28 replies to this topic

[Aphrodite]

From http://fightaging.org/ Dec. 19, 2008

You'll recall that experiments restricting intake of the dietary amino acid methionine - without restricting calories - demonstrate some of the same beneficial health effects as calorie restriction. This suggests that the level of methionine ingested is primarily what cues our biochemistry to produce the benefits it does under a low calorie diet that still supplies the right levels of micronutrients. See, for example:

• Methionine Restriction and Longevity
• The Metabolic Basis of Longevity
• On Methionine Restriction, Suppression of Mitochondrial Dysfunction and Aging

Now here's a reversal of these experiments, in which researchers restrict all the other dietary amino acids except methionine, and come to much the same conclusion:

Previous studies have shown that the decrease in mitochondrial reactive oxygen species (mitROS) generation and oxidative damage to mitochondrial DNA (mtDNA) that occurs during life extending dietary restriction also occurs during protein or methionine restriction, whereas it does not take place during carbohydrate or lipid restriction. In order to study the possible effects of other amino acids, in this investigation all the dietary amino acids, except methionine, were restricted by 40% in male Wistar rats (RESTAAS group). After 6-7 weeks, experimental parameters were measured in the liver.

...

[The] results, together with previous ones, strongly suggest that the decrease in mitROS generation and oxidative damage to mtDNA that occurs during dietary restriction is due to restriction of a single amino acid: methionine. They also show for the first time that restriction of dietary amino acids different from methionine decreases mitochondrial protein oxidative modification [and] increases SIRT1, in rat liver.

Meaning that while methionine restriction accounts for much of calorie restriction, it doesn't account for all of it. There may be multiple parallel mechanisms operating, which in turn suggests that building calorie restriction mimetic drugs that capture anywhere near the entire effect of actual calorie restriction will be challenging. Meanwhile, while research groups are spending hundreds of millions to billions of dollars on research an development, you can obtain the whole benefit of calorie restriction for just about free. Just start eating less, sensibly, while ensuring that your intake of micronutrients remains optimal.

[sthira]

Thanks for the report. I wonder if I should cut back on the amount of Brazil nuts I eat, which is about an ounce a day, for their selenium?

[Aphrodite]

Is anybody here currently practicing methionine restriction? If you are would you mind sharing your experience? I'm considering starting.

[CobaltThoriumG]

Soy lacks methionine. I now use whey for most of my protein intake. Maybe I could substitute some soy for whey and add some BCAAs to the soy.

[Aphrodite]

Here's a few calculations I did to show the levels of methionine in different types of protein sources. According to my calculations, soy protein does indeed have the least amount of methionine.

According to lef.org, one scoop (20 g.) of their whey protein isolate (supplying 17 grams of protein) provides 0.38 g (or 380 mg.) of methionine. Based off the data provided by nutritiondata.com, 1 ounce (28 g.) of soy protein isolate provides 22.6 g of protein, of which 316 mg. is methionine. 30 grams of hemp protein (popular among raw foodists) provides 15 g of protein and 0.3 g or 300 mg. of methionine.





In other words, here’s the breakdown:



20 g. of whey protein isolate = 17 g. of protein = 380 mg. methionine



21.06 g. of soy protein isolate = 17 g. of protein = 237.7 mg. methionine



34 g. of hemp protein = 17 g. of protein = 340 mg. of methionine

[CobaltThoriumG]

Here's a few calculations I did to show the levels of methionine in different types of protein sources. According to my calculations, soy protein does indeed have the least amount of methionine.

Thanks. I was under the wrong impression that soy had a lot less methionine than that. If I substituted soy for half of the whey I use, that would only be a reduction of 20% or so total. Probably not worth it.

Edited by Michael, 30 December 2008 - 12:38 PM.
Redundant/excessive quotation

[edward]

Looks like the only solution is protein restriction, which in my opinion is a dicey thing if you want to maintain lean body mass.

[CobaltThoriumG]

Looks like the only solution is protein restriction, which in my opinion is a dicey thing if you want to maintain lean body mass.

Agreed, and the people who seem not so concerned about lean body mass, the CR'rs, don't need to worry about this. I may get 40% of my calories from protein, though. If I chooped that to even 30%, which may still be higher than I need, but not much, and substituted soy for half the whey, that would be more significant, like a 40% reduction in methionine, which you might think is what CR'rs get on average with a 40% reduction in calories, other things being equal.

