM.

[Olive_skin]

Anyone care to ponder whether the anti-methionine argument applies to SAM-e supplementation?


PMID: 12711653 [PubMed - indexed for MEDLINE]Free Article

Either way, would it matter that much for the usual SAM-e dosages though? My 200mg SAM-e capsule has 75,5 mg methionine according to the nutritional information on the package. If it can enhance the effects of astragalus on telomeres, I am willing to take that trade off.