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Dietary Inhibition of mTOR Signaling


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#1 Michael

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Posted 03 January 2010 - 05:17 PM


All:

On the CR list, Al Pater recently pointed to (1), an useful review on metabolic pathways modulated by -- and possibly involved in the anti-aging, life-extending effects of -- CR. One central focus of the paper is the mTOR pathway. There is now a great deal of converging evidence (as is dug into in much more detail in (2) (also available full-text thanks to Al)) that inhibiting mTOR plays a significant role in CR's anti-aging life extension effects -- most recently including the breakthrough report of robust life extension in mice using the rapamycin, an mTOR-inhibiting drug (3). This suggests that lowering leucine intake may enhance this mechanism of CR's effects.

Along with Calories and insulin signaling, a key regulator of mTOR is the branched-chain amino acid leucine, and there are now many reports (eg. (11-19)) that intake of either isolated leucine, or whey protein (which is unusually enriched in this and other BCAAs), enhances mTOR signaling relative to other aminos or proteins in rats and humans alike. This, in fact, is the basis for a lot of whey's popularity with bodybuilders: by activating mTOR, leucine (and to a lesser extent other branched-chain aminos) inhibits autophagic catabolism of muscle, leading to higher net muscle protein.

Of course, that same enhanced signaling inhibits the recycling of defective and damaged proteins, which is likely one of the core reasons that CR and other modes of mTOR inhibition retard aging.

Leucine is ubiquitous in protein, so one straightforward way to lower your leucine intake is to just cut your protein intake. Alternatively/additionally, because the amount of leucine per unit protein does vary quite a bit from food to food (whey protein being exceptionally high, as its vendors will enthusiastically remind you), you can look for foods low in leucine per unit protein with Nutritiondata.com's nutrient search tool.

A couple of gems from my own digging for relatively protein-rich foods low in leucine AND methionine: lentils and fava beans. A simple and tasty-sounding recipe I found for the latter:

Fool Medames (Egyptian Beans)
1 lb Dried sm. fava or pink beans
Lightly salted water
1/2 c Red lentils
3 tb Lemon juice
1/4 c Olive oil
1/2 ts Cumin, ground
Salt and pepper to taste
1/2 c Green onions, chopped

Sort and rinse dried beans. Place in a large saucepan and add lightly salted water to cover. Bring to a boil. Reduce heat and cover. Simmer over low heat 2 1/2 hours. If necessary, add more water to keep beans covered. Add lentils and cover. Simmer 30 minutes longer or until lentils and beans are tender and mixture is thick but not soupy. Stir in lemon juice, olive oil, cumin, salt and freshly ground pepper. Serve hot, sprinkling each serving with a portion of green onions.


The same site has many other fava bean recipes, and indeed recipes for a variety of legumes.

FWIW, replacing casein with lactalbumin (~70% of the protein in whey) in AL diets doesn't seem to affect longevity in F344 rats, whereas using soy is clearly better for them (4,5); however, this may not mean much, as F344s are somewhat weird animals to work with because of their high vulnerability to nephropathy, which soy protein significantly alleviates. Lactalbumin has inconsistent (depending especially on gender) but generally favorable effects compared with commercial diets in hamsters (6,7); and it was reported to extend longevity when substituted for casein late in life in mice (8), possibly due to the presence of precursors of glutathione, during the time when age-related oxidative stress has begun to set in and recycling of GSH becomes impaired.

-Michael

1. Metabolic reprogramming, caloric restriction and aging. Anderson RM, Weindruch R. Trends Endocrinol Metab. [Epub ahead of print] PMID: 20004110

2. The TOR pathway comes of age. Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK. Biochim Biophys Acta. 2009 Jun 15. [Epub ahead of print] PMID: 19539012

3. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009 Jul 16;460(7253):392-5. Epub 2009 Jul 8. PubMed PMID: 19587680; PubMed Central PMCID: PMC2786175.

4. Shimokawa I, Higami Y, Yu BP, Masoro EJ, Ikeda T. Influence of dietary components on occurrence of and mortality due to neoplasms in male F344 rats. Aging (Milano). 1996 Aug;8(4):254-62. PubMed PMID: 8904955.

