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A Report from the First International Mini-Symposium on Methionine Restriction and Lifespan


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#1 reason

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Posted 23 May 2014 - 09:10 PM


Methionine is an essential amino acid. Our metabolism cannot produce it, but is nonetheless an important raw material for the manufacture of proteins, and thus must be obtained in the diet. If you don't obtain enough of it, you die. Fortunately just about any sensible diet, and even most deficient diets, contain far more than you actually need to get by. Very few foodstuffs are lacking in methionine.

If you are the sort who likes undertaking strict and novel diets for the inherent challenge involved, rather than the outcome, then you should give up whatever you are doing right now and give a low methionine diet a try. You will be faced with challenging research to identify appropriate levels of methionine for a human low methionine diet, poor and contradictory nutritional data on the methionine content of various foodstuffs, and a comprehensive avoidance list that includes most of the standard staples and fallback alternatives used in the recipes of any given culinary tradition. I feel quite sorry for those who are forced into such a diet through suffering one of a few rare medical conditions such as homocystinuria, as the challenges inherent in organizing your own low methionine diet almost rise to the level of making the expensive tailored medical diets produced by a variety of big name companies look cost-effective.

Why undertake a low methionine diet if not forced to do so by pressing medical circumstances? For the same reasons one would undertake calorie restriction or intermittent fasting, both of which are far easier propositions: just like these two options, methionine restriction has been shown to extend life and improve health in a range of laboratory species. The evidence for calorie restriction to bring health benefits to human practitioners is compelling, and further bolstered by a mountain of animal studies results accumulated over decades. In the case of methionine restriction there is, so far as I know, only very sparse data for humans, but a good enough set of data from rodent studies to make it interesting. Methionine restriction is likely an important underlying mechanism for the operation of calorie restriction, which makes sense as a lesser intake of food generally means a lesser intake of methionine. Thus anyone advocating that you give methionine restriction a try for health reasons would argue on the basis of studies in mammals that strongly suggest it is a cause of calorie restriction benefits, and then point to the supporting data mountain for calorie restriction.

Caveat emptor, of course. I'm one who has in the past debated whether it is wise to try alternate day fasting given that there is much more data for straight calorie restriction, so you can probably imagine my views on methionine restriction. Being a conservative late adopter in all things has a lot going for it.

In a like fashion the research community is generally very conservative and and slow-moving in most matters. It takes a while, sometimes decades, for research to percolate through the system. Methionine restriction is beginning to be considered more widely among those who work with calorie restriction or fasting, however. So we have the small symposium noted below, for example, as a sign that folk are talking on this topic. Where there is presently discussion and modest scientific meetings there will later be conferences and commercial ventures - and possibly better and more reliable information on whether and how to practice methionine restriction were one inclined to do so:

The First International Mini-Symposium on Methionine Restriction and Lifespan

It has been 20 years since the Orentreich Foundation for the Advancement of Science, under the leadership Dr. Norman Orentreich, first reported that low methionine (Met) ingestion by rats extends lifespan. Since then, several studies have replicated the effects of dietary methionine restricted (MR) in delaying age-related diseases.

We report the abstracts from the First International Mini-Symposium on Methionine Restriction and Lifespan held in Tarrytown, NY, September 2013. The goals were (1) to gather researchers with an interest in MR and lifespan, (2) to exchange knowledge, (3) to generate ideas for future investigations, and (4) to strengthen relationships within this community. The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed.

The symposium also emphasized the value of other species, e.g., the naked mole rat, Brandt's bat, and Drosophila, in aging research. Overall, the symposium consolidated scientists with similar research interests and provided opportunities to conduct future collaborative studies.

Among the presentations discussed is one of the only studies on methionine restriction in humans I've seen, preliminary and brief as it was. It is worth noting in passing that in comparison to the mild reduction in methionine here, rodent life span studies on methionine restriction tend to cut down methionine levels in the diet by a much larger proportion.

Previous findings in rodent models that dietary MR increases maximum lifespan and reduces the development of aging-related impairments suggest that MR may have important implications as a preventive or therapeutic strategy in humans. However, to date, there have been few studies aimed at translating these pre-clinical findings to the clinic.

To this end, we conducted a short-term controlled cross-over feeding study of MR in healthy adults. This study consisted of two isocaloric diet groups (control and 86% MR). Our objectives were to determine the feasibility of feeding an MR diet and to assess the effects of MR on relevant blood biomarkers. The study was conducted with 12 healthy adults and consisted of two 3-week experimental feeding periods with a 2-week washout. The MR diet was well-tolerated by all subjects with no negative side-effects reported.