[kismet]

Personally I wouldn't do methionine restriction, because eventually it results in similar, maybe slightly less, restricted growth as with CR, but the long term side-effects are a big unknown.

Looks like the only solution is protein restriction, which in my opinion is a dicey thing if you want to maintain lean body mass.

No creative work arounds possible? Do you think methionine degrading enzymes might work (thanks to aidanpryde for bringing this up in one of our discussions)?
I guess the only problem would be their cost and availability or maybe dose and delivery. Would you add the enzyme to your food, ingest it or deliver it via s.c. injection?
Recombinant methioninase (rMETase) is being tested as a cancer treatment. Price, however, could be very high, because rMETase has 398 amino acid residues per subunit [3] and consists of 4 subunits (insanely expensive hGH has "only" 191 to give you an idea).
Maybe you could contact some supliers if you want to find out more about costs, if the idea has any merit that is. They sell the enzyme in units. So how many units do we need? All tests seem to be done in nude mice:
"rMETase at 15 units/g/day for 5 days depleted tumor methionine in all four tumor types to approximately 30% of untreated control." [1]
"A single i.p. injection of 300 units of rMETase can lower the serum methionine level in the mice from 70 microM to less than 1 microM within 2 h and maintain this depleted level for 8 h." [2]
PEGylated rMETase may be a solution:
"Plasma methionine was depleted from a baseline of 40 µM to less than 5 µM within 1 h by 80 U naked and the three PEGylated conjugates (Fig. 5) . However, PEG/rMETase-30, PEG/rMETase-60 and PEG/rMETase-120 depleted the plasma methionine level below 5 µM for 8, 24, and 48 h, respectively, which is 2-, 6-, and 12-fold longer than naked rMETase (Table 2B)" [3]

Suppliers I have come up with via google:
A. http://www.biocompar...ecombinant.html
B. http://www.bioresear...1?VNETCOOKIE=NO


Just one of the many articles on cancer and methioninase:

Bull Cancer. 2008 Jan;95(1):69-76.
[Methionine dependency of cancer cells: a new therapeutic approach?]
Durando X, Thivat E, Gimbergues P, Cellarier E, Abrial C, Dib M, Tacca O, Chollet P.
Département d'oncologie médicale, Centre Jean Perrin, 58, rue Montalembert, 63011 Clermont-Ferrand, France.

Metabolic abnormalities of tumor cells offer opportunities of therapeutic targeting. In contrast to normal cells, tumor cells have absolute requirement for methionine (Met), an essential amino acid. Many molecular mechanisms have been considered to explain Met dependency. Several approaches have been used To reduce Met in vivo. As the main Met source was food, synthetic Met free diet were widely used. Alternatively, Met restriction was archived by the use of Met analogs or enzymatic degradation by methioninase. In animal models, Met restriction permit to limit tumor growth and to reduce tumor volume. However, interruption of Met restriction induce the regrowth of tumor. Moreover Met restriction induce several cells modifications suggesting its use in association with conventional chemotherapy. Preclinical studies have shown synergistic effect of the association of Met restriction and different cytostatic agents. Currently, few clinical investigations have been realised to test this therapeutic strategy.

[1] Clin Cancer Res. 1999 Aug;5(8):2157-63.
Efficacy of recombinant methioninase in combination with cisplatin on human colon tumors in nude mice.
Tan Y, Sun X, Xu M, Tan X, Sasson A, Rashidi B, Han Q, Tan X, Wang X, An Z, Sun FX, Hoffman RM.
[2] Cancer Res. 1998 Jun 15;58(12):2583-7.
Anticancer efficacy in vivo and in vitro, synergy with 5-fluorouracil, and safety of recombinant methioninase.
Yoshioka T, Wada T, Uchida N, Maki H, Yoshida H, Ide N, Kasai H, Hojo K, Shono K, Maekawa R, Yagi S, Hoffman RM, Sugita K.
[3] In Vivo Efficacy of Recombinant Methioninase Is Enhanced by the Combination of Polyethylene Glycol Conjugation and Pyridoxal 5'-Phosphate Supplementation
Full: http://cancerres.aac...full/63/23/8377

Edited by kismet, 25 December 2008 - 08:13 PM.