5. Shimokawa I, Higami Y, Hubbard GB, McMahan CA, Masoro EJ, Yu BP. Diet and the suitability of the male Fischer 344 rat as a model for aging research. J Gerontol. 1993 Jan;48(1):B27-32. PubMed PMID: 8418135.

6. Birt DF, Schuldt GH, Salmasi S. Survival of hamsters fed graded levels of two protein sources. Lab Anim Sci. 1982 Aug;32(4):363-6. PubMed PMID: 7144109.

5. Birt DF, Baker PY, Hruza DS. Nutritional evaluations of three dietary levels of lactalbumin throughout the lifespan of two generations of Syrian hamsters. J Nutr. 1982 Nov;112(11):2151-60. PubMed PMID: 7131092.

8. Bounous G, Gervais F, Amer V, Batist G, Gold P. The influence of dietary whey protein on tissue glutathione and the diseases of aging. Clin Invest Med. 1989 Dec;12(6):343-9. PubMed PMID: 2692897.

11: Drummond MJ, Rasmussen BB. Leucine-enriched nutrients and the regulation of mammalian target of rapamycin signalling and human skeletal muscle protein synthesis. Curr Opin Clin Nutr Metab Care. 2008 May;11(3):222-6. Review. PubMed PMID: 18403916.

12: Dreyer HC, Drummond MJ, Pennings B, Fujita S, Glynn EL, Chinkes DL, Dhanani S, Volpi E, Rasmussen BB. Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle. Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E392-400. Epub 2007 Dec 4. PubMed PMID: 18056791; PubMed Central PMCID: PMC2706121.

13: Stipanuk MH. Leucine and protein synthesis: mTOR and beyond. Nutr Rev. 2007 Mar;65(3):122-9. Review. PubMed PMID: 17425063.

14: Norton LE, Layman DK. Leucine regulates translation initiation of protein synthesis in skeletal muscle after exercise. J Nutr. 2006 Feb;136(2):533S-537S. PubMed PMID: 16424142.

15: Norton LE, Layman DK, Bunpo P, Anthony TG, Brana DV, Garlick PJ. The leucine content of a complete meal directs peak activation but not duration of skeletal muscle protein synthesis and mammalian target of rapamycin signaling in rats. J Nutr. 2009 Jun;139(6):1103-9. Epub 2009 Apr 29. PubMed PMID: 19403715.

16: Hulmi JJ, Tannerstedt J, Selänne H, Kainulainen H, Kovanen V, Mero AA. Resistance exercise with whey protein ingestion affects mTOR signaling pathway and myostatin in men. J Appl Physiol. 2009 May;106(5):1720-9. Epub 2009 Mar 19. PubMed PMID: 19299575.

17: Anthony TG, McDaniel BJ, Knoll P, Bunpo P, Paul GL, McNurlan MA. Feeding meals containing soy or whey protein after exercise stimulates protein synthesis and translation initiation in the skeletal muscle of male rats. J Nutr. 2007 Feb;137(2):357-62. PubMed PMID: 17237311.

18: Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ. Hypothalamic mTOR signaling regulates food intake. Science. 2006 May 12;312(5775):927-30. PubMed PMID: 16690869.

19: Wu P, Jiang C, Shen Q, Hu Y. Systematic gene expression profile of hypothalamus in calorie-restricted mice implicates the involvement of mTOR signaling in neuroprotective activity. Mech Ageing Dev. 2009 Sep;130(9):602-10. Epub 2009 Jul 30. PubMed PMID: 19647013.
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#2 Sillewater

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Posted 03 January 2010 - 05:44 PM

Thanks for the recipe. I have been wanting to introduce ways of eating more lentils. Something that is also tasty is idlis.

I'll definitely be watching my leucine intake from now on. By restricting leucine you might also get rid of more fat:

Leucine deprivation decreases fat mass by stimulation of lipolysis in WAT and upregulation of UCP1 in BAT.

Cheng Y, Meng Q, Wang C, Li H, Huang Z, Chen S, Xiao F, Guo F.

Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, the Graduate School of the Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai, China 200031.

Objective- White adipose tissue (WAT) and brown adipose tissue (BAT) play distinct roles in adaptation to changes in nutrient availability, with WAT serving as an energy store and BAT regulating thermogenesis. We previously showed that mice maintained on a leucine-deficient diet unexpectedly experienced a dramatic reduction in abdominal fat mass (1). The cellular mechanisms responsible for this loss, however, are unclear. The goal of current study is to investigate possible mechanisms. Research design and methods- Male C57BL/6J mice were fed either control, leucine-deficient, or pair-fed diets for 7 days. Changes in metabolic parameters and expression of genes and proteins related to lipid metabolism were analyzed in WAT and BAT. Results- We found that leucine deprivation for 7 days increases oxygen consumption, suggesting increased energy expenditure. We also observed increases in lipolysis and expression of beta-oxidation genes, and decreases in expression of lipogenic genes and activity of fatty acid synthase (FAS) in WAT, consistent with increased utilization and decreased synthesis of fatty acids, respectively. Furthermore, we observed that leucine deprivation increases expression of uncoupling protein (UCP)1 in BAT, suggesting increased thermogenesis. Conclusions- We show for the first time that elimination of dietary leucine produces significant metabolic changes in WAT and BAT. The effect of leucine deprivation on UCP1 expression is a novel and unexpected observation and suggests that the observed increase in energy expenditure may reflect an increase in thermogenesis in BAT. Further investigation will be required to determine the relative contribution of UCP1 upregulation and thermogenesis in BAT to leucine deprivation-stimulated fat loss.


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#3 JLL

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Posted 03 January 2010 - 06:48 PM

This, in fact, is the basis for a lot of whey's popularity with bodybuilders: by activating mTOR, leucine (and to a lesser extent other branched-chain aminos) inhibits autophagic catabolism of muscle, leading to higher net muscle protein.

Of course, that same enhanced signaling inhibits the recycling of defective and damaged proteins, which is likely one of the core reasons that CR and other modes of mTOR inhibition retard aging.


What I don't understand is that intermittent fasting induces autophagy but does not increase lifespan.
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#4 prophets

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Posted 03 January 2010 - 08:16 PM

doesn't activating AMPK inhibit mTOR. wouldn't taking resveratrol/AICAR/metformin (or exercising) inhibit the effects of whey, and down regulate mTOR?

i know its probably a silly way of going about it, but im just curious if i have the biology right.

Edited by prophets, 03 January 2010 - 08:17 PM.

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#5 Taurus Londoño

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Posted 01 March 2010 - 06:48 PM

Hmmm....well, this is an interesting development I'd not fully appreciated before.

I have generally restricted protein across the board (though not drastically) which would seem prudent as far as MET is concerned, but I'd been big on Whey powder. I'm guessing whatever additional restriction of LEU I might have otherwise had was essentially thrown into the garbage by my consistent Whey consumption.

I was really keen on Glutathione, but it looks like I might be the end of my relationship with Whey. :(

Luckily, I'm a bean lover!
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#6 oehaut

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Posted 01 March 2010 - 08:43 PM

I'm starting to feel like, from a longevity standpoint, soon there will not be much left to eat :) We're left with what now, bean, vegetables and nuts? There seem to be something wrong with about any food except maybe these.

There's no way I can go on a low-protein diet.

Is there still benefits from CR even if you're not low protein?

Edited by oehaut, 01 March 2010 - 08:45 PM.

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#7 niner

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Posted 02 March 2010 - 01:19 AM

I'm starting to feel like, from a longevity standpoint, soon there will not be much left to eat :) We're left with what now, bean, vegetables and nuts? There seem to be something wrong with about any food except maybe these.

There's no way I can go on a low-protein diet.

It's easy, oehaut; just follow nightlight's nutritional advice. Replace the missing protein with cigarettes. (Smoked, of course; not eaten.)
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#8 Super K

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Posted 02 March 2010 - 01:29 AM

It's easy, oehaut; just follow nightlight's nutritional advice. Replace the missing protein with cigarettes. (Smoked, of course; not eaten.)