Decreases in plasma levels of Met (22%) and cysteine (15%) were observed in the MR group after 3 weeks. MR significantly decreased plasma total cholesterol (15%), LDL (23%), and uric acid (25%), but had no effects on leptin, adiponectin, IGF-1, or glutathione.

Altogether, these findings demonstrate the feasibility of a MR diet in humans and indicate that MR has significant short-term effects on blood lipids similar to those observed in laboratory animal models. In addition, the lack of effects on blood adipokines and glutathione are consistent with more recent laboratory findings that indicate that restrictions in both Met and Cys may be required for the full range of beneficial effects on adipokines and longevity.


View the full article at FightAging

#2 Darryl

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Posted 24 May 2014 - 05:49 PM

There may be benefits from simply keeping methionine in the adequate (but not deficient) zone. Methionine moderation is actually rather easy: a vegan diet with only moderate amounts of legumes and whole grains (ie a bit more calories from nuts, rice, fruit). Perhaps glycine supplementation to clear excess methionine.

 

Here are some studies of methionine supplementation.  They're all consistent with the story from severe methionine restriction studies: excess methionine increases mitochondrial oxidative stress, DNA damage, and accelerates the progression of aging associated diseases.

 

Zhou, J., Møller, J., Danielsen, C. C., Bentzon, J., Ravn, H. B., Austin, R. C., & Falk, E. (2001). Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice.Arteriosclerosis, thrombosis, and vascular biology21(9), 1470-1476.

Troen, A. M., Lutgens, E., Smith, D. E., Rosenberg, I. H., & Selhub, J. (2003). The atherogenic effect of excess methionine intake. Proceedings of the National Academy of Sciences100(25), 15089-15094.

Zhang, R., Ma, J., Xia, M., Zhu, H., & Ling, W. (2004). Mild hyperhomocysteinemia induced by feeding rats diets rich in methionine or deficient in folate promotes early atherosclerotic inflammatory processes. The Journal of nutrition134(4), 825-830.

Virtanen, J. K., Voutilainen, S., Rissanen, T. H., Happonen, P., Mursu, J., Laukkanen, J. A., ... & Salonen, J. T. (2006). High dietary methionine intake increases the risk of acute coronary events in middle-aged men. Nutrition, metabolism and cardiovascular diseases16(2), 113-120.

Yalçınkaya, S., Ünlüçerçi, Y., & Uysal, M. (2007). Methionine-supplemented diet augments hepatotoxicity and prooxidant status in chronically ethanol-treated rats. Experimental and Toxicologic Pathology58(6), 455-459.

Park, C. M., Cho, C. W., Rosenfeld, M. E., & Song, Y. S. (2008). Methionine Supplementation Accelerates Oxidative Stress and Nuclear Factor κ B Activation in Livers of C57BL/6 Mice. Journal of medicinal food11(4), 667-674.

Gomez, J., Caro, P., Sanchez, I., Naudi, A., Jove, M., Portero-Otin, M., ... & Barja, G. (2009). Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart.Journal of bioenergetics and biomembranes41(3), 309-321.

Song, Y., Cho, M., Cho, C., & Rosenfeld, M. E. (2009). Methionine-induced hyperhomocysteinemia modulates lipoprotein profile and oxidative stress but not progression of atherosclerosis in aged apolipoprotein E knockout mice.Journal of medicinal food12(1), 137-144.

Yalçinkaya-Demirsöz, S., Depboylu, B., Doğru-Abbasoğlu, S., Ünlüçerçi, Y., & Uysal, M. (2009). Effects of high methionine diet on oxidative stress in serum, apo-B containing lipoproteins, heart, and aorta in rabbits. Annals of Clinical & Laboratory Science39(4), 386-391.

Zulli, A., & Hare, D. L. (2009). High dietary methionine plus cholesterol stimulates early atherosclerosis and late fibrous cap development which is associated with a decrease in GRP78 positive plaque cells. International journal of experimental pathology90(3), 311-320.

McCampbell, A., Wessner, K., Marlatt, M. W., Wolffe, C., Toolan, D., Podtelezhnikov, A., ... & Savage, M. (2011). Induction of Alzheimer’s‐like changes in brain of mice expressing mutant APP fed excess methionine.Journal of neurochemistry116(1), 82-92.

