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Amino Acid Supplement Makes Mice Live Longer


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#1 resveratrol

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Posted 05 October 2010 - 08:30 PM


From http://www.scienceda...01005121710.htm:


Amino Acid Supplement Makes Mice Live Longer


ScienceDaily (Oct. 5, 2010) — When mice are given drinking water laced with a special concoction of amino acids, they live longer than your average mouse, according to a new report in the October issue of Cell Metabolism, a Cell Press publication. The key ingredients in the supplemental mixture are so-called branched-chain amino acids, which account for 3 of the 20 amino acids (specifically leucine, isoleucine, and valine) that are the building blocks of proteins.

"This is the first demonstration that an amino acid mixture can increase survival in mice," said Enzo Nisoli of Milan University in Italy, noting that researchers last year showed that leucine, isoleucine, and valine extend the life span of single-celled yeast.

In the new study, the researchers gave middle-aged, male mice extra branched-chain amino acids (BCAA) in their drinking water. The animals were otherwise healthy and eating standard mouse chow.

Animals that were given the extra amino acids over a period of months lived longer, with a median life span of 869 days compared to 774 days for untreated control animals, the researchers report. That's an increase of 12 percent.

Those survival gains were accompanied by an increase in mitochondria in cardiac and skeletal muscles. Mitochondria are the cellular components responsible for powering cells. The supplement-fed mice also showed increased activity of SIRT1, a well-known longevity gene, and of the defense system that combats free radicals. They therefore showed fewer signs of oxidative damage.

The benefits of the amino acid supplements appear similar to those earlier ascribed to calorie restriction, Nisoli said.

Treated animals also showed improvements in their exercise endurance and in motor coordination, the researchers report. (It is important to note that the animals in the current study were all male, Nisoli said. They plan to test the effects in females in future studies.)

The findings in older mice suggest that the supplementary mixture may be specifically beneficial for those who are elderly or ill. "It may not be useful in young people or body builders," who are already in good condition, he said. But it might be a useful preventive strategy, he added, emphasizing that the mice they studied "were just aged, not sick."

Nisoli emphasized that consuming amino acid supplements is different from consuming proteins containing those amino acids. That's because they do not have to be digested, and can enter the bloodstream immediately. "They come with no energy cost."

He suspects that BCAA nutritional supplements may prove to be particularly helpful for people with heart failure, the muscle-wasting condition known as sarcopenia, chronic obstructive pulmonary disease, or other conditions characterized by energy defects. In fact, there are already some small studies in human to support that idea and BCAA supplements are already available for purchase in several countries, including Italy.

The challenge, Nisoli says, will be convincing clinicians that these supplements might be a benefit to their patients. He says a large clinical trial is needed, but there is little incentive for companies to do such trials for dietary supplements as opposed to drugs.

Overall, Nisoli said the new work supports a "general philosophy of a nutritional approach to disease, aging, and problems of energy status."

The researchers include Giuseppe D'Antona, Pavia University, Pavia, Italy; Maurizio Ragni, Milan University, Milan, Italy; Annalisa Cardile, Milan University, Milan, Italy; Laura Tedesco, Milan University, Milan, Italy, Brescia University, Brescia, Italy; Marta Dossena, Milan University, Milan, Italy, Brescia University, Brescia, Italy; Flavia Bruttini, Pavia University, Pavia, Italy; Francesca Caliaro, Pavia University, Pavia, Italy; Giovanni Corsetti, Brescia University, Brescia, Italy; Roberto Bottinelli, Pavia University, Pavia, Italy; Michele O. Carruba, Milan University, Milan, Italy, Brescia University, Brescia, Italy; Alessandra Valerio, Milan University, Milan, Italy, Brescia University, Brescia, Italy; and Enzo Nisoli, Milan University, Milan, Italy, Brescia University, Brescia, Italy.


This is good news; BCAA supplements are easily available and often used by weightlifters.

#2 PWAIN

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Posted 05 October 2010 - 11:44 PM

The paper can be found here:

http://www.cell.com/...00304-9#Summary

If you look in the Supp Info section ( http://www.cell.com/...0304-9#suppinfo ) (download the pdf) you find a table with the percentages of each AA that was used. I'll skip the ones where it is not indicated (suggesting 0%).

