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Dean Pomerleau

Mechanism by which a High Protein Diet Worsens Heart Disease

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I found this new mouse study [1] to be fascinating. It found feeding mutant mice (genetically prone to forming artherosclerotic plaques like humans) a diet high in fat and protein, especially high in the amino acid leucine (found most abundantly in meat, eggs and dairy) resulted in 30% more unstable plaque formation in the mice's arteries than a diet with the same (large) amount of fat but normal in protein (i.e. with more simple carbs in place of protein).

What was most fascinating was the study's level of detail and specificity regarding the causal pathway.

Here is the visual abstract and summary of the mechanism:

Ingestion and digestion of dietary protein first lead to an acute rise in blood amino acid levels and in turn tissue amino acid levels (including the atherosclerotic plaque). On exposure to rising amino acid levels, mTORC1 is activated in plaque macrophages. A critical downstream effect of activated mTORC1 is inhibition of mitophagy. The resultant build-up of dysfunctional mitochondria triggers the intrinsic apoptosis pathway. Enhanced apoptosis of plaque macrophages contributes to necrotic core formation and a rise in plaque complexity (a surrogate of the vulnerable plaques).

Screenshot_20200204-165014_Foxit PDF.jpg

In other words and in a little more detail, the high fat in the diet triggers macrophage cells in the bloodstream to try to absorb droplets of fat, especially oxidized fat. This leads to "toxic lipid intermediates" inside the macrophage cells that end up damaging the macrophage's mitochondria. Normally, these damaged mitochondria would be detected and cleared out through the process called mitophagy. But in the presence of a high concentration of amino acids (esp. leucine), part of the MTOR complex (MTORC1) inside the macrophage cell is activated in such a way as to promote cell growth while at the same time inhibiting mitophagy.  As a result, damaged mitochondria build up inside the macrophage cell. A high concentration of dysfunctional mitochondria in turn triggers apoptosis of the macrophage cell, effectively killing it off.

Dead macrophage cells overloaded with lipids are a fundamental component of unstable artherosclerotic plaques embedded in artery walls that ultimately are what typically triggers a heart attack. So this study helps elucidate exactly how a diet high in fat and protein increases heart attack risk.

--Dean

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[1] Nature Metabolism 2, 110–125 (2020). https://doi.org/10.1038/s42255-019-0162-4

High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy

Xiangyu Zhang1,2, Ismail Sergin1, Trent D. Evans1, Se-Jin Jeong1,2, Astrid Rodriguez-Velez1,
Divya Kapoor1,2, Sunny Chen1, Eric Song1, Karyn B. Holloway1,2, Jan R. Crowley3, Slava Epelman   4,
Conrad C. Weihl5, Abhinav Diwan   1,2, Daping Fan6, Bettina Mittendorfer7, Nathan O. Stitziel1,
Joel D. Schilling1,8, Irfan J. Lodhi3 and Babak Razani   1,7,8*

High-protein diets are commonly utilized for weight loss, yet they have been reported to raise cardiovascular risk. The mechanisms underlying this risk are unknown. Here, we show that dietary protein drives atherosclerosis and lesion complexity.
Protein ingestion acutely elevates amino acid levels in blood and atherosclerotic plaques, stimulating macrophage mammalian target of rapamycin (mTOR) signalling. This is causal in plaque progression, because the effects of dietary protein are
abrogated in macrophage-specific Raptor-null mice. Mechanistically, we find amino acids exacerbate macrophage apoptosis
induced by atherogenic lipids, a process that involves mammalian target of rapamycin complex 1 (mTORC1)-dependent inhibition of mitochondrial autophagy (mitophagy), accumulation of dysfunctional mitochondria and mitochondrial apoptosis. Using
macrophage-specific mTORC1- and autophagy-deficient mice, we confirm this amino acid–mTORC1–autophagy signalling axis
in vivo. Our data provide insights into the deleterious impact of excessive protein ingestion on macrophages and atherosclerotic
progression. Incorporation of these concepts in clinical studies is important to define the vascular effects of protein-based
weight loss regimens.

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Beautiful find Dean.

 This highlights that you neither need to restrict protein ( nor methionine) to dangerous nor to an unrealistic degree to benefit from moderately limiting this macronutrient.

Limiting protein ( or methionine in particular) further has been one of my cornerstone healthspan   interventions over recent years.  If you have the time and inclination this was a magnificent review on the subject you may enjoy: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30239-7/fulltext

( “The impact of dietary protein intake on longevity and metabolic health”)

 

 

 

 

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17 hours ago, Dean Pomerleau said:

But in the presence of a high concentration of amino acids (esp. leucine), part of the MTOR complex (MTORC1) inside the macrophage cell is activated in such a way as to promote cell growth while at the same time inhibiting mitophagy. 