Aissa, A. F., Gomes, T. D. U. H., Almeida, M. R., Hernandes, L. C., Darin, J., Bianchi, M. L. P., & Antunes, L. M. G. (2013). Methionine concentration in the diet has a tissue-specific effect on chromosomal stability in female mice. Food and Chemical Toxicology62, 456-462.

 

There's at least twice the volume of recent studies with methionine restriction, but the story remains the same. Personally, I'm pretty excited by these results with glycine:

 

Fukada, S. I., Shimada, Y., Morita, T., & Sugiyama, K. (2006). Suppression of methionine-induced hyperhomocysteinemia by glycine and serine in rats.Bioscience, biotechnology, and biochemistry70(10), 2403-2409.

Brind, J., Malloy, V., Augie, I., Caliendo, N., Vogelman, J. H., Zimmerman, J. A., & Orentreich, N. (2011). Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats. The FASEB Journal25, 528-2.

 

I also support engineering approaches to aging. But prudence demands using safe and practical means to reduce physiological aging wherever available, if only to survive till engineering approaches are available, and enter engineering therapies with fewer deficits.

 

Mechanics can do little to rescue combustion engines if run without oil or on the wrong fuel. 

 

 

I would have preferred to provide links to all of these, but the direct linking facility is gone and all of you know how to use Scholar, Library Genesis, etc.


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#3 blood

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Posted 25 May 2014 - 11:17 AM

Brind, J., Malloy, V., Augie, I., Caliendo, N., Vogelman, J. H., Zimmerman, J. A., & Orentreich, N. (2011). Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats. The FASEB Journal, 25, 528-2.


Anyone know if this was published as a full article, or just as an abstract?

#4 Darryl

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Posted 25 May 2014 - 11:07 PM

Just a poster abstract. There are good reasons to be skeptical (Joel Brind is CEO of a glycine supplement Co., and his other scientific controversies merit a Wikipedia entry), but there are a number of other studies that suggest a high glycine/methionine dietary ratio reduces harmful effects of excess methionine.

 

Sugiyama, K., Ohishi, A., Siyu, H., & Takeuchi, H. (1989). Effects of methyl-group acceptors on the regulation of plasma cholesterol level in rats fed high cholesterol diets. Journal of nutritional science and vitaminology35(6), 613-626.
Morita, T., Oh-hashi, A., Takei, K., Ikai, M., Kasaoka, S., & Kiriyama, S. (1997). Cholesterol-lowering effects of soybean, potato and rice proteins depend on their low methionine contents in rats fed a cholesterol-free purified diet. The Journal of nutrition127(3), 470-477.
Rowling, M. J., McMullen, M. H., Chipman, D. C., & Schalinske, K. L. (2002). Hepatic glycine N-methyltransferase is up-regulated by excess dietary methionine in rats. The Journal of nutrition132(9), 2545-2550.
Gudbrandsen, O. A., Wergedahl, H., Liaset, B., Espe, M., & Berge, R. K. (2005). Dietary proteins with high isoflavone content or low methionine-glycine and lysine-arginine ratios are hypocholesterolaemic and lower the plasma homocysteine level in male Zucker fa/fa rats. British journal of nutrition94(03), 321-330.
Fukada, S. I., Shimada, Y., Morita, T., & Sugiyama, K. (2006). Suppression of methionine-induced hyperhomocysteinemia by glycine and serine in rats.Bioscience, biotechnology, and biochemistry70(10), 2403-2409.
 
Whether glycine acts as the anti-methionine directly, through encouraging methionine disposal by glycine N-methyltransferase, or via other mechanisms, remains an open question. I'm working through folders of papers dealing with benefits of glycine supplementation and methionine restriction or harms of high-methionine diets or supplementation. There seems considerable overlap in oxidative stress and inflammatory disorders like atherosclerosis. Almost no one is looking at glycine with an eye to its connection to methionine.
 
There's one dietary source with an extremely high glycine/methionine ratio, gelatin (31.7), and the animal collagen its rendered from. In general, however, plant proteins have a somewhat higher glycine/methionine ratio (averages over USDA nutrition entries):
 
fruit 4.3, non-starchy vegetables 3.7, nuts 3.6, legumes 3.4, cured meat 2.6, mollusks 2.6, grains 2.2, tubers 2.2, crustaceans 2.1, poultry 2.0, red meats 2.0, pork 1.9, fish 1.6, eggs 1.1, dairy 0.8, cheese 0.7
 
While there may be advantages to vegan diets in increasing this ratio, ovo-lacto vegetarianism that relies on eggs and dairy for a large fraction of protein may have the lowest glycine/methionine ratio of any diet.