I take it nightlight didn't quite manage to convince you.
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#9 Forever21

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Posted 21 May 2011 - 01:43 AM

That's one thing longest living people have in common. Legumes.

Posted Image

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#10 Sillewater

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Posted 21 May 2011 - 03:33 AM

Well comparing these populations based on their varied dietary habits probably isn't very useful. First is that populations like the Okinawans and Sardinians went through extensive poverty in World War II. For e.g. in Greece when the Nazi's took over and kept all the good food for themselves, the Greeks were left with the plants (thus their diet today). The Sardinians may also have a strong genetic component to their longevity (isolated environment).

The Seventh Day Adventist just live healthy lives in general (selection for those who can follow the rules?). In the end what I observe is that centenarians are smaller in stature.

Of course the other factors in your figure are great for health.
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#11 yoyo

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Posted 21 May 2011 - 05:33 AM

I'm not quite sure what you are saying there. Those with 'thrifty gene' should have survived exploitive incursions that took their caloric foods.

I do agree legumes are good for a daily food. Making some black mungs right now.

Edited by yoyo, 21 May 2011 - 05:39 AM.

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#12 Michael

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Posted 22 May 2011 - 01:27 PM

Well comparing these populations based on their varied dietary habits probably isn't very useful. First is that populations like the Okinawans and Sardinians went through extensive poverty in World War II. For e.g. in Greece when the Nazi's took over and kept all the good food for themselves, the Greeks were left with the plants (thus their diet today).

In fact, the Okies' environmentally-imposed CR long predated and postdated WWII and only ended in the '60s -- and while I don't actually know whether the Nazis did indeed significantly alter the Sardinians' diets during WWII, that clearly doesn't explain their very distinctive diets from the end of WWII to the present. But even if we take that premise for the sake of argument, and stipulating that I agree that cross-cultural comparisons are always fraught, the fact that the Okies' and Sardinians' diets were constrained by environmental conditions isn't really an objection. If you want to study the effects of individuals' or populations' diets on their health, reasons for the diet aren't the issue (except as confounders): the fact of the diet is the issue. (And, ) After all, CR animals don't exactly have self-selected diets, either ;) .

I'm not quite sure what you are saying there. Those with 'thrifty gene' should have survived exploitive incursions that took their caloric foods.

Er ... sure. Sorry, but (and I'm not being snarky -- I'm asking seriously) what's your point, here?
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#13 yoyo

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Posted 22 May 2011 - 06:43 PM

Hm, i'm not sure, really. just thinking aloud. But people who survived on calorie restricted war rations might do better on calorie restriction post-war than people who died when calories were restricted. I think death from starvation was fairly prominent. But, people with a handy supply of adipose tissue would also be better at surviving.
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#14 Sillewater

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Posted 22 May 2011 - 06:47 PM

In fact, the Okies' environmentally-imposed CR long predated and postdated WWII and only ended in the '60s -- and while I don't actually know whether the Nazis did indeed significantly alter the Sardinians' diets during WWII, that clearly doesn't explain their very distinctive diets from the end of WWII to the present. But even if we take that premise for the sake of argument, and stipulating that I agree that cross-cultural comparisons are always fraught, the fact that the Okies' and Sardinians' diets were constrained by environmental conditions isn't really an objection. If you want to study the effects of individuals' or populations' diets on their health, reasons for the diet aren't the issue (except as confounders): the fact of the diet is the issue. (And, ) After all, CR animals don't exactly have self-selected diets, either ;) .


That's true.



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#15 Logan

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Posted 06 July 2011 - 03:08 AM

because the amount of leucine per unit protein does vary quite a bit from food to food..., you can look for foods low in leucine per unit protein with Nutritiondata.com's nutrient search tool.

A couple of gems from my own digging for relatively protein-rich foods low in leucine AND methionine: lentils and fava beans. ... and indeed recipes for a variety of legumes.


Lentils and other legumes make me feel like shit for some reason. I like them, they just make me feel bad.

Edited by Michael, 26 September 2011 - 06:32 PM.

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