Hi Dean!

Very nice find.  

I'm a little confused though:  Why does the article single out leucine?  ("esp. leucine").   I understand the special significance of methionine (it is the first amino acid used in anabolic processes) -- but what's special about leucine?

  --  Saul

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Hi Saul, leucine besides being highly anabolic via multiple mechanisms including IGF-1 signaling ( along with other BCAA, etc.), it is a particularly potent mTORC1 stimulator:

https://www.cell.com/cell-metabolism/pdfExtended/S1550-4131(18)30514-X

Earlier mechanistic work was pioneered and continued in large part by David Sabatini’s lab at the Whitehead Institute and others; simple video follows or heard as an informal narrative on Peter Attia’s interviews on The Drive podcast 


Podcastnotes provides a summary of the interview on “The Drive” and link to the audio:


https://podcastnotes.org/2018/08/14/mtor/

 

Edited by Mechanism

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Good article. Here is something else which supports its conclusions (I am not sure if it has been posted elsewhere here):

"we have now found that altered dietary quality – the precise amino acid composition of the diet – regulates metabolic health. Specifically reducing the three branched chain amino acids (leucine, isoleucine, and valine) to the same level as found in a low protein diet is sufficient to improve many aspects of metabolic health, including glucose tolerance and body composition, as effectively as a 2/3rds reduction in total consumption of dietary amino acids."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947548/#!po=31.2500

At first glance, I am not sure how to reconcile this with the methionine restriction studies.

Also, it seems as if the definition of "low" needs to be clarified. With methionine I see studies which consider intake of anything lower than 1.3g per kg to be "low." I am not sure what "low" means for leucine.

Edited by Ron Put

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Mechanism,

Thanks for the Sabatini videos. Fascinating stuff. 

Saul, as Mechanism indicates, Sabatini's lab has found that the level of several amino acids are involved in regulating mTORC1. Here is a screen capture from the first Sabatini video that indicates three amino acids, leucine, arginine and lysine are involved in turning on mTORC1:

Screenshot_20200205-143723_YouTube.jpg

In addition, it's been found that the other amino acid you mention, methionine (met) activates mTORC1, as shown in the following diagram. Notice that binding sites by which leucine (leu) and arginine (arg) influence mTORC1 activity are also shown in this diagram:

Screenshot_20200205-144858_YouTube.jpg

You'll also notice that the sequence of steps by which these amino acids have their influence on mTORC1 are incredibly long and complicated.

But all of these amino acids seem to upregulate mTORC1, putting the cell into an anabolic state. Unfortunately, this anabolic state includes suppressing the breakdown of damaged mitochondria (mitophagy) in macrophages. The accumulation of these damaged mitochondria ultimately appears to cause suicide (apoptosis) of lipid-filled macrophages embedded in artery walls, contributing to the buildup of unstable plaques that reduce blood flow and which can eventually rupture to cause an artery blockage which starves the heart of oxygen (i.e. a heart attack).

I've heard the analogy that macrophages are like firefighters who rush to the scene of a fire, get incapacitated by smoke inhalation, thereby becoming part of the problem rather than part of the solution.

The new paper that started this thread seems to show that the reason the macrophages become incapacitated is that the normal catabolic processes that perform cleanup to keep the macrophages healthy are inhibited by mTORC1 activation, triggered by excess circulation amino acids from a high protein diet. 

--Dean

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Thanks Mechanism, Ron and Dean.  So the branched amino acids are highly anabolic.  

Animal protein is almost always higher in methionine than vegetable. Is the same true for the branched amino acids?

  --  Saul 

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5 hours ago, Saul said:

...Animal protein is almost always higher in methionine than vegetable. Is the same true for the branched amino acids?

Yes, animal protein appears to generally beat plant protein in BCAAs, unless one eats pumpkin seeds by the pound:

"Amount of BCAAs in prepared foods:

Edited by Ron Put

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On 2/5/2020 at 8:30 PM, Clinton said:

Anyone want the rest of my vanilla flavored Leanfit Whey protein powder??  😉

 

LOL, but I think you can use it post-workout without big detriment (Most of its leucine will be sequestered by muscle cells)

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2 hours ago, mccoy said:

LOL, but I think you can use it post-workout without big detriment (Most of its leucine will be sequestered by muscle cells)

I agree and as with anything - the key is 'moderation' - using a couple Tablespoons per day of whey (although whey is a high concentration of protein and BCAAs) when added to a plant-based diet or lacto-ovo vegetarian diet I do not believe falls into the category of a 'high protein' diet; especially when muscles are starving for some AA's from resistance training.