Edited by Darryl, 25 May 2014 - 11:55 PM.

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#5 LexLux

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Posted 26 May 2014 - 12:09 AM

"In addition, the lack of effects on blood adipokines and glutathione are consistent with more recent laboratory findings that indicate that restrictions in both Met and Cys may be required for the full range of beneficial effects on adipokines and longevity."

 

Why should cysteine be restricted? Also worth pointing out that methionine restriction is useful for cancer growth control, cancer cells have an absolute methionine dependency. 

 

Bull Cancer. 2008 Jan;95(1):69-76. doi: 10.1684/bdc.2008.0550.

[Methionine dependency of cancer cells: a new therapeutic approach?].

[Article in French]
Abstract

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.

 

Cancer Treat Rev. 2003 Dec;29(6):489-99.

Methionine dependency and cancer treatment.
Abstract

Conventional chemotherapies have showed their limits, notably for patients with advanced cancer. New therapeutic strategies must be identified, and the metabolic abnormalities of cancer cells offer such opportunities. Many human cancer cell lines and primary tumors have absolute requirements for methionine, an essential amino acid. In contrast, normal cells are relatively resistant to exogenous methionine restriction. The biochemical mechanism for methionine dependency has been studied extensively, but the fundamental mechanism remains unclear. A number of investigators have attempted to exploit the methionine dependence of tumors for therapeutic effects in vivo. To reduce in vivo methionine in plasma and tumours, dietary and pharmacological treatments have been used. Methionine-free diet or methionine-deprived total parenteral nutrition causes regression of a variety of animal tumours. Alternatively, methionine depletion was achieved by the use of methioninase. This enzyme specifically degrades methionine and inhibits tumour growth in preclinical models. Because of potential toxicity and quality of life problems, prolonged methionine restriction with diet or with methioninase is not suitable for clinical use. Methionine restriction may find greater application in association with various chemotherapeutic agents. Several preclinical studies have demonstrated synergy between methionine restriction and various cytotoxic chemotherapy drugs. The experimental results accumulated during the last three decades suggest that methionine restriction can become an additional cancer therapeutic strategy, notably in association with chemotherapy.

 


Edited by LexLux, 26 May 2014 - 12:09 AM.


#6 Darryl

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Posted 26 May 2014 - 12:42 AM

There's one-way metabolism of methionine to cystathionine and thence to cysteine (and glutathione), so both methionine and cysteine spare requirements for the other. I believe more cysteine means this pathway is downregulated, and there's less effective methionine restriction.

 

A good review of cancer methionine dependency is: 

 

Cavuoto, P., & Fenech, M. F. (2012). A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension. Cancer treatment reviews38(6), 726-736.

 

Available (in manuscript) here: https://publications...112966&dsid=DS1

 

Turns out the methionine dependency of many cancers is almost accidental, due to a genetic deletion that spans both the gene for tumor suppressor p16 and the adjacent gene for methylthioadenosine phosphorylase (in a methionine salvage pathway).


Edited by Darryl, 26 May 2014 - 12:46 AM.

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#7 LexLux

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Posted 26 May 2014 - 12:46 AM

Hmmm... so supplementing NAC while on a low methionine diet could be counter productive? W/o NAC wouldn't one be risking low glutathione among other things? I guess one could always supplement glutathione directly.


Edited by LexLux, 26 May 2014 - 01:38 AM.


#8 Darryl

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Posted 26 May 2014 - 06:32 PM

This paper does a nice job of illustrating the amino acid pools around methionine:

 

Sugiyama, Kimio, Shin-ichiro Fukada, and Tatsuya Morita. "Effects of various amino acids on methionine-induced hyperhomocysteinemia in rats."Bioscience, biotechnology, and biochemistry 72.7 (2008): 1940-1943.

http://ir.lib.shizuo...1/080904003.pdf

 

15dt8qw.gif               oj0ysi.gif

 

Under methionine supplementation, cysteine supplementation markedly increases Hcy concentration (a marker for free methionine concentration), while glycine and serine (and to a lesser extent, glutamate, histidine, and arginine) markedly reduces it. I'm still taking 200 mg NAC, but I also take some glycine (as sweetener) in my tea.

