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life span extension w/methionine limiting diet


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#1 trh001

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Posted 12 February 2006 - 01:26 AM


1) is anyone aware of additional studies published or in progress?
2) Is anyone doing this?
3) Whey and soy seem to have the least Met, btw


--------------
2003 reference (www.pubmed.org, PMID: 12543260) to a feeding study with
calorically pair matched controls. The test diet (met 0.86% >> met 0.17%)
increased mean and maximal survival in Fischer rates by about **40%***.
Glutathione levels were also monitored. While the study implements
additional controls to address the questions of modest reductions in caloric
intake affecting the results, the study that (has this been done?) would be
useful would be 1) CR +/- met restricted diet, and 2) gene expression study
comparing CR to met restriction. Anyone know if these have been done?

Discussion snippet on Met restriction done with pair-fed rats:

"MR has repeatedly resulted in life span extension comparable to that seen
in energy restricted animals. In one of our typical studies using Fischer
344 rats, MR resulted in a 42% increase in mean survival and a 44% increase
in maximal longevity (Fig. 1). While living longer, animals on MR grow
significantly less (Fig. 2), and consume more food when food intake is
expressed on a per body mass basis. This latter observation has led to some
controversy, since when expressed on a per animal basis, MR rats, being
smaller, consume slightly less food per animal than their C-fed
counterparts. This has left open the possibility that the effect of
methionine restriction on life span is secondary to a restriction of caloric
intake, and not due to methionine deficiency. In order to examine the
proposition that MR might be an effect secondary to CR, we have pair-fed
rats, so that animals consumed control diet in the same quantity as consumed
by methionine restricted rats. Since animals fed in this way will consume
exactly the same energy levels regardless of which diet they consume, this
would exclude caloric intake as an explanation for the MR effect. When C
rats were fed in quantities equivalent to that consumed by MR animals they
consumed all of the food offered, and there was a modest reduction in weight
gain relative to ad libitum fed C animals. However, there was no
prolongation of life span (Fig. 3) associated with the slightly reduced food
intake and body size (Fig. 4), indicating that life span extension
associated with restricted methionine intake is not primarily due to reduced
energy consumption."

Discussion snippet on impact on [GSH] across body tissues...

"If GSH is, indeed, necessary to protect tissues against oxidative damage
during senescence, then feeding a diet that has neither cysteine nor
cystine, and only limited quantities of methionine, might be expected to
reduce survival since cysteine is the limiting amino acid in GSH synthesis
([Noda et al]). We have therefore measured blood GSH levels in aging Fischer
344 rats consuming either C or MR, and found that methionine restriction
brought about a 2-fold increase over controls despite the marked restriction
in sulfur-containing amino acid intake ( [Richie et al]). In most other
tissues MR was associated with maintenance of normal GSH levels throughout
senescence, the exceptions being liver (60% reduction) and kidney (25%
reduction). The unexpected maintenance of blood GSH levels in aged rats fed
a diet severely deficient in the rate limiting precursor cysteine probably
signals that there are important, and highly regulated, processes invoked by
MR."

#2 streety

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Posted 12 February 2006 - 02:10 PM

Do you have access to the complete publication? There are a couple of studies in the references.

Orentreich et al., 1993. N. Orentreich, J.R. Matias, A. DeFelice and J.A. Zimmerman, Low methionine ingestion by rats extends life span. J. Nutr. 123 (1993), pp. 269–274. Abstract-EMBASE | Abstract-MEDLINE | Abstract + References in Scopus | Cited By in Scopus

Richie et al., 1994. J.P. Richie, Jr., Y. Leutzinger, S. Parthasarathy, V. Malloy, N. Orentreich and J.A. Zimmerman, Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J. 8 (1994), pp. 1302–1307. Abstract-MEDLINE | Abstract-EMBASE

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#3 opales

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Posted 12 February 2006 - 04:59 PM

I am not sure whether this is useful to you trh001 as you obviosly are already familiar with the CRsociety list (which everyone here should be, level of discussion seems to be higher there as people there are more hardcore life-extensionist), but searching the archives there yields better answers than asking here IMHO. someone even started doing this, maybe you could ask that person about the results (link below). few posts.

Michael Rae lists existing studies+discusses results

Discussion on reducing met

#4 trh001

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Posted 13 February 2006 - 12:10 AM

Thanks for the tips, Opales.

As for the originals I don't have access to J.Nutr. or FASEB, it appears.

#5 trh001

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Posted 19 February 2006 - 08:06 AM

A few more references, and some thoughts...

