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Low Protein Intake Associated with Major Reduction in Mortality in the 65 and Younger but Not Older Population

low protein igf-1 mortality cancer

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#1 Elus

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Posted 06 March 2014 - 09:12 PM


Low Protein Intake Is Associated with a Major Reduction in IGF-1, Cancer, and Overall Mortality in the 65 and Younger but Not Older Population

Mice' class='bbc_url' title='External link' rel='nofollow external'>http://www.cell.com/cell-metabolism/abstract/S1550-4131%2814%2900062-X']Mice and humans with growth hormone receptor/IGF-1 deficiencies display major reductions in age-related diseases. Because protein restriction reduces GHR-IGF-1 activity, we examined links between protein intake and mortality. Respondents aged 50–65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer death risk during the following 18 years. These associations were either abolished or attenuated if the proteins were plant derived. Conversely, high protein intake was associated with reduced cancer and overall mortality in respondents over 65, but a 5-fold increase in diabetes mortality across all ages. Mouse studies confirmed the effect of high protein intake and GHR-IGF-1 signaling on the incidence and progression of breast and melanoma tumors, but also the detrimental effects of a low protein diet in the very old. These results suggest that low protein intake during middle age followed by moderate to high protein consumption in old adults may optimize healthspan and longevity.

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Edited by Elus, 06 March 2014 - 09:13 PM.

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#2 beatsme

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Posted 18 March 2014 - 02:32 AM

**Animal** protein, it seems, not protein in general.

when the percent calories from animal protein was controlled for, the association between total protein and all-cause or cancer mortality was eliminated or significantly reduced, respectively, suggesting animal proteins are responsible for a significant portion of these relationships. When we controlled for the effect of plant-based protein, there was no change in the association between protein intake and mortality, indicating that high levels of animal proteins promote mortality and not that plant-based proteins have a protective effect



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#3 Phoenicis

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Posted 23 March 2014 - 04:47 PM

so in over 65s IGF-1 benfits outweight the risks wheras in under 65s the opposite effect is observed? "Respondents aged 50–65 reporting high protein intake had a 75% increase in overall mortality and a 4-fold increase in cancer death risk during the following 18 years."

Edited by Phoenicis, 23 March 2014 - 04:49 PM.


#4 Phoenicis

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Posted 23 March 2014 - 04:55 PM

**Animal** protein, it seems, not protein in general.

when the percent calories from animal protein was controlled for, the association between total protein and all-cause or cancer mortality was eliminated or significantly reduced, respectively, suggesting animal proteins are responsible for a significant portion of these relationships. When we controlled for the effect of plant-based protein, there was no change in the association between protein intake and mortality, indicating that high levels of animal proteins promote mortality and not that plant-based proteins have a protective effect


IGF-1 seems to be the main thing here, its found in meat

Edited by Phoenicis, 23 March 2014 - 04:56 PM.


#5 InquilineKea

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Posted 29 March 2014 - 04:08 AM

They showed similar IGF1 increases from both soy protein and animal protein.

Fundamentally, the only difference between animal protein and plant protein is that plant protein has less methionine. But I'd think that the branched-chain amino acids would be more important for mTOR stimulation.

Personally I don't know what to believe. They need to separate out the effects of processed meat, since processed meat is so incredibly deleterious to begin with.
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#6 Olafur Pall Olafsson

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Posted 08 April 2014 - 09:01 PM

Elus, thanks for posting this study. I don't have time to analyze it in detail but I have some general comments below that may be valuable.

IGF-1 seems to be the main thing here, its found in meat

Good thinking, IGF-1 may well play a role in the results of this study because high levels of it are negative for longevity and protein intake can elevate IGF-1 in the blood of humans. However if IGF-1 plays a role here it is not because it is found in meat. Any IGF-1 that is found in the meat will get destroyed when the meat is ingested, because being a protein it will be broken down during digestion and will not reach the circulation intact. Meat ingestion can still increase IGF-1 levels but the effect is indirect. It is mainly the protein in the meat that causes the increase in IGF-1 levels. Ingestion of high amounts of protein has been shown to increase IGF-1 levels in humans, and meat, being a rich source of protein, can certainly contribute to such an increase.