 

Contradicting this is another study where cysteine supplementation reduced Hcy with low methionine diets:

Kawakami, Yoshiko, et al. "Hypohomocysteinemic effect of cysteine is associated with increased plasma cysteine concentration in rats fed diets low in protein and methionine levels." Journal of nutritional science and vitaminology 55.1 (2009): 66-74.

http://dev.europepmc...t2G96bro2kikx.0

 

As cysteine and serine are at lower concentrations in most proteins than methionine and cysteine, a consideration of (Gly + Ser) / (Met + Cys) ratios doesn't change matters much: legumes (4.1), nuts (3.0), mollusks (2.8), grains (2.5), tubers (2.4), red meat, poultry (2.4), dairy, pork (2.3), fish (2.1). Among "supplemental" proteins, gelatin still reigns: gelatin (36.0), soy (3.4), pea (3.2), egg whites, whey (1.8). There's nothing comparable among plant proteins to gelatin. the closest is ginko nuts (6.6) while buckwheat (4.3) is notably high for a grain.


Edited by Darryl, 26 May 2014 - 07:01 PM.

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#9 LexLux

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Posted 28 May 2014 - 12:00 AM

Interesting, I wonder how significant the elevation in methionine would be from supplementing 600mg NAC daily. Of course it would be even more interesting to know how much glycine is required to reduce excessive methionine. Also I'm sure I read somewhere that glycine is a neurotransmitter involved in glutaminergic neurtransmission.


Edited by LexLux, 28 May 2014 - 12:23 AM.


#10 Darryl

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Posted 28 May 2014 - 01:07 AM

Those rats (25CM) were getting a 1.8% (wt/wt) methionine diet, while the control rats were getting 0.8%. So between 0.8% and 1.8% (range likely depends on other amino acid intake), the ability to regulate Hcy was overwhelmed. Supplemental intake of 2.5% glycine or serine (beyond the 1.8% Gly + Ser in the base diet) largely eliminated the Hcy elevation. For supplementation, perhaps 2 or 3:1 supplemental glycine/excess dietary methionine (wt/wt) is a useful target. On the other hand, that Brind study mimicked Met restriction with 8% Gly in a 0.43% Met diet (18:1), and didn't think their 4% Gly diet (9:1) results were worth mentioning in the abstract. 

 

The Met requirement for human adults is 10 mg/kg, and for Met+Cys its 15 mg/kg, according to the WHO. That's just 0.7 g Met and 1 g Met+Cys for a 70 kg adult or somewhere around 0.15% and 0.20% of calories (in a 2000 kcal/d diet), The median methionine + cysteine intake among 90s Americans was about 2.65 grams, or 250% of the requirement. 600 mg NAC (445 g cysteine) might raise that median composite intake by 17%.

 

The lowest percentile of Met+Cys intake was 1.06 g. Ie, less than 1% of 90s Americans were close to methionine restriction (many likely elderly with diminished appetite, or junk food/alcohol addicts). Its nigh impossible to achieve true methionine restriction on a whole foods diet, intakes as low as 1 g Met+Cys heavily rely on fruits, fatty nuts or low-protein staples like taro and yams.

 

Hence my interest in the  (Gly + Ser) / (Met + Cys) ratio. The median intake of glycine in that American survey was only 3 g, and making some statistical assumptions, the median (Gly + Ser) / (Met + Cys) intake ratio would be 2.4 (unsurprising given a grain+animal products diet). A few studies have estimated that endogenous glycine production is ~3 g and requirements for collagen synthesis and other uses (glutathione etc) are 10g, so the median adult could be at a 4 g deficit. Glycine may be restricted in modern diets. See:

 

Meléndez-Hevia, E., de Paz-Lugo, P., Cornish-Bowden, A., & Cárdenas, M. L. (2009). A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesisJournal of biosciences34(6), 853-872.

Wang, W., Wu, Z., Dai, Z., Yang, Y., Wang, J., & Wu, G. (2013). Glycine metabolism in animals and humans: implications for nutrition and healthAmino acids45(3), 463-477.


Edited by Darryl, 28 May 2014 - 01:46 AM.

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#11 LexLux

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Posted 28 May 2014 - 02:08 AM

As a vegan I think my methionine should be quite low, so I may stay with 600mg NAC / day for the time being. I ordered some glycine to try as tea sweetener, thanks for that idea :-).

 

I just read that glycine is also abundant in plant foods:

 

 


Edited by LexLux, 28 May 2014 - 02:09 AM.