Increasingly it seems that content of diet during CR may well be important
(2, 3), in that CR may well be undermined by a single micro/macro-nutrient
excess, or deficiency, especially in light of one's own ill-defined genetic
predisposition (See human study on Met-synthase polymorphism, 1). Also, as
the proteosome (specifically, in this case, Met-synthase and the methionine
sulfoxide reductase system) ages, avoidance of EXCESS met (or at least
protein overall) may become even more important, per (4), and implied by
(1).

Data in the literature on MET is increasingly suggestive (even compelling)
to me that even restricting to no more than RDA may be too lax -- especially
in old age.

I've been using DWIDP (www.walford.com) software to ensure that I at least
don't *exceed* the RDA for methionine, as well as making sure sources of
methyl donors are present in my diet. I'll be getting homocystine levels
checked in future, as well, though as noted below, it's far from clear MET
correlations with morbidity and mortality are exclusive to such a mechanism.
---------------


1) The methionine synthase polymorphism c.2756A >> G (D919G) is relevant for
disease-free longevity. [Human Study] Int J Mol Med. 2005 Oct;16(4):759-61.
PMID: 16142417

Methionine synthase polymorophism (re-synthesis of MET from homo-cystine)
found to be associated with longevity. "The functional polymorphism
methionine synthase (MTR) c.2576A-->G (D919G) influences homocysteine and
folate metabolism and has been reported to be of protective function against
oncological, neurodegenerative and vascular diseases. We analyzed 329
healthy individuals to confirm whether this polymorphism might be of
epidemiological impact on disease-free longevity. In our sample, prevalence
of the G-allele was significantly higher in the older than in the younger
individuals (p=0.005) supporting the thesis that MTR c.2576A-->G is
beneficial to disease-free longevity."

2) Methionine-deficient diet extends mouse lifespan, slows immune and lens
aging, alters glucose, T4, IGF-I and insulin levels, and increases
hepatocyte MIF levels and stress resistance. Aging Cell. 2005
Jun;4(3):119-25. PMID: 15924568

A diet deficient in the amino acid methionine has previously been shown to
extend lifespan in several stocks of inbred rats. We report here that a
methionine -deficient (Meth-R) diet also increases maximal lifespan in
(BALB/cJ x C57BL/6 J)F1 mice. Compared with controls, Meth-R mice have
significantly lower levels of serum IGF-I, insulin, glucose and thyroid
hormone. Meth-R mice also have higher levels of liver mRNA for MIF
(macrophage migration inhibition factor), known to be higher in several
other mouse models of extended longevity. Meth-R mice are significantly
slower to develop lens turbidity and to show age-related changes in T-cell
subsets. They are also dramatically more resistant to oxidative liver cell
injury induced by injection of toxic doses of acetaminophen. The spectrum
of terminal illnesses in the Meth-R group is similar to that seen in control
mice. Studies of the cellular and molecular biology of methionine-deprived
mice may, in parallel to studies of calorie-restricted mice, provide
insights into the way in which nutritional factors modulate longevity and
late-life illnesses.


3) Protein methionine content and MDA-lysine adducts are inversely related
to maximum life span in the heart of mammals. Mech Ageing Dev. 2005 Oct;126
(10):1106-14. PMID: 15955547

In this study, we found for the first time that methionine content of
proteins is negatively correlated with mammalian MLSP in a strong way, in
agreement with the lower methionine content of pigeon versus rat skeletal
muscle (Portero-Otín et al., 2004). This is a striking finding, since many
recent investigations point to a relationship between methionine and aging
(Moskovitz et al., 2001, Ruan et al., 2002, Stadtman et al., 2003 and
Stadtman et al., 2005). There are various possible mechanisms by which high
methionine content could induce damage. Methionine residues of proteins are
the most susceptible to oxidation by ROS (Moskovitz et al., 2001 and
Slyshenkov et al., 2002) and sensitivity of proteins to oxidative stress
increases as a function of the number of methionine residues in the protein
(Stadtman et al., 2005). Methionine dietary supplementation also increases
iron and lipid peroxidation in rat liver (Mori and Hirayama, 2004).
Oxidation of methionine residues generates methionine sulfoxide in proteins,
which deprives proteins of their function as methyl donors and may lead to
loss of their biological activity (Carp et al., 1982 and Ciorba et al.,
1997). However, this modification can be repaired by methionine sulfoxide
reductase in a thioredoxin-dependent reaction. In this context, it is most
interesting that knocking out methionine sulfoxide reductase-A lowers MLSP
and increases protein carbonyls and sensitivity to hyperoxia in mice
(Moskovitz et al., 2001). The opposite manipulation, overexpression on
methionine sulfoxide reductase A has been reported to increase life span
and to delay the start of the aging process in Drosophila (Ruan et al.,
2002). On the other hand, the oxidized form of thioredoxin produced in the
reduction of methionine sulfoxide can be converted back to reduced
thioredoxin by the enzyme thioredoxin reductase. In agreement with the
methionine oxidation hypothesis above, overexpression of thioredoxin
reductase seems to increase longevity in mice (Nakamura et al., 2002 and
Mitsui et al., 2002).