L-Cysteine 3.8%
L-Histidine 3.8%
L-Isoleucine 15.6%
L-Leucine 31.3%
L-Lysine 16.2%
L-Methionine 1.3%
L-Phenylalanine 2.5%
L-Threonine 8.8%
L-Tryptophan 0.5%
L-Tyrosine 0.7%
L-Valine 15.6%

Shouldn't be too hard to get a batch made up to match this. Sure if asked, trueprotein.com would do it.

Average lifespan increase may not be the main gaol but it is certainly a step in the right direction.

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#3 malbecman

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Posted 05 October 2010 - 11:47 PM

I have the paper. Mixture #3 looked best in vitro cardiomyocytes in terms of activating mitochondrial biogenesis. Mixture #3 was ~15% ILE, ~30% LEU and ~15% VAL for the BCAAs...


Looks like resvhead beat me to it!!!! ;-)

Edited by malbecman, 05 October 2010 - 11:48 PM.


#4 e Volution

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Posted 06 October 2010 - 12:25 AM

BCAAs don't get much attention on ImmInst but they seem to be talked about a lot in all the sites/forums I frequent that have more of a performance over longevity bias. Art de Vany loves them...

edit: I don't get it BCAAs give LE, and at the same time protein/calorie restriction gives LE. Just as I thought protein was looking like the bad guy...

Edited by e Volution, 06 October 2010 - 12:28 AM.


#5 maxwatt

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Posted 06 October 2010 - 01:07 AM

I think an equally valid interpretation could be that the amino acid supplementation was making up for something lacking in the basic regimen of the controls. I don't know the strain of mouse used, but I think both groups of mice had lifespans considerably shorter than the control groups in other studies. Two and a half years is a typical mouse lifespan. Bad lab conditions? Poor chow? Or am I overly skeptical?

#6 niner

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Posted 06 October 2010 - 02:32 AM

I think an equally valid interpretation could be that the amino acid supplementation was making up for something lacking in the basic regimen of the controls. I don't know the strain of mouse used, but I think both groups of mice had lifespans considerably shorter than the control groups in other studies. Two and a half years is a typical mouse lifespan. Bad lab conditions? Poor chow? Or am I overly skeptical?

One always has to consider the 'making up for bad husbandry' angle, but then again, how many of us are living under conditions of optimal husbandry? Both control and treatment animals had free access to a diet that was 20 kcal% protein, so unless the chow was defective, I'm not sure what an AA mixture would have added. It wasn't just BCAAs, either. The protein supplement was enriched in BCAAs, but it had a significant amount of lys and thr, too. Incidentally, threonine was one of the components of that new supplement that was based on gene expression analysis in Methuselah flies.

In the experimental section of this paper, they said that they fed the animals 1.5mg protein mixture/g body weight in their drinking water. I presume that was calculated such that the mice actually consumed that amount of the protein mixture, and it wasn't mostly getting poured out at the end of each day. That's a lot of protein- 105g/d for a 70kg man, on top of the 20% in their regular diet. Since we're talking about macronutrients, this might be a case where the interspecies scaling rules really should be applied, in which case it might be substantially less added protein for a human.

The application to sarcopenia has me thinking about BCAAs for my elderly father in law. The mitochondrial biogenesis piques my interest as well.

#7 e Volution

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Posted 06 October 2010 - 02:52 AM

The application to sarcopenia has me thinking about BCAAs for my elderly father in law. The mitochondrial biogenesis piques my interest as well.

What about the LE at best harmless at worst angle? Or you got enough supps that fit that description already? ;)

#8 niner

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Posted 06 October 2010 - 03:20 AM

The application to sarcopenia has me thinking about BCAAs for my elderly father in law. The mitochondrial biogenesis piques my interest as well.

What about the LE at best harmless at worst angle? Or you got enough supps that fit that description already? ;)

Ha ha. I have a lot of LE at best, but no harmless at worst... The intellectual whiplash of "protein is evil, no, protein is good" is kind of annoying. I wish they didn't use so damn many AAs in their mixture. I suppose maybe you can raise certain AAs, and as long as certain other essential AAs are low you'll still get the increased autophagy of a generalized protein restriction. Could that be it?