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I am still curious though, has anyone come across some sort of a standard definition of what constitutes a diet "low in methionine" or "low in BCAAs" as it applies to humans?

For methionine, I remember seeing a human study which deemed "low" to be anything 1.3g per kg or less.

But I haven't seen anything defining what "low" means for BCAAs. I can't even find what is the average intake based on SAD, or any other population.

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Ron,

I suggest as a starting point carefully reading sections 3 - 5 of the Lancet review I dubbed "magnificent" in my first reply above ( https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30239-7/fulltext ).  

Though you are inquiring about BCAA ( ie leucine, isoleucine, and valine), rather than methionine,  it is good to keep in mind Michael's perspective that MetR is neither realistically attainable on a natural-food diet (thus requiring a synthetic diet such as used in research protocols) nor desirable .  For purposes of this thread, I am using MetR to designate restriction of Met AND Cys since Cys supplementation essentially abrogates the potential benefits of methionine restrictions.   Some prefer calling this total sulfur AA (TSAA) restriction.  In any case, Michael's objections that true MetR is neither possible with a natural diet, nor desirable in people ( he recommends 100% RDA but no more, which is not the same things as MetR) is well-summarized here: 

MetR is in some respects better characterized than BCAA restriction whereby per the National Academy of Sciences, the Met+Cys RDA is 19 mg/kg•d ( with an EAR of 15 mg/kg•d), and in mice most MetR studies have classically been in the 17% - 33% range; that is a 66-83% reduction in met+cys.  Tables of NAS RDAs and EAR can be found here: https://www.nal.usda.gov/sites/default/files/fnic_uploads/DRIEssentialGuideNutReq.pdf  Although these figures don't add up perfectly, the RDA corresponds to a Met recommendation of 10.4 mg/kg BW/day and a Cys recommendation of 4.1mg/kg BW/day.

More explicitly at least for rodents "the range of dietary methionine restriction which elicits leanness without protein wasting and food aversion is 0.12 to 0.25 g per 100 g diet, as compared to the 0.43 to 0.86 g per 100 g in complete rodent diets [5,6]. However, most studies to date utilize methionine levels ranging between 0.12 to 0.17 g per 100 g diet with 0.17 g per 100 g diet the most well-studied restriction level " and "By restricting the methionine content from 0.86 to 0.17 g per 100 g diet(~80% reduction) throughout the adult lifespan of the animals, the authors observed an approximate 40% extension in average lifespan compared to unrestricted rats." [ Source: "Dietary Sulfur Amino Acid Restriction and the Integrated Stress Response: Mechanistic Insights" (2019):  https://pubmed.ncbi.nlm.nih.gov/31208042-dietary-sulfur-amino-acid-restriction-and-the-integrated-stress-response-mechanistic-insights/ ].  This same review is helpful if you wish to learn more about some of the "robust physiological improvements with SAAR in rodent models" that are independent of CR since as they note SAAR tend to lose weight too.  That in itself is interesting given that  rodents lose weight despite  feeding more: "the increased energy expenditure seen in  SAA restricted animals has been well-delineated and found to be, at least in part, dependent on a 
number of mechanisms including β-adrenergic signaling."  Among these CR-independent mechanisms that extend healthspan and lifespan that review focus on the "integrated stress response (ISR)  [....] a lesser-understood candidate in mediating leanness and/or longevity by SAAR."  This includes a variety of metabolic and other health measures with concomittant increase in FGF21 and other candidate mediators, though as with all interventions not without potentially concerning caveats such as the observation that "recent findings suggest that male mice subjected to SAAR display decreased bone tissue density in both trabecular and cortical bone, simultaneous with an observed induction in fat accumulation in bone marrow."

A potential counter-argument regarding attainability of SAAR in humans is that at least one study found that mere 40% MetR - something more realistically attained -"decreases heart mitochondrial ROS production at complex I during forward electron flow, lowers oxidative damage to mitochondrial DNA and proteins, and decreases the degree of methylation of genomic DNA." ( that's from Gusavo Barja's work:  https://link.springer.com/article/10.1007/s10863-011-9389-9 ).  However it should be kept in minds that these are merely biomarkers for health and longevity and thus do not necessarily demonstrate life extension per se.