High methionine content could also be detrimental because it is sequentially
converted to and increases the levels of S-adenosyl-methionine and
homocysteine (Mori and Hirayama, 2004). Homocysteine levels increase with
age in humans and they are a risk factor for aging and free
radical-associated pathologies including atherosclerosis, thrombosis,
cancer, stoke, wasting, chronic kidney disease and Parkinson's disease
(Drögue, 2001, Durand et al., 2001, Ninomiya et al., 2004 and Ferrari,
2004). Homocysteine has a free thiol group that can be readily oxidized
leading to protein mixed disulfides or thiol bridges between proteins. On
the other hand, S-adenosyl-methionine is a potent alkylating agent by virtue
of its destabilizing sulfonium ion. The methyl group of
S-adenosyl-methionine is subject to attack by nucleophiles and is thus
strongly reactive (Lehninger, 2005). Interestingly, long-lived Ames dwarf
mice have altered methionine metabolism including lowered tissue
S-adenosyl-methionine levels (Uthus and Brown-Borg, 2003).

Irrespective of the mechanism involved, it is well known that methionine
dietary restriction increases MLSP in mammals (Richie et al., 1994 and
Zimmerman et al., 2003), also agreeing with our finding of low methionine
levels in long-lived animal species. One of the most plausible mechanisms by
which caloric restriction extends life span is by decreasing mitochondrial
ROS production (Barja, 2004a and Barja, 2004b). It has been recently found
that such decrease also occurs after restricting only the intake of protein
(Sanz et al., 2004), a manipulation that also increases MLSP (Horakova et
al., 1988). Thus, it is possible that methionine restriction can be
responsible for the decrease in ROS production observed both in protein and
in caloric restriction and for the ensuing decrease in aging rate. This
possibility warrants further investigation.

By all these reasons, at a first glance, both the limited methionine content
in long-lived species reported here and the fact that protein restriction
benefits may be due to a reduction in methionine intake are findings that
would suggest a pure pro-oxidant effect for methionine. However, a putative
anti-oxidant effect cannot be discarded. Thus, it is possible that
methionine cycling can have a protective anti-oxidant effect in particular
individuals, or in particular critical settings within a protein chain,
such as an active site, but that "superfluous" methionines tend to be
eliminated by natural selection in long-lived species. Since these species
do not show reduction in methionine reductase expression or activities, we
should assume that redox cycling of the remaining methionine residues is
still important. So, it might be simply that the anti-oxidant activity is
better focused in long-lived species, leaving less to chance.


4) Protein maintenance in aging and replicative senescence: a role for the
peptide methionine sulfoxide reductases. Biochim Biophys Acta. 2005 Jan
17;1703(2):261-6. Review. PMID: 15680234

"Importantly, the peptide methionine sulfoxide reductase system has been
implicated in increased longevity and resistance to oxidative stress in
different cell types and model organisms. In a previous study, we reported
that peptide methionine sulfoxide reductase activity as well as gene and
protein expression of MsrA are decreased in various organs as a function of
age. More recently, we have shown that gene expression of both MsrA and
MsrB2 (Cbs-1) is decreased during replicative senescence of WI-38
fibroblasts, and this decline is associated with an alteration in catalytic
activity and the accumulation of oxidized protein."

"Recent data indicate that the peptide methionine sulfoxide reductase
system, is also impaired with age and during replicative senescence, thus
acting as a potential contributor to the age-associated build-up of
oxidized protein and impaired redox homeostasis. "

#6 syr_

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Posted 20 February 2006 - 07:21 PM

Michael Rae lists existing studies+discusses results

Discussion on reducing met


How do you register there? I cant see the list.

#7 hallucinogen

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Posted 24 February 2006 - 08:46 AM

Username: archiveguest@calorierestriction.org
Password: guest

You silly geese:p

#8 syr_

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Posted 24 February 2006 - 12:17 PM

You silly geese:p


LOL!
I cant believe I didnt see those in parentheses right after the input fields...