#9 maxwatt

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Posted 06 October 2010 - 04:42 AM

I think an equally valid interpretation could be that the amino acid supplementation was making up for something lacking in the basic regimen of the controls. I don't know the strain of mouse used, but I think both groups of mice had lifespans considerably shorter than the control groups in other studies. Two and a half years is a typical mouse lifespan. Bad lab conditions? Poor chow? Or am I overly skeptical?

One always has to consider the 'making up for bad husbandry' angle, but then again, how many of us are living under conditions of optimal husbandry? Both control and treatment animals had free access to a diet that was 20 kcal% protein, so unless the chow was defective, I'm not sure what an AA mixture would have added. It wasn't just BCAAs, either. The protein supplement was enriched in BCAAs, but it had a significant amount of lys and thr, too. Incidentally, threonine was one of the components of that new supplement that was based on gene expression analysis in Methuselah flies.

In the experimental section of this paper, they said that they fed the animals 1.5mg protein mixture/g body weight in their drinking water. I presume that was calculated such that the mice actually consumed that amount of the protein mixture, and it wasn't mostly getting poured out at the end of each day. That's a lot of protein- 105g/d for a 70kg man, on top of the 20% in their regular diet. Since we're talking about macronutrients, this might be a case where the interspecies scaling rules really should be applied, in which case it might be substantially less added protein for a human.

The application to sarcopenia has me thinking about BCAAs for my elderly father in law. The mitochondrial biogenesis piques my interest as well.

The strains of mouse used were different than the strain (C57BL) I based my earlier remark on, implying bad husbandry. I take it back.

The mice were getting 1% of daily caloric intake from BCAA protein mixture, which would correspond to about 20 calories on a 2000 calorie diet in a human, or 5 grams o protein powder. I am suggesting that a scaling factor might not be appropriate here, There are some BCAA rich protein mixes, sport supplements, that might approximate the ratios used in the study, something to look into.

#10 malbecman

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Posted 06 October 2010 - 03:48 PM

I find the study intriguing. The overall rationale was to see if effects noted in yeast could also be seen in a mammalian species and it appears to be the case.
In the discussion, they also note some other positive effects of BCAAs in humans:

"The BCAAem, besides increasing average life span in normally fed mice, was found to promote several healthy effects in humans, since it reduced sarcopenia
(Solerte et al., 2008b) and decreased inflammatory markers in chronic heart failure patients (Kalantar-Zadeh et al., 2008).


So I certainly think they (BCAAs) are something to keep an eye on...........

#11 AgeVivo

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Posted 06 October 2010 - 08:58 PM

Interesting, somewhat confusing with the idea the methionine and cysteine restriction increase lifespan, but why not. This indicates how much more we could gain simply by tseting many different types of food to optimize nutrition.

If you have read the article in details, what is the degree of confidence you would give to this life extension? (no crypto-CR, sufficient number of mice, not-too-short-lived controls)

#12 SloMoSandy

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Posted 06 October 2010 - 09:04 PM

I'm not sure. They stated that young people OR bodybuilders (somewhy) may not need this as "they are already in a good shape", but for older people, kind of an additional prevention. Tho' the mt-oxidation pops again. It seems that some kind of these, in development, mt-antioxidants may really hold some potential.

Talking about the screening of various compunds, Genescient (a corporation of M.Rose) is doing exactly that and some of the results or even a product may be released in a near future.

Edited by VidX, 06 October 2010 - 09:05 PM.


#13 SloMoSandy

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Posted 07 October 2010 - 01:32 AM

I was just about to buy BCAA complex, but now I'm glad I haven't, YET, as the one I wanted to - has just a part of the mentioned a-acids (and I've found another one which has most of these). Though it'd be nice to calculate the real analogue amount for a human, by bodyweight (even if just out of curiosity, to compare it with the ones written on the label).