#12 Phoenicis

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Posted 28 May 2014 - 05:55 PM

I've just read that glycine stimulates growth hormone (GH) which in turn stimulates IGF-1? What's the point in taking high amounts then?

 

 



#13 Darryl

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Posted 28 May 2014 - 06:49 PM

Ooh. Good find. Here's a recent review which covers 5 studies on glycine and GH

 

Growth Hormone: Amino Acids as GH Secretagogues

 

That certainly presents problems with glycine as a methionine restriction mimetic for longevity.



#14 Phoenicis

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Posted 28 May 2014 - 06:55 PM

I'm bummed, I was getting ready to order it, looks like erythritol is my sweetener. I feel like a shopaholic sometimes... 



#15 Phoenicis

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Posted 28 May 2014 - 07:17 PM

These studies are all indicating increases in GH - 

Unfortunately for me I have been seeing the results of elevated IGF-1 already.  I have psoriasis and angiogenic mediators like IGF-1 and VEGF are needed for karatinocyte hyperproliferation and recruitment of lymphocytes, neutophils and dendric cells [1]. Basically I've been going overboard with NAC, BA, ALCAR, Creatine, Lysine and taurine. I was under the naive impression that these wouldn't raise IGF-1 for some reason and was wondering why psoriasis became active again all of a sudden. I can literally see the effects of IGF-1, because of the enhanced angiogenisis; this is the common pathological component of both psoriasis and cancer. [2] I have to supplement these minimally if at all.

 

 

[1]John Y. M. Koo et al, Mild to Moderate Psoriasis, Third Edition (22 Apr 2014)

[2]Ibid

 


Edited by Phoenicis, 28 May 2014 - 07:27 PM.


#16 APBT

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Posted 29 May 2014 - 09:05 PM

Phoenicis

Do you exercise?  Does this have any negative impact on your psoriasis? I ask, because exercise is known to release GH - particularly high intensity exercise.



#17 LexLux

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Posted 02 June 2014 - 08:14 PM

This is just my humble non-medical research, get independent medical advice if anything - 

 

Upon further investigation, I think the best way to lower IGF-1 signalling even further, if this so desired, would be to consume medium chain triglycerides. These will raise levels of the ketone beta-hydroxybutyrate, which was traditionally thought of as an alternative source of energy for the brain when glucose levels are low, but has recently been found to act as a signalling molecule and an HDAC inhibitor.

 

A mere 30g/d produces a mild ketosis, similar to calorie restriction, one could also reasonably expect similar effects. Aside from more energy and less appetite, these would be -

 

(Ref: John C. Newman, Ketone bodies as signaling metabolites, Trends Endocrinol Metab. 2014 Jan;25(1):42-52. [Be sure to see the full text])

  • lower mTOR activity
  • less IGF-1 signalling
  • more AMPK activity
  • Upregulation of FOXO3
  • more protein acetylation
  • more stress resistance

In Addition 


Edited by LexLux, 02 June 2014 - 08:38 PM.

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#18 blood

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Posted 08 June 2014 - 08:05 AM

I've just read that glycine stimulates growth hormone (GH) which in turn stimulates IGF-1? What's the point in taking high amounts then?


What do you make of findings like these?
 

Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy.

Abstract

OBJECTIVE:
To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages.

METHODS:
Dementia-free Framingham participants from generation 1 (n = 789, age 79 ± 4 years, 64% women) and generation 2 (n = 2,793, age 61 ± 9 years, 55% women; total = 3,582, age 65 ± 11 years, 57% women) had serum IGF-1 measured in 1990-1994 and 1998-2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999-2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE ε4, plasma homocysteine, waist-hip ratio, and physical activity.

RESULTS:
Mean IGF-1 levels were 144 ± 60 μg/L in generation 1 and 114 ± 37 μg/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 ± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14-2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (β/SD increment in IGF-1 was 0.55 ± 0.24, p = 0.025; and 0.26 ± 0.06, p < 0.001, for generations 1 and 2, respectively).

CONCLUSION:
Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.

PMID: 24706014 [PubMed - in process] PMCID: PMC4013812 [Available on 2015/5/6]



The Relationship between Serum Insulin-Like Growth Factor I Levels and Ischemic Stroke Risk

Abstract

Objective

The aim of the study was to assess the relationship between insulin-like growth factor I (IGF-I) serum levels and acute ischemic stroke (AIS) in a Chinese population.