 

They showed similar IGF1 increases from both soy protein and animal protein.

Fundamentally, the only difference between animal protein and plant protein is that plant protein has less methionine. But I'd think that the branched-chain amino acids would be more important for mTOR stimulation.

You are right in that the branched-chain amino acids are more important for mTOR stimulation than methionine. Most of the effects on mTOR are caused by the amino acid leucine specifically, which is one of the brahcned-chain amino acids. However, high methionine intake is also negative for longevity and that is one reason why meat protein should be consumed in moderation in favor of plant protein.

 

Overall what I recommend for longevity in terms of protein ingestion, (this is in line with the recommendations we will make at Live120Plus), is to consume fairly low amounts of protein and to be particularly moderate when it comes to animal protein, because it is richer in methionine. The reasons for this recommendation are mainly because consuming moderately low amounts of protein will help in reducing mTOR levels, reducing IGF-1 levels, and reducing unnecessary protein synthesis (which increases the synthesis of erroneous proteins) by reducing methionine levels. This should be beneficial for longevity, in part by causing increased autophagy..


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#7 Phoenicis

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Posted 08 April 2014 - 09:12 PM

Elus, thanks for posting this study. I don't have time to analyze it in detail but I have some general comments below that may be valuable.

IGF-1 seems to be the main thing here, its found in meat

Good thinking, IGF-1 may well play a role in the results of this study because high levels of it are negative for longevity and protein intake can elevate IGF-1 in the blood of humans. However if IGF-1 plays a role here it is not because it is found in meat. Any IGF-1 that is found in the meat will get destroyed when the meat is ingested, because being a protein it will be broken down during digestion and will not reach the circulation intact. Meat ingestion can still increase IGF-1 levels but the effect is indirect. It is mainly the protein in the meat that causes the increase in IGF-1 levels. Ingestion of high amounts of protein has been shown to increase IGF-1 levels in humans, and meat, being a rich source of protein, can certainly contribute to such an increase.

 

They showed similar IGF1 increases from both soy protein and animal protein.

Fundamentally, the only difference between animal protein and plant protein is that plant protein has less methionine. But I'd think that the branched-chain amino acids would be more important for mTOR stimulation.

You are right in that the branched-chain amino acids are more important for mTOR stimulation than methionine. Most of the effects on mTOR are caused by the amino acid leucine specifically, which is one of the brahcned-chain amino acids. However, high methionine intake is also negative for longevity and that is one reason why meat protein should be consumed in moderation in favor of plant protein.

 

Overall what I recommend for longevity in terms of protein ingestion, (this is in line with the recommendations we will make at Live120Plus), is to consume fairly low amounts of protein and to be particularly moderate when it comes to animal protein, because it is richer in methionine. The reasons for this recommendation are mainly because consuming moderately low amounts of protein will help in reducing mTOR levels, reducing IGF-1 levels, and reducing unnecessary protein synthesis (which increases the synthesis of erroneous proteins) by reducing methionine levels. This should be beneficial for longevity, in part by causing increased autophagy..

 

Thanks for that informative reply, so the three branched chain maino acids are leucine, isoleucine and valine correct? Would lysine (not leucine) stimulate mTOR or IGF-1?


Edited by Phoenicis, 08 April 2014 - 09:19 PM.


#8 Olafur Pall Olafsson

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Posted 08 April 2014 - 10:26 PM

Thanks for that informative reply, so the three branched chain maino acids are leucine, isoleucine and valine correct? Would lysine (not leucine) stimulate mTOR or IGF-1?

Yes, that is correct. With respect to whether lysine would stimulate mTOR I am pretty sure it does not stimulate it directly like leucine does, but don't take my word for it. If it doesn't have direct effect on mTOR it may well have some indirect effects. Being curious I did a short search and found this study that indicates that lysine is able to increase mTOR levels, or at least prevent the reduction in mTOR levels when it is added to muscle cell culture in vitro at a high concentration.

 

Mol Cell Biochem. 2014 Feb 15. [Epub ahead of print]
Lysine suppresses protein degradation through autophagic-lysosomal system in C2C12 myotubes.
Sato T1, Ito Y, Nedachi T, Nagasawa T.