#14 niner

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Posted 07 October 2010 - 02:27 AM

I was just about to buy BCAA complex, but now I'm glad I haven't, YET, as the one I wanted to - has just a part of the mentioned a-acids (and I've found another one which has most of these). Though it'd be nice to calculate the real analogue amount for a human, by bodyweight (even if just out of curiosity, to compare it with the ones written on the label).

NOW Foods BCAAs are at least in the same proportion as used in this study, but all the other AAs are missing. I suspect that the only ones that might matter, aside from the BCAAs, are Lys and Thr. Those could be supplemented separately. The fact that Genescient's supplement has Threonine is making me not want to discount it here.

#15 Decimus

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Posted 07 October 2010 - 11:08 PM

So who is going to try this? Any ideas about dosing?

#16 maxwatt

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Posted 08 October 2010 - 01:29 AM

As pointed out earlier, The mice were getting 1% of daily caloric intake from BCAA protein mixture, which would correspond to about 20 calories on a 2000 calorie diet in a human. This would be 5 grams of protein powder. I do not think we need to scale as we usually do for supplements. This is not a xenobiotic, it's basically food. Absent any other factors, percent calories should be percent calories. It's already scaled for body mass.

The protein mix contained these critical BCAAs:
L-Isoleucine 15.6%
L-Leucine 31.3%
L-Valine 15.6%

The ratio of each amino is the same in the BCAA supplements. Total pct is 63.8 of the 5 grams, or 3.14 grams of BCAA supplement. IF as niner suggested, the other aminos aren't critical to the effect, then about 3 grams BCAA powder should do the trick. If you want to be on the safe side (again as niner suggested), add the following:

L-Lysine 16.2% = .8 grams
L-Threonine 8.8% = .44 grams

I do not think great precision is needed for these, just a good approximation. On the other hand, I think most of us are getting sufficient protein that only the BCAAs will be needed.

Body builders and weight lifters have been supplementing with this mix of BCAAs for at least a decade. It might also be helpful with sarcopenia in the elderly, or with the muscle deterioration that goes with a more or less sedentary lifestyle. Athletes use BCAAs to replenish muscle wasted after intense exercise. It may benefit most people who use it, OR it might be another useless nostrum. Any opinions? Anyone want to try it? And what kind of baseline measurement could be used to tell if it's having an effect?

#17 rubegoldberg

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Posted 08 October 2010 - 02:15 AM

VPX power shock appears to have most of the BCAAs mentioned but they do no disclose the ratios of their "proprietary" formula.
I'd think it's a fair assumption that the L-Isoleucine - L-Leucine - L-Valine ratio is 1-2-1 since virtually every BCAA sup I looked at in the local vitamin shoppe had the same ratio.

8,000 mg
Proprietary Essential Amino Acid Blend
L-Leucine
L-Lysine
L-Phenylalanine
L-threonine
L-Isoleucine
L-Valine
L-Histidine
L-Methionine

3,000 mg
Proprietary Designer Amino Acid Blend
L-Leucine Nitrate
L-Valine Nitrate
L-Isoleucine Nitrate
Beta-Alanine
L-Citrulline Malate
Anserine (beta-alanyl-1methylhistidine)
L-Citrulline Nitrate
Beta-Alanine Nitrate

here's their marketing spiel...

Behold the all NEW Power Shock™ -- powered by the world’s most cutting edge anabolic discovery of all time called BCAA Nitrates! You heard it right! VPX has engineered Branched Chain Amino Acids fused to a nitrate moiety! This provides for far greater BCAA stability and transport across intestinal and muscle cell membranes. An exciting property of nitrates is their capability to act as permeation enhancers of intestinal absorption. Consequently, nitrate bound compounds effortlessly bypass the intestinal wall to be absorbed intact into the bloodstream.(1, 2) In fact, they are so effective that large polypeptides can even be absorbed intact if administered with a nitrate donor. This also greatly improves the absorption of all the ingredients like BCAA Nitrates and Beta-Alanine Nitrate in the Power Shock formula.(3) The nitrate bound amino acids innovation is a novel science far superior to free form amino acids and even other chemical salts. One of the premier advantages of nitrates is rapid and potent vasodilation. This results in increased blood flow to radically enhance the distribution of nutrients to the muscles and other tissues. Myogenic Regulatory Factors are activated when the muscle is engorged with anabolic nutrient-dense blood. Further, stamina, strength and recovery are enhanced.(4) While recent research has verified that arginine supplementation fails to increase blood Nitric Oxide levels, nitrates are scientifically proven to induce vasodilation via Nitric Oxide. Nitrates increase blood Nitric Oxide levels by exerting their vasodilating effect by releasing an NO2 or NO3 group. NO3 is reduced to NO2 in the blood vessels’ epithelial cells where it reacts to yield Nitric Oxide.