Methods

All consecutive patients with first-ever AIS from August 1, 2011 to July 31, 2013 were recruited to participate in the study. The control group comprised 200 subjects matched for age, gender, and conventional vascular risk factors. IGF-I serum levels were determined by chemiluminescence immunoassay. The National Institutes of Health Stroke Scale (NIHSS) score was assessed on admission blinded to serum IGF-I levels.

Results

The median serum IGF-1 levels were significantly (P = 0.011) lower in AIS patients (129; IQR, 109153 ng/mL) compared with control cases (140; IQR, 125159 ng/mL). We found that an increased risk of AIS was associated with IGF-I levels ≤135 ng/mL (unadjusted OR: 4.17; 95% CI: 2.526.89; P = 0.000). This relationship was confirmed in the dose-response model. In multivariate analysis, there was still an increased risk of AIS associated with IGF-I levels ≤135 ng/mL (OR: 2.16; 95% CI:1.333.52; P = 0.002) after adjusting for possible confounders.

Conclusion

Lower IGF-I levels are significantly related to risk of stroke, independent from other traditional and emerging risk factors, suggesting that they may play a role in the pathogenesis of AIS. Thus, strokes were more likely to occur in patients with low serum IGF-I levels in the Chinese population; further, post-ischemic IGF-I therapy may be beneficial for stroke.



#19 Darryl

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Posted 21 June 2014 - 11:14 PM

A new connection between MR and FGF21:

 

Lees, E. K., Król, E., Grant, L., Shearer, K., Wyse, C., Moncur, E., ... & Delibegovic, M. (2014). Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21Aging Cell.

 

Most studies have examined MR in young animals; therefore, the aim of this study was to investigate the ability of MR to reverse age-induced obesity and insulin resistance in adult animals. Male C57BL/6J mice aged 2 and 12 months old were fed MR (0.172% methionine) or control diet (0.86% methionine) for 8 weeks or 48 h. Food intake and whole-body physiology were assessed and serum/tissues analyzed biochemically. Methionine restriction in 12-month-old mice completely reversed age-induced alterations in body weight, adiposity, physical activity, and glucose tolerance to the levels measured in healthy 2-month-old control-fed mice. This was despite a significant increase in food intake in 12-month-old MR-fed mice. Methionine restriction decreased hepatic lipogenic gene expression and caused a remodeling of lipid metabolism in white adipose tissue, alongside increased insulin-induced phosphorylation of the insulin receptor (IR) and Akt in peripheral tissues. Mice restricted of methionine exhibited increased circulating and hepatic gene expression levels of FGF21, phosphorylation of eIF2a, and expression of ATF4, with a concomitant decrease in IRE1α phosphorylation. Short-term 48-h MR treatment increased hepatic FGF21 expression/secretion and insulin signaling and improved whole-body glucose homeostasis without affecting body weight. Our findings suggest that MR feeding can reverse the negative effects of aging on body mass, adiposity, and insulin resistance through an FGF21 mechanism.

 

 



#20 ikon2

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Posted 06 November 2014 - 08:48 PM

I guess the question ends up being what is the higher net benefit relative to the CR mimetic effect effects of extra glycine as a Met scavenger and parallel rise in IGF versus a non-Met restriction diet, no extra glycine consumption, resulting lower IGF levels but higher Met levels.

 

Any thoughts on what the best route would be?


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#21 Darryl

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Posted 10 March 2015 - 11:14 PM

An interesting connection of methionine restriction to mitochondrial uncoupling, which I somehow missed:

 

Wanders, D., Burk, D. H., Cortez, C. C., Van, N. T., Stone, K. P., Baker, M., ... & Gettys, T. W. (2015). UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivityThe FASEB Journal, fj-14.

 

We propose that the MR-induced increase in EE limits fat deposition by increasing sympathetic nervous system–dependent remodeling of white adipose tissue and increasing uncoupling protein 1 (UCP1) expression in both white and brown adipose tissue. In independent assessments of the role of UCP1 as a mediator of MR’s effects on EE and insulin sensitivity, EE did not differ between wild-type (WT) and Ucp1−/− mice on the control diet, but MR increased EE by 31% and reduced adiposity by 25% in WT mice. In contrast, MR failed to increase EE or reduce adiposity in Ucp1−/− mice. However, MR was able to increase overall insulin sensitivity by 2.2-fold in both genotypes. Housing temperatures used to minimize (28°C) or increase (23°C) sympathetic nervous system activity revealed temperature-independent effects of the diet on EE. Metabolomics analysis showed that genotypic and dietary effects on white adipose tissue remodeling resulted in profound increases in fatty acid metabolism within this tissue. These findings establish that UCP1 is required for the MR-induced increase in EE but not insulin sensitivity and suggest that diet-induced improvements in insulin sensitivity are not strictly derived from dietary effects on energy balance.

