All:
The evidence is now pretty convincing that actual methionine *restriction* (reducing Met + Cys intake to way-below-RDA levels) does slow down aging in mammals (rodents) independently of CR per se. However, MetR to the degree required to actually retard aging is crazy to attempt as a human, and cannot be achieved while eating natural foods, despite the fact that folks keep confusing MetR with what one might call "Met moderation:" simply trying to avoid going too far over the RDA of Met (or the more evidence-based targets discussed in the post linked below).
That said, there IS good reason to practice "Met moderation!" There is prospective epidemiology supporting the deleterious impact of high met on coronary disease.
All this and more, including the practicalities of MM, are discussed in some detail and rigorously documented in the following post:
http://www.mfoundati...37&postcount=11
(Note that this post was heavy on emphasizing the limitations of the MetR research at that time; today, I find it pretty convincing -- just irrelevant for human application).
Additionally: a previous rodent study (1) had found that excess Met, independent of its effects on Hcy, could accelerate atherosclerosis in mutant mice designed to model the disease:
"Animals with genetic hyperhomocysteinemia have so far not displayed atheromatous lesions. However, when methionine-rich diets are used to induce hyperhomocysteinemia, vascular pathology is often observed. Such studies have not distinguished the effects of excess dietary methionine from those of hyperhomocysteinemia. We fed apolipoprotein E-deficient mice with experimental diets designed to achieve three conditions: (i) high methionine intake [~2.33 times what's in normal rodent chow] with normal blood homocysteine [because of a little extra B-vitamins]; (ii) high methionine intake with B vitamin deficiency and hyperhomocysteinemia; and (iii) normal methionine intake with B vitamin deficiency and hyperhomocysteinemia."
" Mice fed methionine-rich diets had significant atheromatous pathology in the aortic arch even with normal plasma homocysteine levels, whereas mice fed B vitamin-deficient diets developed severe hyperhomocysteinemia without any increase in vascular pathology. Our findings suggest that moderate increases in methionine intake are atherogenic in susceptible mice."(1)
This might explain why elevated Hcy is *reasonably* consistently associated with risk of atherosclerosis and other bad CVD outcomes, but administration of B-vitamins to correct it in clinical trials don't improve outcomes, and may even worsen them.
Now the reason why I've called you here today
is a new study (2) investigating the reasons why homocysteine seems to be linked to risk of Alzheimer's:"we elevated plasma homocysteine by feeding mutant amyloid precursor protein (APP)-expressing mice [who develop beta-amyloid plaques and some limited cognitive deficits somewhat similar to AD -MR] diets with either high methionine (HM) [~5-fold the amount in their regular chow -- see Table S1] or deficient in B-vitamins and folate (B Def). "
"Mutant APP mice fed HM demonstrated increased brain beta amyloid. Interestingly, this increase was not observed in mutant APP mice fed B Def diet, nor was it observed in C57Bl6 [non-mutant] or YAC-APP mice fed HM. ["YAC-APP mice express human APP, including its proximal genomic DNA, express Aβ at levels greater than endogenous, but lower than those achieved with the NFEV mutation. Also, none of these lines develop plaque pathology."] Furthermore, HM, but not B Def, produced a prolonged increase in *brain* homocysteine only in mutant APP mice but not wild-type mice. These changes were time-dependent over 10 weeks. Further, by 10 weeks HM increased brain cholesterol and phosphorylated tau in mutant APP mice. Transcriptional profiling experiments revealed robust differences in RNA expression between C57Bl6 and mutant APP mice. The HM diet in C57Bl6 mice transiently induced a transcriptional profile similar to mutant APP cortex, peaking at 2 weeks, following a time course comparable to brain homocysteine changes." (2)
One caveat, in addition to the fact that these mice aren't really great models of human AD: while many normal human diets contain 5 RDA of Met + Cys, it appears that the effects the increase in Met intake in (2) was substantially greater: "The concentration of methionine used in these studies is at the upper range of tolerability. While mice appeared healthy and exhibited normal locomotor and exploratory activity, growth retardation was noticed. Methionine excess could alter more than just Hcy metabolism, such as disrupting the balance of amino acid metabolism. Despite such non-specific consequences, we believe there are reasons to think the changes are relevant to APP metabolism. These reasons include (i) evidence of a specific gene–diet interaction; (ii) links between APP, Hcy, and cholesterol; and (iii) the unbiased approach of transcriptional profiling."
References
1: Troen AM, Lutgens E, Smith DE, Rosenberg IH, Selhub J. The atherogenic effect
of excess methionine intake. Proc Natl Acad Sci U S A. 2003 Dec
9;100(25):15089-94. Epub 2003 Dec 1. PubMed PMID: 14657334; PubMed Central PMCID:
PMC299913.
http://www.pnas.org/...0/25/15089.long
2: McCampbell A, Wessner K, Marlatt MW, Wolffe C, Toolan D, Podtelezhnikov A, Yeh
S, Zhang R, Szczerba P, Tanis KQ, Majercak J, Ray WJ, Savage M. Induction of
Alzheimer's-like changes in brain of mice expressing mutant APP fed excess
methionine. J Neurochem. 2011 Jan;116(1):82-92. doi:
10.1111/j.1471-4159.2010.07087.x. Epub 2010 Dec 2. PubMed PMID: 21054384.
http://onlinelibrary...10.07087.x/full
http://onlinelibrary...7-TableS1-2.pdf