#9 trh001

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Posted 02 April 2006 - 02:46 PM

Biochim Biophys Acta. 2006 Feb 24; [Epub ahead of print] Links


Mitochondrial oxidative stress, aging and caloric restriction: The protein and methionine connection.

Pamplona R, Barja G.

Department of Basic Medical Sciences, University of Lleida, Lleida 25008, Spain.

Caloric restriction (CR) decreases aging rate and mitochondrial ROS (MitROS) production and oxidative stress in rat postmitotic tissues. Low levels of these parameters are also typical traits of long-lived mammals and birds. However, it is not known what dietary components are responsible for these changes during CR. It was recently observed that 40% protein restriction without strong CR also decreases MitROS generation and oxidative stress. This is interesting because protein restriction also increases maximum longevity (although to a lower extent than CR) and is a much more practicable intervention for humans than CR. Moreover, it was recently found that 80% methionine restriction substituting it for l-glutamate in the diet also decreases MitROS generation in rat liver. Thus, methionine restriction seems to be responsible for the decrease in ROS production observed in caloric restriction. This is interesting because it is known that exactly that procedure of methionine restriction also increases maximum longevity. Moreover, recent data show that methionine levels in tissue proteins negatively correlate with maximum longevity in mammals and birds. All these suggest that lowering of methionine levels is involved in the control of mitochondrial oxidative stress and vertebrate longevity by at least two different mechanisms: decreasing the sensitivity of proteins to oxidative damage, and lowering of the rate of ROS generation at mitochondria.

PMID: 16574059 [PubMed - as supplied by publisher]

#10 scottl

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Posted 02 April 2006 - 03:10 PM

Lowering methionine may have other actions e.g. IIRC methionine is a precursor of homocysteine.

#11 trh001

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Posted 02 April 2006 - 03:12 PM

[Edit: Per "Biochim Biophys Acta. 2006 Feb 24" above...]

"[..] and can be responsible for around 50% of the increase in MLSP observed in caloric restriction." ....vs. the other contributions such as, it would seem per other publications, insulin sensitivity of tissues in CR [search "caloric restriction" and "insulin sensitivity" in PUBMED], increases in proteome turnover in CR [such as PMID: 11394882], to reference two prominent aspects. Even a connection to mebrane bilayer fluidity maintenance seems plausible [PMID: 12796449]

----------------------------------------------------
Most of the available data indicate that 40% caloric restriction decreases the rate of generation of mitochondrial reactive oxygen species and lowers oxidative damage to mitochondrial DNA and proteins in rodent organs [100]. Long-lived species also have lower levels of these parameters than short-lived ones, suggesting the existence of at least one common mechanism of longevity extension in both cases [7]. However, it was not known what specific dietary components, if any, mechanistically cause those decreases during CR. It is known that 40% protein restriction (PR) increases maximum longevity (Table 2) and that this increase is smaller (around 20%) than that observed in 40% CR (around 40% increase). In the case of methionine restriction (MetR), a 44% increase in MLSP has been observed [119], but this increase was found after restricting methionine by 80%, not by 40%. Thus, it is most likely that 40% MetR increases MLSP to a smaller extent, similar to the one observed in PR (around 20% increase in MLSP). Therefore, the decrease in methionine intake could be responsible for all or most of the increase in MLSP observed in PR as well as for around 50% of the increase in MLSP observed in CR. On the other hand, it was recently found that 40% protein restriction without CR decreases MitROS generation and oxidative damage to mtDNA (8-oxodG), PR totally mimicking CR quantitatively and qualitatively in this respect [106], whereas lipid restriction does not change those parameters [127]. Furthermore, it was recently found that MetR also decreases ROS generation in rat liver and heart mitochondria. All these suggest that the reduction in methionine intake during CR and PR can be the cause of the decrease in MitROS production and oxidative damage to mtDNA, and can be responsible for around 50% of the increase in MLSP observed in caloric restriction (Fig. 3). Moreover, it was found that methionine is the only amino acid whose abundance in tissues strongly (and negatively) correlates with MLSP: the longer the life span, the smaller the level of methionine in intracellular proteins. Many other kinds of studies also connect methionine and its metabolites, including homocysteine, to aging.




Fig. 3. Model of likely cause–effect relationships concerning the mitochondrial free radical theory of aging. This model further delineates recent views (8) on the mechanistic connection between CR, MitROS production and oxidative stress, and aging, taking into account two relevant recent findings: (a) the methionine content of tissue proteins negatively correlates with maximum longevity in mammals and birds; (b) 80% methionine restriction, like 40% CR and 40% PR, significantly decreases the rate of ROS generation at complex I and mtDNA 8-oxodG in rat heart and liver mitochondria. It is known that CR, PR and MetR significantly increase maximum longevity in rats (Table 2 and Table 3). The low MitROS production of CR and PR animals seems to be due to their low methionine ingestion. Other unknown mechanisms different from MitROS production can contribute to decrease aging rate in CR. DBI (double bond index) indicates membrane fatty acid unsaturation. MDA = malondialdehyde. “Prot.ox.” represents various markers of protein oxidative modification.