While highly significant, BCAAs are just part of the Power Shock muscle cell splitting matrix. Scientific research has proven that EAAs (essential amino acids) are the key anabolic activators for muscle protein synthesis and are far superior to BCAAs alone.(5) Moreover, science has proven that adding non-essential amino acids such as glutamine does nothing to promote muscle mass in healthy, well-nourished humans.(6) Despite the promise of higher nitric oxide levels, six grams per day of arginine supplementation had no effect on nitric oxide production, lactate and ammonia metabolism and performance in intermittent anaerobic exercise in well-trained male athletes.(7) So, if you see glutamine or arginine on the label, you’re wasting your money. To further fuel lean muscle mass Power Shock contains Owoc’s latest mind blowing muscle compounds: Anserine or Beta-Alanyl-1-Methylhistidine along with Beta-Alanine Nitrate and Citrulline Nitrate.

•Powered by BCAA Nitrates, Beta-Alanine Nitrate & Citrulline Nitrate for Greater Stability & Muscle Transport!
•Moiety Nitrates are Novel Science far Superior to Free Form Aminos & Other Chemical Salts!
•Nitrates are Scientifically Proven to Induce Vasodilation via Nitric Oxide (NO)!>
•NO Increases Blood Flow to Engorge Muscle with Nutrient-Dense Blood!
•Stamina, Strength and Recovery are Enhanced!
•EAAs (Essential Amino Acids): Key for Protein Synthesis Proven Superior to BCAAs!
•Contains Potent Anserine for Muscle Performance and Proton Buffering!

References:
1. Takahashi K et al. Characterization of the influence of nitric oxide donors on intestinal absorption of macromolecules. Int J Pharm 2004;286:89-97.
2. Fetih G et al. Nitric oxide donors can enhance the intestinal transport and absorption of insulin and [Asu(1,7)]-eel calcitonin in rats. J Control Release 2005;106:287-97.
3. Fetih G et al. Excellent absorption enhancing characteristics of NO donors for improving the intestinal absorption of poorly absorbable compound compared with conventional absorption enhancers. Drug Metab Pharmacokinet 2006;21:222-9.
4. Larsen FJ et al. Effects of dietary nitrate on oxygen cost during exercise. Acta Physiol (Oxf) 2007;191:59-66.
5. Dreyer H et al. 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;294:E392-400.
6. Gleeson M. Dosing and efficacy of glutamine supplementation in human exercise and sport training. J Nutr 2008;138:2045S-2049S.
7. Liu TH et al. No effect of short-term arginine supplementation on NO production, metab and performance in intermittent exercise in athletes. J Nutr Biochem 2009;20:462-8.
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#18 e Volution

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Posted 08 October 2010 - 05:20 AM

Just a thought I've been having lately--I am a big advocate of an evolutionary approach to diet (Paleo) however I am starting to speculate that its effects on health are so good that they could potentially reduce LE towards the back-end of life, 80+ years old, where evolutionary selection pressures would have been almost entirely absent in our ancestors. This view is in light of the more proven LE methods such as CR, Protein-restriction, Methionine-restriction which is quite counter-intuitive essentially tricking the body into thinking it's on its way to dying (crude simplification) aiding longevity.

What do you guys think? Is it possible that this distinction could be being missed or confounding results in these rodent studies, sort of like how their high rates of cancer can cloud other LE outcomes?

Edited by e Volution, 08 October 2010 - 05:21 AM.