Muscle mass is determined between protein synthesis and protein degradation. Reduction of muscle mass leads to bedridden condition and attenuation of resistance to diseases. Moreover, bedridden condition leads to additional muscle loss due to disuse muscle atrophy. In our previous study (Sato et al. 2013), we showed that administered lysine (Lys), one of essential amino acid, suppressed protein degradation in skeletal muscle. In this study, we investigated that the mechanism of the suppressive effects of Lys on skeletal muscle proteolysis in C2C12 cell line. C2C12 myotubes were incubated in the serum-free medium containing 10 mM Lys or 20 mM Lys, and myofibrillar protein degradation was determined by the rates of 3-methylhistidine (MeHis) release from the cells. The mammalian target of rapamycin (mTOR) activity from the phosphorylation levels of p70-ribosormal protein S6 kinase 1 and eIF4E-binding protein 1 and the autophagic-lysosomal system activity from the ratio of LC3-II/I in C2C12 myotubes stimulated by 10 mM Lys for 0-3 h were measured. The rates of MeHis release were markedly reduced by addition of Lys. The autophagic-lysosomal system activity was inhibited upon 30 min of Lys supplementation. The activity of mTOR was significantly increased upon 30 min of Lys supplementation. The suppressive effect of Lys on the proteolysis by the autophagic-lysosomal system was maintained partially when mTOR activity was inhibited by 100 nM rapamycin, suggesting that some regulator other than mTOR signaling, for example, Akt, might also suppress the autophagic-lysosomal system. From these results, we suggested that Lys suppressed the activity of the autophagic-lysosomal system in part through activation of mTOR and reduced myofibrillar protein degradation in C2C12 myotubes.

PMID: 24532005

 

Note that this doesn't necessarily mean that lysine directly stimulates mTOR like leucine does, and I still think leucine is definitely more negative overall, being a strong inducer of mTOR. However the results of this study certainly do indicate that lysine is also able to increase mTOR, or at least prevent its reduction, which will be negative for autophagy and longevity. One potential mechanism by which lysine could be negative is by being used as fuel by the cell which would lower the need to use other amino acids for fuel, such as leucine. That is a way in which high levels of lysine might indirectly increase mTOR levels.

 

With respect to whether lysine would stimulate IGF-1, I don't know for sure and I haven't looked into it specifically. What I do know is that protein intake tends to lead to increased levels of IGF-1, and studies on animals given diets low in methionine show that they have lower IGF-1 levels which indicates that methionine is a big part of that, if not the major factor responsible for the increase in IGF-1 in response to protein intake. Therefore I don't think lysine is of specific importance here, but rather the total protein and methionine intake.

 

One thing that makes sense to me about methionine increasing IGF-1 levels is the fact that IGF-1 is a growth factor that promotes growth, and in order for growth to occur the body needs materials to use as building blocks. When it comes to protein synthesis these materials are amino acids, and among amino acids methionine stands out in being the amino acid that initiates translation during protein synthesis, meaning it acts as a signal to start the building out of the the amino acids. It makes sense for the cells to increase signals of growth more when there is abundance of materials to use as building material than when it is lacking, and since methionine is found in high amounts in most foods rich in protein, abundance of methionine can act as a signal that plenty of amino acids (the building material) are present for growth. Therefore, when the cells are exposed to methionine, it makes sense for them to increase signals of growth, IGF-1 being one such signal, mTOR being another example. This is not something I have verified by research, just a theory based on what I think is logical given how the body works.


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#9 Phoenicis

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Posted 08 April 2014 - 10:54 PM

 

Thanks for that informative reply, so the three branched chain maino acids are leucine, isoleucine and valine correct? Would lysine (not leucine) stimulate mTOR or IGF-1?

Yes, that is correct. With respect to whether lysine would stimulate mTOR I am pretty sure it does not stimulate it directly like leucine does, but don't take my word for it. If it doesn't have direct effect on mTOR it may well have some indirect effects. Being curious I did a short search and found this study that indicates that lysine is able to increase mTOR levels, or at least prevent the reduction in mTOR levels when it is added to muscle cell culture in vitro at a high concentration.