Finally, it is commonly considered that maintenance of the organism is the key for a high longevity. But what are the fundamental mechanisms of maintenance in long-lived species? Concerning oxidative stress, available evidence points to two general mechanisms: (1) decreasing the rate of generation of endogenous damage (e.g., the rate of MitROS production) and (2) possession of macromolecules less sensitive to oxidative damage; this is obtained in the case of lipids by decreasing the degree of fatty acid unsaturation, and in the proteins at least by decreasing the number of methionine residues. Of these two general longevity mechanisms, caloric restriction uses the first one, decreasing the rate of MitROS generation. This seems to be due to a great extent to the decrease in methionine intake of the caloric restricted animals.

#12 opales

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Posted 03 April 2006 - 08:02 AM

I am not sure if this has been brought up before but..

Since methionine metabolises to homocysteine, could it be that correlation between elavated homocysteine and risk of various diseases could be at least mostly just due to excessive amount of methionine in the diet and not because of homocysteine itself? That might explain the some of the recent results of lowering homocysteine with vitamins not producing lowered incidence of recurrent cardiovascular events. Or is there evidence that homocysteine (at least partly) mediates the deleterious effects of high methionine (as Scottl seemed to speculate)?

It seems that that folate and b12 lower homocysteine levels via converting it BACK to methionine, but b6 by further metabolizing it. Has anyone tested how the levels of these individual vitamins actually relate cardiovascular diseases? It could be that either conversion back to methionine negates the effect of actually breking down homocysteine with b6 OR that the metabolites of homocysteine are somehow causally involved in the negative effects of high methionine diet OR both.

Edited by opales, 03 April 2006 - 10:57 AM.


#13 tedsez

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Posted 05 April 2006 - 09:48 PM

Would this be a reason to take Sam-e supplements, since they affect methionine levels?

#14 stephen_b

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Posted 23 April 2008 - 03:37 PM

I found this study, "Effect of excess methionine and methionine hydroxy analogue on growth performance and plasma homocysteine of growing Pekin ducks", PMID 17704389.

One experiment was conducted to study the effect of excess dl-methionine (DLM) and dl-2-hydroxy-4-methylthiobutanoic acid free acid (dl-HMB-FA) on duck growth. One-day-old male white Pekin ducklings were fed common starter diets from hatch to 21 d of age and then fed the experimental diets from 21 to 42 d of age. Three hundred twenty 21-d-old birds were allotted to 40 raised wire-floor pens with 8 birds per pen according to similar pen weight. There were 5 dietary treatments that included a methionine-adequate control diet and control diets supplemented with 2 levels of dry DLM (1 or 2%) or 2 equimolar levels of liquid dl-HMB-FA (1.13 or 2.26%). Each dietary treatment was replicated 8 times. At 42 d of age, weight gain, feed intake, and gain/feed were measured and plasma was collected to analyze homocysteine. Compared with ducks fed control diets, excess DLM or dl-HMB-FA supplementation reduced weight gain and feed intake of birds significantly. However, on the equimolar basis, at 1 or 2% supplemental methionine activity, dl-HMB-FA was less growth-depressing than DLM. According to the growth response to excess methionine, the tolerable upper limit of dietary methionine for growing ducks may be less than 1.38% when the methionine level of the control diet (0.38%) was considered. On the other hand, plasma homocysteine was elevated markedly when 2% DLM or 2.26% dl-HMB-FA was added to control diets, but plasma homocysteine of ducks fed 2.26% dl-HMB-FA supplemented diets was lower significantly than birds fed equimolar DLM-supplemented diets, which indicated the toxicity of excess methionine sources and less toxicity of dl-HMB-FA relative to DLM.


So, excess methionine suppresses growth and results in toxic levels of homocysteine in these ducks. Is that the correct conclusion?

Stephen

#15 s123

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Posted 23 April 2008 - 07:43 PM

I practice a methionine restriction diet. I don't remember when I started but it has to be something like 6 months ago. I do this by eating tofu as my protein source. Once in a while (maybe 2 or 3 times a month) I eat some salmon (high in methionine). I also practice between 25 and 30% CR.