#19 resveratrol

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Posted 08 October 2010 - 01:53 PM

VPX power shock appears to have most of the BCAAs mentioned but they do no disclose the ratios of their "proprietary" formula.
I'd think it's a fair assumption that the L-Isoleucine - L-Leucine - L-Valine ratio is 1-2-1 since virtually every BCAA sup I looked at in the local vitamin shoppe had the same ratio.


Nice!

Lord knows I can't get enough proton buffering. Oh yeah. Gotta buffer me some o' them protons.

However, I'm starting to think the methionine specifically should be omitted from a BCAA mix, due to research like this:

In fact, when the researchers studied the effect further, they found that levels of a particular amino acid known as methionine were crucial to maximising lifespan without decreasing fertility. Adding methionine to a low calorie diet boosted fertility without reducing lifespan; likewise, reducing methionine content in a high calorie diet prolonged lifespan. Previous studies have also shown that reducing the intake of methionine in rodents can help extend lifespan.

http://www.scienceda...91202131622.htm


Edited by Michael, 12 October 2010 - 10:11 PM.
Trim quotes


#20 1kgcoffee

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Posted 09 October 2010 - 01:29 AM

Strange. I thought BCAA's were MTOR activators. Not an expected result.

#21 Michael

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Posted 12 October 2010 - 10:21 PM

This is just 'the usual nonsense' of claims of extended LS: short-lived controls. As one can see:

Posted Image

The mean, median, and max LS of WT BCAA-fed vs control mice were (reespectively) 773 vs 843 d, 774 vs 869 d, and 938 vs 981 d. Ie, ALL the animals were short-lived, compared to the standard control groups in studies run by people who know what they're doing (Spindler, Weindruch, Miller, etc); those that got branched-chain amino acids lived a little longer, but still not nearly as long as a normal, healthy, well-husbanded, non-genetically-fucked-up mouse (which will on av'g live ~900 days at maximum (tenth-decile survivorship) >1100 d.

By contrast, Spindler's *late-onset* CR animals had an av'g LS of 1076 d, and max LS of 1325 d.

It's probably true, as the press story says, "that the supplementary mixture may be specifically beneficial for those who are elderly or ill," particularly granted (as someone noted) widespread sarcopenia in that population; OTOH, as the survival data shows, there is a clear element of either Lady Macbeth protesting to much, or more likely ignorance, when the researcher "emphasiz[ed] that the mice they studied "were just aged, not sick." " And as to "it might be a useful preventive strategy:" as someone noted, the effects of BCAAs on lean mass are generated by activating mTOR ...

One always has to consider the 'making up for bad husbandry' angle, but then again, how many of us are living under conditions of optimal husbandry?

Nearly anyone participating on thiis board. The lifespan curve of humans in industrialized countries is very nicely-rectangularized, and that includes significant subpopulations of smokers, diabetics, and people that really do live on fast food. We live in a country with significant coverage of vaccines, have clean water and access to fresh vegetables, and I hope no one here likes to fight with hir cagemates.
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#22 e Volution

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Posted 13 October 2010 - 11:40 AM

Haha MR = the voice of reason! I would put you alongside Richard Dawkins as someone I cannot actually imagine losing a logical debate!

Thanks for saving me money on those BCAAs :)

#23 capsun

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Posted 13 October 2010 - 04:18 PM

But Michael, how could you possibly know that if the mice fed BCAA's were well cared for, that they would not live longer than "normal, healthy, well-husbanded, non-genetically-fucked-up" mice?

#24 chrono

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Posted 14 October 2010 - 06:33 AM

I think the result regarding enhanced SIRT1 expression in middle-aged mice supplemented with BCAA for 3 months is pretty interesting:

Posted Image


The authors also note the effects on mTOR:

A relevant point is the molecular mechanism(s) involved in the BCAAem-increased mitochondrial biogenesis and survival. Interestingly, BCAAs have been reported to increase mTORC1 activity (Avruch et al., 2009), which correlates positively with cell oxidative capacity (Schieke et al., 2006) and regulates PGC-1a coactivation of its own promoter and mitochondrial gene expression in muscle cells (Cunningham et al., 2007). Moreover, rapamycin was shown to reduce eNOS expression and NO production (Barilli et al., 2008). Based on our results, one can hypothesize that BCAAem-activated mTOR signaling could enhance mitochondrial biogenesis partly through increasing the NO-generating system. In turn, our findings are consistent with recent reports showing that NO upregulates mTOR activity and its downstream targets (Pervin et al., 2007), suggesting that a positive feedback mechanism between eNOS and mTOR exists. Interestingly, selective knockout of either mTOR or the mTORC1 component raptor in skeletal muscle decreased oxidative capacity, mitochondrial gene expression, and survival (Bentzinger et al., 2008; Risson et al., 2009). In contrast, the absence of raptor in adipose tissue results in lean mice with enhanced mitochondrial respiration (Polak et al., 2008). Accordingly, BCAAem supplementation induces mitochondrial biogenesis in muscle but not in fat or liver.

Several studies indicate that reduced TOR signaling underlies life span extension by CR (see Stanfel et al., 2009 for review). Mice fed rapamycin live longer than control mice fed unsupplemented chow, even when treatment begins in late life (Harrison et al., 2009), and mice with deletion of S6K have increased life span and resistance to age-related pathologies (Selman et al., 2009). However, the reported prolongevity effects of chronic rapamycin treatment in mice do not conclusively prove that mTOR inhibition is the mechanism involved. Notably, rapamycin has been recently shown to be ineffective to increase life span in Drosophila (Harrison et al., 2010). Moreover, unlike CR, rapamycin is more efficacious in female than in male mice (Harrison et al., 2009), while S6K deletion increases life span in female but not in male mice (Selman et al., 2009). Again, the role of mTOR in CR is probably tissue specific, in that CR reduces mTOR signaling in liver (Jiang et al., 2008) but increases it in WAT and heart (Linford et al., 2007) and increases mitochondrial function in different tissues (Nisoli et al., 2005), a finding that is not consistent with reduced mTOR signaling. Although we did not specifically investigate the contribution of mTOR in BCAAem-mediated increase of survival, our findings support the notion that the role of mTOR in CR mechanisms is complex and not conclusively clarified at the moment (Anderson and Weindruch, 2010).


Also posted to the CR list was the point that, according to Elango et al (2008a), (2009), and (2010), the DRI for several BCAAs are significantly undervalued according to proper analysis of nitrogen balance: leucine, isoleucine, and valine DRIs are .6-3x under optimal:

Posted Image


So while Michael's point about sub-M Prize-level methodology and lifespans is a very good one, I'm not sure if his declaration of 'nonsense' should be conversation-ending.


@resvhead: I'm reminded of the Chuck Jones cartoon "Rabbit Seasoning," wherein Daffy Duck ends up at the wrong end of a shotgun because of "pronoun trouble." But since it's highly irrelevant to this topic, why don't we pick our battles, in the interest of quality discussion.

Edited by chrono, 14 October 2010 - 06:34 AM.


#25 maxwatt

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Posted 14 October 2010 - 02:03 PM

I moved the discussion on grammar re: their and hir, here: Hir and Their.

(To which some may say "hear, hear!")

#26 Michael

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Posted 18 October 2010 - 03:47 PM

All:

I think the result regarding enhanced SIRT1 expression in middle-aged mice supplemented with BCAA for 3 months is pretty interesting:

It might be, if there were any compelling evidence that enhancing SIRT1 activity has any effect on increasing lifespan in the aforementioned nnormal, healthy, well-husbanded, non-genetically-fucked-up mice (as opposed to yeast, diabetic-obese mice, mice with severe defects in chromosome maintenance, etc) ;) . Remember (or know ye!): resveratrol does not increase lifespan such mice, and similarly giving mice a transgenic boost of SIRT1 also does not extend lifespan.

The authors also note the effects on mTOR


... with special pleading. Inhibiting mTOR has now robustly extended the lives of numerous organisms, including in particular the op cit healthy mice -- a result reproduced independently under rigorous conditioins as part of the NIA's Intervention Testing Protocol by labs that actually know how to raise healthy mice (Richard Miller at U of M, Arlen Richardson at the Barshop Institute for Longevity and Aging Studies, and the team at The Jackson Laboratories). These guys can't even get their control group to live out a normal life, and want to pretend that a supplement that help mice survive their crummy little lifestyles a little bit longer means something about aging. Uh-uh. Their mice would have been be better off just eating regular chow in Steve Spindler's lab.