 

This lab's earlier study:

 

Hasek, B. E., Stewart, L. K., Henagan, T. M., Boudreau, A., Lenard, N. R., Black, C., ... & Gettys, T. W. (2010). Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted statesAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology299(3), R728-R739.

 

In Fischer 344 (F344) rats consuming control or MR diets for 3, 9, and 20 mo, mean energy expenditure (EE) was 1.5-fold higher in MR vs. control rats, primarily due to higher EE during the night at all ages. The day-to-night transition produced a twofold higher heat increment of feeding (3.0°C vs. 1.5°C) in MR vs. controls and an exaggerated increase in respiratory quotient (RQ) to values greater than 1, indicative of the interconversion of glucose to lipid by de novo lipogenesis. The simultaneous inhibition of glucose utilization and shift to fat oxidation during the day was also more complete in MR (RQ ∼0.75) vs. controls (RQ ∼0.85). Dietary MR produced a rapid and persistent increase in uncoupling protein 1 expression in brown (BAT) and white adipose tissue (WAT) in conjunction with decreased leptin and increased adiponectin levels in serum, suggesting that remodeling of the metabolic and endocrine function of adipose tissue may have an important role in the overall increase in EE.

 

Induction of uncoupling proteins by MR would certainly account for the reduced mitochondrial ROS generation and oxidative damage to DNA/proteins. And its certainly safer than dinitrophenol. See section 6.1:

 

Gruber, J., Fong, S., Chen, C. B., Yoong, S., Pastorin, G., Schaffer, S., ... & Halliwell, B. (2013). Mitochondria-targeted antioxidants and metabolic modulators as pharmacological interventions to slow ageingBiotechnology advances31(5), 563-592.



#22 Darryl

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Posted 12 April 2016 - 01:24 AM

Turns out MR probably helps with gut permeability to endotoxins (one of my other recent fascinations).

 

Mullin JM et al. 2015. Methionine restriction fundamentally supports health by tightening epithelial barriersAnnals of the New York Academy of Sciences.

MR has been found to modify the protein composition of tight junctional complexes surrounding individual epithelial cells in a manner that renders the complexes less leaky. This has been observed in both a renal epithelial cell culture model and in gastrointestinal tissue. In both cases, MR increased the transepithelial electrical resistance across the epithelium, while decreasing passive leak of small nonelectrolytes

Edited by Darryl, 12 April 2016 - 01:27 AM.


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#23 Darryl

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Posted 30 June 2018 - 07:56 PM

A new mouse survival study, which focuses on the renal effects of dietary restriction, dietary restriction with 9 essential amino acids, and dietary restriction with 8 essential amino acids (excluding methionine):

 

Yoshida, et al, 2018. Role of dietary amino acid balance in diet restriction‐mediated lifespan extension, renoprotection, and muscle weakness in aged miceAging Cell, p.e12796.

 

This study was designed to identify a dietary method of extending lifespan, promoting renoprotection, and preventing muscle weakness in aged mice, with a focus on the importance of the balance between dietary essential (EAAs) and nonessential amino acids (NEAAs) on the dietary restriction (DR)-induced antiaging effect. Groups of aged mice were fed ad libitum, a simple DR, or a DR with recovering NEAAs or EAAs. Simple DR significantly extended lifespan and ameliorated age-related kidney injury; however, the beneficial effects of DR were canceled by recovering dietary EAA but not NEAA. Simple DR prevented the age-dependent decrease in slow-twitch muscle fiber function but reduced absolute fast-twitch muscle fiber function. DR-induced fast-twitch muscle fiber dysfunction was improved by recovering either dietary NEAAs or EAAs. In the ad libitum-fed and the DR plus EAA groups, the renal content of methionine, an EAA, was significantly higher, accompanied by lower renal production of hydrogen sulfide (H2S), an endogenous antioxidant. Finally, removal of methionine from the dietary EAA supplement diminished the adverse effects of dietary EAA on lifespan and kidney injury in the diet-restricted aged mice, which were accompanied by a recovery in H2S production capacity and lower oxidative stress.

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