There are already some discussions on Imminst about methionine restriction:

http://www.imminst.o...o...ionine&st=0
http://www.imminst.o...p;hl=methionine
http://www.imminst.o...p;hl=methionine

They put 6 weeks old female mice on a normal diet or a diet that only contained 23% of the normal amount of methionine. Many of the animals died. Then they increased the dose to 28% (the animals were now 4 months old). At 6 months of age they again raised the amount of methionine to 33%. The oldest animals in the control group lived 1144 days but the methionine restricted animals lived 100 days longer.


http://sageke.scienc...ll/2005/16/nf31

#16 AgeVivo

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Posted 26 April 2008 - 02:01 PM

It would be nice to make cows and pigs that lack methionine.
If someone here knows how to introduce that...
I am sure many people would buy such meat.

#17 s123

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Posted 26 April 2008 - 02:27 PM

It would be nice to make cows and pigs that lack methionine.
If someone here knows how to introduce that...
I am sure many people would buy such meat.


You cannot make cows or pigs that completely lack methionine because they would die.
Methionine is an essential amino acid. You would also die if you would stop eating methionine, just like the mice did (and they did eat methionine but too little).

#18 AgeVivo

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Posted 26 April 2008 - 04:23 PM

of course. I meant: with reduced methionine

#19 treonsverdery

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Posted 26 April 2008 - 05:22 PM

it is possible that there are metabolic processes that remove elemental S from the body; this may be similar to the cysteine gene variant

being a vegetarian reduces both homocysteine as well as methionine

nutritional determinants of plasma homocysteine.
http://www.ncbi.nlm....Pubmed_RVDocSum

Krajcovicova-Kudlackova M, Blazicek P, Mislanova C, Valachovicova M, Paukova V, Spustova V.
Slovak Medical University, Bratislava, Slovakia. marica.kudlackova@szu.sk
The total Hcy, methionine, vitamin B12, folic acid and vitamin B6 blood concentrations were measured in apparently healthy adult subjects aged 20-30 years with three types of nutrition - 52 normal weight subjects of general population on traditional mixed diet (non-vegetarians), 52 normal weight vegetarians and 24 overweight and obese non-vegetarians. In the groups with lower methionine intake (vegetarians, normal weight non-vegetarians; methionine intake 0.45-2.12 g/day), Hcy values are dependent on vitamin B12 and folic acid. Vegetarian Hcy concentration is significantly increased and hyperhomocysteinemia was found in 35% of vegetarians vs 10% of non-vegetarians. Elevated Hcy values in vegetarians are the consequence of vitamin B12 deficiency - 31% of vegetarians with deficient serum values vs 2% of non-vegetarians (vitamin is not contained in plant food). Non-vegetarians are more deficient in folic acid (8% vs 0% in vegetarians) due to of lower consumption of food rich in folic acid (vegetables, whole grain products, pulses, seeds). The results suggest that in healthy population, a correct nutritional regime with an optimal intake of nutritional Hcy determinants is crucial for the maintenance of Hcy concentration in normal range and for the prevention of hyperhomocysteinemia (Tab. 2, Fig. 2, Ref. 27). Full Text (Free, PDF) www.bmj.sk.

People for the ethical treatment of animals lettuce lady urges us to become vegetarians
Posted Image

Edited by treonsverdery, 26 April 2008 - 05:31 PM.


#20 treonsverdery

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Posted 26 April 2008 - 10:09 PM

rate of transcription research
transfer RNA gets its start from the methionine contaning AUC codon
using the tRNA rate regulation approach is similiar to methionine rate regulation; methionine is the part of the start codon thus perhaps reducing methionine makes every (dna erosion junk -> transcibed protein::cumulative tissue errors) or hayflick effect more gradual

pubmed.org list hundreds of refs on inhibitors of trna synthetase there is active research on this as changing the rate of transcription is a way to address MRSA; mupirocin is a currently approved antibiotic that halves transcriprion rate it would be nifty so read about the effect of mupirocin on longevity

rate of transcription research
using the tRNA rate regulation approach is similiar to methionine rate regulation pubmed.org list hundreds of refs on inhibitors of trna synthetase there is active research on this as changing the rate of transcription is a way to address MRSA

it might be possible to make an effect atherosclerosis drug that changes the rate of transcription among the cytes that do plaque formation

tRNA regulators look like drugs that could create longevity with the methionine effect; gradualizing hayflick; reducing body burden of unfelt chronic disease; reducing atherosclerosis; possibly minimizing scar tissue if scar tissue is related to rate of repair (I think I've read that rapid repair causes scar tissue)

anyway here is a database of 240 potential tRNA longevity drugs http://www.ncbi.nlm....Pubmed_RVDocSum

Edited by treonsverdery, 26 April 2008 - 10:10 PM.