[Forever21]

Is anybody here currently practicing methionine restriction? If you are would you mind sharing your experience? I'm considering starting.

not really practicing but i try to avoid high-met food
fish, meats, eggs (egg white), milk, dairy, cereals, grains, sesame seeds, brazil nuts

http://www.methusela...read.php?p=4676

i rely on
tempeh & legumes for protein. mostly lentils

Edited by Forever21, 26 December 2008 - 01:48 PM.

[athrahasis]

Crap. Most of my protein is [Goat and Lactoferrin rich AOR dairy] whey, egg whites and almond butter. W/o egg whites I average .9g a day per the CRONometer. Maybe I'll just lower protein below 20% of daily calories from my high of 40%. Does anything bind to methionine to make it less biologically accessible?

What are you guys doing in terms of P:C:F ratios? I'm shooting for 17:37:45 daily now.

Edited by athrahasis, 27 December 2008 - 01:37 AM.

[niner]

If you're willing to eat amino acids in their free (hydrolyzed) form instead of intact protein, then it's possible to get any amino acid percentage you want. You could get part of your protein from a source like soy, perhaps including small amounts of meat etc, and supplement the missing AAs. All it takes is money... It would be a significant bioengineering problem, but if there were a market for a low methionine, complete protein, I bet it would be possible to genetically engineer a bug to over-express such a protein, then grow lots of it in culture. I looked into Met restriction at one time, but quickly gave up on it when I found that virtually everything I like has it. If all I had to do was give up Brazil nuts, I'd have it made. For the time being, I'm working on tuning my carbohydrate and lipid intakes. Once I get that sorted out, maybe I'll take another look at Met.

[yoyo]

It might be possible to figure out what methionine is doing that is harmful and attack that directly.

[wydell]

A guess would be the creation homocysteine, as methionine has a relationship to homocysteine levels. And of course, there are ways of lowering homocysteine with b vitamins and tmg. Some studies show no benefit from lowered homocysteine. Others do show a benefit. And of course there might be more problems caused by methionine besides homcysteine.

Interestingly enough, Barry Sears cites a study and claims it indicates that have high homcysteine leads to three times shorter telomeres or less telomerase. (I cannot remember the exact marker referenced in the study).

If you connect the dots, perhaps that's the connection. Probably not that simple and many more studies would be needed.

It might be possible to figure out what methionine is doing that is harmful and attack that directly.

[kismet]

It might be possible to figure out what methionine is doing that is harmful and attack that directly.

I don't know if I'm alone here, but I'm advocating the theory of methionine as growth regulator. It is the start codon of every amino acid, so low levels of methionine should affect transcription of every single protein. I'm pretty sure that is the mechanism of action of rMETase against cancer, because cancer growth starts as soon as treatment stops and it does not seem to kill or damage the cancer cells in any way.
Growth arrest and retardation in the form of CR has long been shown to slow down aging, it may be a similar mechanism.  In my opinion low methionine should provoke catabolism and self-repair as in CR.

A guess would be the creation homocysteine, as methionine has a relationship to homocysteine levels. And of course, there are ways of lowering homocysteine with b vitamins and tmg. Some studies show no benefit from lowered homocysteine. Others do show a benefit. And of course there might be more problems caused by methionine besides homcysteine.

What? I thought it was pretty much consensus that high homocysteine (hyperhomocysteinemia) is detrimental? I've seen it suggested as a co-factor of vascular calcification, I'll report back as soon as I have reviewed the data.

Interestingly enough, Barry Sears cites a study and claims it indicates that have high homcysteine leads to three times shorter telomeres or less telomerase. (I cannot remember the exact marker referenced in the study).

If you connect the dots, perhaps that's the connection. Probably not that simple and many more studies would be needed.

It might be possible to figure out what methionine is doing that is harmful and attack that directly.

I believe it's definitely not the only connection (see above).

[TheFountain]

Soy lacks methionine. I now use whey for most of my protein intake. Maybe I could substitute some soy for whey and add some BCAAs to the soy.

But then you're gambling a hormone imbalance and, consequently, greater overall fat storage throughout your body. Soy is high in phytoestrogens which can lower testosterone and increase fat storage in males.

[CobaltThoriumG]

Soy lacks methionine. I now use whey for most of my protein intake. Maybe I could substitute some soy for whey and add some BCAAs to the soy.

But then you're gambling a hormone imbalance and, consequently, greater overall fat storage throughout your body. Soy is high in phytoestrogens which can lower testosterone and increase fat storage in males.