 

Mol Cell Biochem. 2014 Feb 15. [Epub ahead of print]
Lysine suppresses protein degradation through autophagic-lysosomal system in C2C12 myotubes.
Sato T1, Ito Y, Nedachi T, Nagasawa T.

Muscle mass is determined between protein synthesis and protein degradation. Reduction of muscle mass leads to bedridden condition and attenuation of resistance to diseases. Moreover, bedridden condition leads to additional muscle loss due to disuse muscle atrophy. In our previous study (Sato et al. 2013), we showed that administered lysine (Lys), one of essential amino acid, suppressed protein degradation in skeletal muscle. In this study, we investigated that the mechanism of the suppressive effects of Lys on skeletal muscle proteolysis in C2C12 cell line. C2C12 myotubes were incubated in the serum-free medium containing 10 mM Lys or 20 mM Lys, and myofibrillar protein degradation was determined by the rates of 3-methylhistidine (MeHis) release from the cells. The mammalian target of rapamycin (mTOR) activity from the phosphorylation levels of p70-ribosormal protein S6 kinase 1 and eIF4E-binding protein 1 and the autophagic-lysosomal system activity from the ratio of LC3-II/I in C2C12 myotubes stimulated by 10 mM Lys for 0-3 h were measured. The rates of MeHis release were markedly reduced by addition of Lys. The autophagic-lysosomal system activity was inhibited upon 30 min of Lys supplementation. The activity of mTOR was significantly increased upon 30 min of Lys supplementation. The suppressive effect of Lys on the proteolysis by the autophagic-lysosomal system was maintained partially when mTOR activity was inhibited by 100 nM rapamycin, suggesting that some regulator other than mTOR signaling, for example, Akt, might also suppress the autophagic-lysosomal system. From these results, we suggested that Lys suppressed the activity of the autophagic-lysosomal system in part through activation of mTOR and reduced myofibrillar protein degradation in C2C12 myotubes.

PMID: 24532005

 

Note that this doesn't necessarily mean that lysine directly stimulates mTOR like leucine does, and I still think leucine is definitely more negative overall, being a strong inducer of mTOR. However the results of this study certainly do indicate that lysine is also able to increase mTOR, or at least prevent its reduction, which will be negative for autophagy and longevity. One potential mechanism by which lysine could be negative is by being used as fuel by the cell which would lower the need to use other amino acids for fuel, such as leucine. That is a way in which high levels of lysine might indirectly increase mTOR levels.

 

With respect to whether lysine would stimulate IGF-1, I don't know for sure and I haven't looked into it specifically. What I do know is that protein intake tends to lead to increased levels of IGF-1, and studies on animals given diets low in methionine show that they have lower IGF-1 levels which indicates that methionine is a big part of that, if not the major factor responsible for the increase in IGF-1 in response to protein intake. Therefore I don't think lysine is of specific importance here, but rather the total protein and methionine intake.

 

One thing that makes sense to me about methionine increasing IGF-1 levels is the fact that IGF-1 is a growth factor that promotes growth, and in order for growth to occur the body needs materials to use as building blocks. When it comes to protein synthesis these materials are amino acids, and among amino acids methionine stands out in being the amino acid that initiates translation during protein synthesis, meaning it acts as a signal to start the building out of the the amino acids. It makes sense for the cells to increase signals of growth more when there is abundance of materials to use as building material than when it is lacking, and since methionine is found in high amounts in most foods rich in protein, abundance of methionine can act as a signal that plenty of amino acids (the building material) are present for growth. Therefore, when the cells are exposed to methionine, it makes sense for them to increase signals of growth, IGF-1 being one such signal, mTOR being another example. This is not something I have verified by research, just a theory based on what I think is logical given how the body works.

 

Thanks for taking the time to give such a thorough response! The main reason I was asking about lysine is because I take 2g/day to treat/slow the recurrence of herpes. To me it makes sense to continue using this because the risk of developing alzheimer's has been linked with herpes. As a vegan my protein intake is comparatively low but I do eat legumes about 4 times a week.

 

Overall I think that for me, the benefits of lysine probably outweigh the risks.


Edited by Phoenicis, 08 April 2014 - 11:07 PM.