#21 AgeVivo

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Posted 04 May 2008 - 10:15 PM

in biology there are always many possible explanations and the first one that comes to mind isn't usually the right one (but it might be). various possible mechanisms explaining why the met diet extends life:

* a best guess:
limiting methionine limits the rate of transcription, which limits the rate at which bad proteins accumulate.
which bad proteins? (I'll edit my post with the scientific names if you don't correct me before ;-)
badly formed proteins that have a portion that can not be deleted by the proteasome:
- lipofushin: that pigment that makes skin age spots
- proteins that make 'flying spots' in our vision
- proteins that accumulate in dividing yeast cells and provoke replicative senescence
- proteins that accumulate and provoke senescence of pseudo anserina
lysoSENS is a SENS project that is aimed at fixing that kind of senescence

other guesses:
* cells divide at a lower rate / tumors develop at a lower rate because of the reduced transcription rate
* anti-oxydation via the overexpressed GSH
* the met diet reduces homocysteine and the known associated negative effects (which doesn't explain why homocysteine has those known negative effects)
* genes are more homogeneously expressed (the DNA is less methylated, therefore usually underexpressed genes are overexpressed; the transcription rate is limited, therefore usually overexpressed genes are underexpressed). It
- allows some rarely expressed beneficial genes to be more expressed
- avoids other genes to be too much expressed
- makes cells less specialized in the body (not sure it's a good thing)

Edited by AgeVivo, 04 May 2008 - 10:20 PM.


#22 AgeVivo

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Posted 08 May 2008 - 06:00 AM

Hi,

http://www.methionine-restriction.org : let's build it together!

Most need for now:
- Litterature and summaries
- web skills

#23 teaser

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Posted 21 June 2008 - 02:08 AM

I've been interested in this methionine angle for a while. The other day, I was looking up stuff about Delta-6 desaturate, and things that decrease it, like alcohol or aspirin. There's a theory that creatures with a higher degree of saturation in the mitochondrial membrane live longer. When I was looking up the stuff about Delta-6 desaturase, I came across mention that excess dietary methionine caused an increase in Delta-6 activity in the liver of rats.

delta 6 desaturase, methionine and rats This is my first time posting on this site. Ignore that link. use this one

If this effect of methionine caused a higher degree of unsaturation in the mitochondrial membrane, there's a possibility this could explain some of the life extension caused by methionine restriction. It's even possible, maybe, that this could lead to a lessened need for the antioxidant protection of glutathione. More saturation, less peroxides to worry about. Less need for glutathione in the liver, which is one of the results of methionine restriction. I think one of the early posts in this thread mentioned less peroxidation in the liver with methionine restriction.

I found this interesting;

"These increases induced by methionine were significantly suppressed by additional glycine." Maybe methionine restriction corrects an imbalance in the various amino acids? Caseine has relatively high levels of methionine, and relatively low levels of glycine. I went looking for how low. NutritionData gives 566 mg of glycine, and 861 methionine in a serving of cheddar cheese with 33 total grams of protein. For a seven gram (protein only) serving of whey, they give 126 mg methionine, 120 mg glycine.
Glycine is a supposedly non-essential amino acid, but I gotta wonder. It's in choline, betaine, glutathione, creatine. They feed glycine to people with muscular dystrophy, and urinary creatine increases--suggesting that endogenous glycine synthesis might not be fast enough to optimize creatine synthesis. Sub-optimal creatine levels are associated with aging, and at least one study suggested partial reversal of sarcopenia in the elderly through creatine supplementation.
glycine tumour growth This is interesting--dietary glycine is supposed to have decreased tumour growth by fifteen percent in rats. Glycine administration also slowed wound healing. Aren't decreased tumour growth and slowed wound healing hallmarks of calorie restriction?

I just looked up sardines. Methionine 1086 mg, glycine 1760. Dried Cod methionine 1487, glycine 2412. So the theory here is that fish and whey are healthy, when compared with cheese. Wow. Astonishing news.

Edited by teaser, 21 June 2008 - 02:24 AM.


#24 vyntager

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Posted 22 June 2008 - 11:09 AM

Has there been any studies trying to have animals under CR, but with levels of proteins, or levels of met, that would be as high as those ad lib animals would get ? If so, were the effects of CR on those animals modified ? In other words, does a protein OR methionin rich but otherwise calorie restricted diet still possess the benefits of a normal CR diet ?

Edited by vyntager, 22 June 2008 - 11:11 AM.