I was throwing the idea out there. I'm still on whey isolate and pasteurized liquid egg whites. No soy for me in any form. I like the idea of someone engineering an optimal meal replacement, or several depending on the user's goals. Maybe I'll start a thread about this. One problem is that people just plain like food, so the market would be nearly nonexistent and the cost undoubtedly would be high. I drink most of my meals, so as long as it tasted like chocolate, I would be for it. But starting from scratch I would think we could arrive at some ideal to consume, low in carbs, high in the right fats and mid-range in low-AGE, reduced methionine protein. Food is so old human.

[EmbraceUnity]

Cobalt,

I agree that a perfectly constructed meal replacement would be the only way to be 100% optimal. The problem is that it isn't as cut and dry as you make it seem. Some argue for High Protein, some for High Fat, and some for High Carb. There are also people who believe more in the zone diet with approximately equal portions of each. Since ignorance and large amounts of contradictory data tend to make me more conservative, I personally favor the zone diet. As for those who don't admit their own ignorance, they have a lot of work to do to support their claims.

There are free software programs such as krecipes, CRON-O-Meter, and others which help you to track all your food and supplement intakes. It is the best of both worlds since you can eat a nice variety of food and still optimize your diet with some supplemental vitamins and amino acids or whatever you need for the day. When I have more control over what I eat, I intend to carefully track all that stuff. For now, I eat what my college's meal plan offers.

Edited by progressive, 16 January 2009 - 01:04 AM.

[AgeVivo]

A. Theory: potential mechanisms, among many others :

As pointed out by kismet, yoyo, wydell and others,

1) Less methionine => less homocysteine. That could well explain the life extending effects of methionine restriction. But no body really knows why homocysteine is bad. In fact homocysteine seems to be a marker rather than a cause for cardiovascular risks (among other risks).

2) Less methionine => less protein synthesis => less erroneously synthesized polypeptides (and associated natural repair/removal mechanisms). Indeed in worms it has been shown that inhibition of mRNA translation extends life [Hipkiss AR. On why decreasing protein synthesis can increase lifespan. Mech Ageing Dev. 2007 May-Jun;128(5-6):412-4.]


B. Practice: how to do methionine restriction :

Simple way:
Eggwhites are full of methionine: avoid them as much as possible. Pretty much all meat and fish (in a lesser extent) contain methionine: so avoid consuming meat/fish everyday.
Eat any vegetable/grains otherwise without particular care because it in comparison to meat/fish they are VERY low in methionine.
I'm sure that everyone here agrees that this regimen is safe, as it is mostly what is advized everywhere (high in vegetables and fruits, low in fish/meat). Of course, the positive effect in humans has not been fully evaluated.

Fine tuning:
Jelly, lents and other protein containing vegetables may help to do methionine restriction without doing protein restriction, but to do it adequately i guess that you need to be a vegetalian expert or use a specific program such as Walford's software (free) or CRON-O-meter (free)

Also you may buy protein powders that do not contain methionine, in some supermarkets or specifically those:
- Hominex-2 Amino Acid-Modified Medical Food (Ross Products Division, Abbott Laboratories, Columbus, OH, which is approved for treatment of patients with homocystinuria)
- XMET Maxamum(SHS, Liverpool, England)
Such treatments are used in case of homocystinuria or some cancers and do not seem to be life threatening but i would still be particularly carefull and tell it to my doctor if i was trying that.


C. Research: MFURI projects? Mprize@ home projects?

I had started a thread in the Methuselah Foundation forums, but that was almost one year ago, when the positive results of methione restriction were not as popular as they are now: http://www.methusela...hread.php?t=745
Currently,
- I'd very much like to see wether inhibition of mRNA translation also extends life in mice (i need to investigate if it has been tested already)
- I'd very much like to see fine tuning of methionine restriction in mice/rats for greatly extended lifespans.
In rodents CR has been tried in various degrees/compositions/rythms/ages wherease methioine restriction has been tried in one or two degrees/compositions.

AgeVivo

[EmbraceUnity]

That Walford software is not free in the fullest sense of that term. The CRON-O-Meter is fully free and open source

http://spaz.ca/cronometer/

[Forever21]

Michael wrote an extensive article on MR.

http://www.methusela...read.php?p=4676

"In practice, a high-protein, low-methionine diet is one composed of a lot of non-grain vegetarian protein. All legume proteins are good, and lentils are exceptionally noteworthy as being high %protein, low-Calorie, and unusually low-Met even for a legume, per gram of protein and per Calorie. Dairy (aside from whey) is moderate in methionine, and Quorn, despite its eggwhite content, is also pretty acceptable (certainly compared with meat).