#10 Olafur Pall Olafsson

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Posted 09 April 2014 - 02:10 AM

Thanks for taking the time to give such a thorough response! The main reason I was asking about lysine is because I take 2g/day to treat/slow the recurrence of herpes. To me it makes sense to continue using this because the risk of developing alzheimer's has been linked with herpes. As a vegan my protein intake is comparatively low but I do eat legumes about 4 times a week.

 

Overall I think that for me, the benefits of lysine probably outweigh the risks.

You are taking the right approach here by weighting the positive and negative effects, and I agree with your conclusion that the benefits of lysine probably outweigh the risks in your case.

 

As a vegan with comparatively low protein intake the lysine is less likely to cause you significant harm. Even if it leads to a slight increase in mTOR the result is likely much weaker than that of leucine and 2 grams daily are unlikely to cause much harm in my opinion.

 

It is also very important to prevent and minimize any outbreaks of herpes as much as you can because reactivation of such latent viruses not only causes harmful inflammation in the body (due to activation of the immune system to fight the virus) but also tends to accelerate aging of the immune system. I had forgotten about the increased risk of Alzheimer's, but thanks for the reminder, that is another reason why it is important for you to do what you can to prevent and minimize the duration of herpes outbreaks. Btw taking extra zinc temporarily immediately at the onset of herpes outbreaks and until the outbreak is gone has been shown to be very helpful in some individuals. I think the mechanism for the benefit of zinc for herpes is its immune enhancing effects. Just don't go overboard and take much more than 50 mg of zinc daily for weeks because high doses of zinc have been shown to suppress immunity when taken chronically.



#11 John Schloendorn

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Posted 12 April 2014 - 07:16 PM

They need to separate out the effects of processed meat, since processed meat is so incredibly deleterious to begin with.

 

Yes, exactly.  As it stands, the main finding here is that animal protein intake is correlated with animal meat intake.  Yay taxpayer funded big government science. 


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#12 Sith

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Posted 22 March 2016 - 01:58 PM

Animal protein is said to be the enemy. And the evidence is clear, it does appear to be. But does this include fatty fish like Salmon? Fatty fish have many longevity benefits. 



#13 Darryl

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Posted 22 March 2016 - 10:13 PM

Every whole food has both components that in isolation appear beneficial and others that appear harmful (even if only marginally so). For most eaters, pescetarian diets appear fairly ideal. But for those optimizing diets before advanced ages, and willing to supplement, a lower protein whole plant based diet, minimizing intake of problematic components and supplementing with the beneficial ones, may be better. I suspect most of the benefits of fatty fish could be obtained with refined fish oil/EPA supplements (in the context of a low arachidonic acid diet) plus taurine supplementation.


Edited by Darryl, 22 March 2016 - 10:14 PM.


#14 Sith

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Posted 24 March 2016 - 02:30 PM

Every whole food has both components that in isolation appear beneficial and others that appear harmful (even if only marginally so). For most eaters, pescetarian diets appear fairly ideal. But for those optimizing diets before advanced ages, and willing to supplement, a lower protein whole plant based diet, minimizing intake of problematic components and supplementing with the beneficial ones, may be better. I suspect most of the benefits of fatty fish could be obtained with refined fish oil/EPA supplements (in the context of a low arachidonic acid diet) plus taurine supplementation.

 

I really do advocate pescetarian diets, I feel that isolated fish oil does not have the beneficial effects of whole fish. But in addition to this, epidemiological studies show that pescetarian diets have the lowest cancer rates in the world, lower than vegan and much lower than omnivorous diets. Do you think the hype matches the science?  :)


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#15 truboy

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Posted 26 January 2020 - 12:14 AM

I really do advocate pescetarian diets, I feel that isolated fish oil does not have the beneficial effects of whole fish. But in addition to this, epidemiological studies show that pescetarian diets have the lowest cancer rates in the world, lower than vegan and much lower than omnivorous diets. Do you think the hype matches the science?  :)

 

Need to try it, thank you!



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#16 Blu

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Posted 26 January 2020 - 10:46 AM

Cancer rate is meaningless without overall mortality. If I don't get cancer in old age because I die at 38 from a CVD event, it's not a great bargain.


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