#25 edward

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Posted 01 July 2008 - 06:35 PM

I think the best way to exploit this methionine issue is to find some compound that binds to and renders methionine indigestible. Like orlistat prevents fats from being absorbed. Now if someone came up with something like that... wow, just take it with big protein meals and there you go.

I don't think however its possible.

Edited by edward, 01 July 2008 - 06:36 PM.


#26 edward

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Posted 01 July 2008 - 06:39 PM

This might be an interesting read if anyone has access (no abstract provided)

Effect of Dietary Changes on Intestinal Absorption of Methionine
http://www.ncbi.nlm..../pubmed/5059378

#27 Shepard

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Posted 01 July 2008 - 06:56 PM

This might be an interesting read if anyone has access (no abstract provided)

Effect of Dietary Changes on Intestinal Absorption of Methionine
http://www.ncbi.nlm..../pubmed/5059378


Here you are, sir.

http://www.imminst.o...howtopic=22901#

Doesn't really seem to be much of anything, though.

#28 edward

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Posted 02 July 2008 - 03:31 PM

Thanks. There are a couple bits of information worth storing away.
1. Protein absorption is significantly better in a restricted (50% calories) fed with periods of fasting than in ad lib feeding state.(but we already knew this)

2. Methionine absorption is significantly less in its free form state compared to as a peptide, between 30-48% less is absorbed. But I think this is true for many amino acids, so the only strategy that would work would be to find a specific enzyme or compound that would selectively break down methionine peptides into a free form amino acid (leaving the other aminos alone) and voilà instant 30-48% percent reduction in your methionine absorption. Might be easier then "methionine chelation" but probably still difficult.


This might be an interesting read if anyone has access (no abstract provided)

Effect of Dietary Changes on Intestinal Absorption of Methionine
http://www.ncbi.nlm..../pubmed/5059378


Here you are, sir.

http://www.imminst.o...howtopic=22901#

Doesn't really seem to be much of anything, though.



#29 resveratrol

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Posted 13 July 2008 - 05:40 PM

Would this be a reason to take Sam-e supplements, since they affect methionine levels?


Do you have any references for this? In what way do they affect methionine levels?

Since Sam-e is created from methionine, I would think reducing SAM-e intake would be the better strategy, since it would result in the conversion of more methionine to SAM-e, thus reducing levels of methionine itself.

I'm having a hard time Googling this since "methionine" is the M in "SAM-e".

Edited by resveratrol, 13 July 2008 - 05:43 PM.


#30 stephen_b

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Posted 15 January 2009 - 10:19 PM

From another thread:

From "Caloric restriction and methionine and their effects on longevity in Drosophila melanogaster",

While the data seem to support previous CR studies, the effect of methionine is not clear. Shifts in longevity seemed to be negligible when methionine was added to the medium. The most noticeable shift occurred in males on 4% yeast media with added methionine. Even then, a decrease of only a few days was seen. Some females on 4% yeast media with added methionine may have actually lived longer than those raised solely on a 4% yeast medium. If methionine metabolism is mediated during CR, an increase in methionine seemed to have little or no effect. If metabolic processes are already maximally using amino acids on a normal diet, an increase in amino acid intake would have no effect on the output of these processes. Oxidative free radicals and other harmful cellular products would already be causing their maximum cellular impact. However, if methionine is removed from the diet, these metabolic processes would be in involved less production of metabolites. Because of this, nutrient mediated pathways can't be ruled out. Amino acid metabolism could still have an impact during CR without decreasing longevity when boosted. Even so, the study does little to show that methionine metabolism plays a critical role in longevity.

Granted, that was on fruit flies.

My suspicion is that methionine is a red herring and probably just correlates with AGE content in food.

PMID 11254667 might be interesting:

Although hyperhomocysteinemia (HHcy) is a well-known risk factor for the development of cardiovascular disease, the underlying molecular mechanisms are not fully elucidated. Here we show that induction of HHcy in apoE-null mice by a diet enriched in methionine but depleted in folate and vitamins B6 and B12 increased atherosclerotic lesion area and complexity, and enhanced expression of receptor for advanced glycation end products (RAGE), VCAM-1, tissue factor, and MMP-9 in the vasculature. These homocysteine-mediated (HC-mediated) effects were significantly suppressed, in parallel with decreased levels of plasma HC, upon dietary supplementation with folate and vitamins B6/B12. These findings implicate HHcy in atherosclerotic plaque progression and stability, and they suggest that dietary enrichment in vitamins essential for the metabolism of HC may impart protective effects in the vasculature.

StephenB




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