Eggwhites are very high-Met, so I've cut back dramatically on these (they were for many years a major staple of my diet)."


I personally stick with lentil, legumes, & tempeh.

Edited by Forever21, 18 January 2009 - 06:59 AM.

[remig]

Re methionine restriction:

Stress is not necessarily detrimental. We even deliberately stress our bodies with exercise as a health benefit. Similary ROS are stresses to the cell, but, if the cell can mount the appropriate response, the stress can be fully managed. Damaged molecules can be recycled or eliminated. The idea that accumulated strains from ROS stress cause ageing has problems. Mice neurons are scenescent within three years and human neurons within 80 years, yet both endure about the same rate of ROS stress.

An alternate interpretation of the methionine restriction data is that, in both studies, autophagy is being promoted by nitrogen starvation. Methionine is an essential amino acid meaning the body cannot synthesize it and it must be obtained from the diet. If it were totally eliminated from the diet, all other amino acids could not be used for protein synthesis and would be diverted to energy production instead. Likewise if it were abundant in the diet but another essential amino acid were lacking...

The upregulation of Sirt1 in both cases argues for this interpretation as its purpose seems to be to induce autophagy http://www.pnas.org/...105/9/3374.full .

The missing study is to see if a protein-restricted, high methionine diet shows any longevity benefits.

[AgeVivo]

The missing study is to see if a protein-restricted, high methionine diet shows any longevity benefits.

?? Clarifications?

[remig]

The missing study is to see if a protein-restricted, high methionine diet shows any longevity benefits.

?? Clarifications?

I meant that methionine restriction shows the longevity benefit but that this may be a protein restriction effect unrelated to the observed diminishing of ROS production. The study where all amino acids except methionine produced an increase in ROS did not include a study to see if this effect then extended life spans.

[JLL]

An alternate interpretation of the methionine restriction data is that, in both studies, autophagy is being promoted by nitrogen starvation.

Wouldn't this tie in nicely with the idea of (intermittent) protein restriction? Autophagy, I believe, was the main point of the online book. Cutting out methionine permanently seems difficult, but going for a few days per week without protein/methionine should be relatively easy.

[mat]

This ebook makes some useful observations on methionine restriction.

http://intensedf.com.../Longevity.aspx

[athrahasis]

So, please excuse the simplistic summary, low (no) methionine + Resveratrol (or another SIRT1 activator) = the benefits of calorie restriction? Or are there additional LE pathways that have been identified in CR? This is aside from say raw food/lower AGE consumption etc benefits.

Edited by athrahasis, 25 April 2009 - 10:00 PM.

[DrEvil]

I don't think it is as easy as just avoiding methionine . methionine is most abundend in meat, eggs, fish. If it was that easy vegans would get the full benefit of CR. ((Vegans eat no animal proteins.))

In fact in several studies vegans did not live longer than "average" meat eaters. Vegetarians and occasional meat eaters, health conscious omnivores and fish eaters all lived longer than vegans. I think you can just wiki vegans and vegetarians to find the articles.

[treonsverdery]

well if they prove methionine restriction is associated with the longevity benefits of CR then they could create an alternate variety of the methionine molecule that goes where methionine goes on physiological pathways yet has zero methionine activity This is like a receptor placeholder. A version of this strategy was tried when a scientist who wrote an article at Scientific American gave lab mammals 2 deoxyglucose as food rather than glucose to see if blocking glucose pathways had longevity benefits The 2 deoxyglucose mammals did live longer mimicing CR The scientist noted the right dose was meaningful though

thus grabbing that scientists protocol with a modified methionine could create a modified methionine as longevity drug

Slightly modified amino acids are known effective drugs: zovirax as well as fluoruracil are among these Maybe Fluoromethionine or hydroxylating one of the hydrogens (make OH from H) or Deoxy ( removing the O from the OH) on methionine creates a beneficial longevity drug



The effects of creating Se or Te methionine may be longevizing as well as these two elements could substiture for the s yet have different physiological effects

Edited by treonsverdery, 18 June 2009 - 05:57 PM.