(To be clear: many of their critiques are valid, and should be further probed in future research. But the mTOR story at this point is a remarkably consistent set of findings supporting a highly conserved role in the control of the biological aging process, and it's simply laughable to minimize that body of evidence even while trumpeting mice that die well within the normal range, with the curve shifted leftward, as triumphs of anti-aging science).

Also posted to the CR list was the point that, according to Elango et al (2008a), (2009), and (2010), the DRI for several BCAAs are significantly undervalued according to proper analysis of nitrogen balance: leucine, isoleucine, and valine DRIs are .6-3x under optimal


Sure, but that doesn't mean you need a supplement. I am actively bumping my protein levels down to not much more than the RDA, and am specifically lowering my leucine intake to preserve the full CR effect as likely mediated in part by mTOR, and I still get 89 mg/kg a day (vs. their 55 suggested requirement, and 34 for the DRI).

#27 Gerald W. Gaston

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Posted 15 January 2011 - 06:00 PM

While I have been trying to follow the suggestions to lower protein levels (specifically the aminos leucine AND methionine), I have been looking into what I can use for improving recovery time from a recent surgery. While trying to find any pros and cons on using BCAAs short term for recovery I did run across this study (not done concerning recovery from surgery but still interesting):

Supplementation with Branched-chain Amino Acids Inhibits Azoxymethane-induced Colonic Preneoplastic Lesions in Male C57BL/KsJ-db/db Mice



Purpose: Obesity and related metabolic abnormalities, including insulin resistance and activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis, are risk factors for colon cancer. Supplementation with branched-chain amino acids (BCAA) reduces the risk of liver cancer in cirrhotic patients who are obese, and this has been associated with an improvement of insulin resistance. The present study examined the effects of BCAA on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice that were obese and had hyperinsulinemia.

Experimental Design: Male db/db mice were given 4 weekly s.c. injections of AOM (15 mg/kg of body weight) and then they were fed a diet containing 3.0% BCAA or casein, a nitrogenc content–matched control diet, for 7 weeks.

Results: Feeding with BCAA caused a significant reduction in the number of total aberrant crypt foci and β-catenin accumulated crypts, both of which are premalignant lesions of the colon, compared with the control diet–fed groups. BCAA supplementation caused a marked decrease in the expression of IGF-IR, the phosphorylated form of IGF-IR, phosphorylated glycogen synthase kinase 3β, phosphorylated Akt, and cyclooxygenase-2 proteins on the colonic mucosa of AOM-treated mice. The serum levels of insulin, IGF-I, IGF-II, triglyceride, total cholesterol, and leptin were also decreased by supplementation with BCAA.

Conclusion: BCAA supplementation in diet improves insulin resistance and inhibits the activation of the IGF/IGF-IR axis, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model that was also associated with hyperlipidemia and hyperinsulinemia. BCAA, therefore, may be a useful chemoprevention modality for colon cancer in obese people.



#28 Cephalon

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Posted 17 February 2012 - 01:41 AM

Sorry for digging out this old thread, but it just came to my mind when shopping supplements.
There is a German company called amino-factory I put alot trust in, since they produce all their amino acids on their own, under strict legal requirements.
All products are tested by Eurofins, which is one of, or if not the most trusted lab in my area (Germany, France, Belgium etc.) and you can find current COA online.

I just noticed they have an option where you can request your custom mix through an online form. I see they have all aminos we'd need.
Just in case I would have some money to spend on this sometime, do you still think it would be worth it?
A life extensionist's protein shake? Would you change anything, like cutting out the methionine and cycteine?

http://amino-factory...ellen/index.php

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#29 smithx

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Posted 18 February 2012 - 03:58 AM

I'd definitely cut out the methionine, since there's some evidence that you can get many of the benefits of CR just by restricting methionine.

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