Michael has not advised protein excess however as there is good data suggesting higher than RDA numbers may be deleterious, which is not the same thing as saying RDA numbers are life-extending, merely that RDA numbers prevent excess mortality seen when such thresholds are exceeded.  " A word of caution against excessive protein intake (2019) provided a nice review of some of the problems with excessive protein, sorry it is behind a paywall: https://www.nature.com/articles/s41574-019-0274-7 .  We can recall here that the RDI meeting the needs of 97.5% of the population is 0.8g/kg/day with some controversy for the geriatric population which may need up to 1.0-2.0 g/kg/day or more.  This contrasts with an Estimated Average RequIrement (EAR) of only 0.6 g/kg/day.  And in the UK the Reference Nutrient Intake (RNI) is set at 0.75 g/kg/bw

This difference between the RDI and EAR underlies Mccoy’s periodic reminders on inter-subject variability in protein requirements.

Here's an example to illustrate with nice round numbers: Let's say a 5 foot 8.5 inch tall healthy,( no absorption problem, no renal or hepatic disease, history of inflammatory bowel disease, free from chronic and inflammatory conditions with higher protein requirements such as status post a major burn, etc.) middle-aged ( ie., not geriatric) , active but not-an-athlete nor targeting any particular body composition goals individual practices "mild CR"  is in the low end of normal body weight, a little above the underweight/normal weight demarcation.   For some perspective, at 5 foot 8.5 inches, some milestones include 115 pounds = BMI 17.2 , 120 pounds = BMI 18.0, 125 pounds= BMI 18.7, and 130 pounds = BMI 19.5 .   The cutoff between normal weight and underweight is a BMI of 18.5, which would about 123.15 pounds.  I provide this for perspective.

One quick note -  A common question is whether to use actual or lean body mass.  In theory estimates of lean body mass  ( LBM) may be more accurate than using actual weight - however the difference between the two is likely not that great given the readers are presumably CR members.   For a manuscript making the case LBM is superior, see  "Inadequacy of Body Weight-Based Recommendations for Individual Protein Intake—Lessons from Body Composition Analysis"  2016: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295067/pdf/nutrients-09-00023.pdf   

If you use this method , fat free mass can be determined by bioelectrical impedance (BIA), DEXA, or other methods.

 In either case let's say this individual practices  "mild CR," and either weighs 121.25 pounds ( i.e., a BMI of exactly 18.5), or weighs a little more than that and prefers the FFM approach.  This converts to a nice round number: 55 kilograms. 

So 55 kg *0.8 g/kg/d = 44 g/day total protein RDI  - and this meets the needs of 97.5% of individuals at that FFM.

What does the estimated average requirement ( EAR ) meeting 50% of the population needs look like for that FFM?  0.6 g/kg/day = only 33 g/day total protein.

By comparison Valter Longo in his Longevity Diet, based on his own subjective assessment of risks/benefits for the average healthy individual, recommends 0.31 to 0.36 grams per pound protein per day .  For 125.25 pounds, this corresponds to i the neighborhood of 38.8- 45.1 g/day  

Finally for Met+Cys ( ie, TSAA) with a DRI of 19 mg/kg/day this is 1,045 mg/day or around just over a gram a day.

Two notes:

Note 1: The values above represent only one paradigm, other guidelines are discussed and debated at :

where mccoy cites a great piece going into the underlying molecular mechanisms including areas of knowledge: gaps: https://www.intechopen.com/books/muscle-cell-and-tissue/molecular-mechanisms-controlling-skeletal-muscle-mass .  Sarcopenia yields significant morbidity such as from frailty and loss of independence as well as survival  with aging, so preserving lean muscle mass warrants attention to be balanced with the benefits of not exceeding minimum requirements for maintaining muscle and molecular structure and function.

For just a taste of the complexity and controversy over how best to estimate protein requirements, consider this passage:

"Because the concept of protein requirement is predicated on an appropriate supply of the essential  AAs and sufficient nonessential AAs and nitrogen, it is imperative the AA requirements are determined appropriately. To assess AA requirements properly, careful consideration must be given to the experimental design, statistical analyses, and interpretation of the results. Methods of assessing protein and AA requirements and availability have focused on outcome measures such as nitrogen balance, AA oxidation, growth, and blood concen- trations of urea nitrogen and plasma AAs in 
studies where animals were adapted to the diets over days or 1–2 weeks, depending on the outcome measures. [...] The majority of AA requirements have been mea- sured using short adaptation periods, usually anywhere from 2 to 14 days. This short duration fails to account for physiological adaptations over longer time periods. Indeed, the potential effects of PR or Met restriction (MetR) are likely repercussions of much longer feeding periods and are there- fore associated with protein accommodation rather than adaptation. Scrimshaw and Young19 eloquently described how accommodation to lower protein intakes results in loss of lean body mass and reduced rates of protein and AA turnover, and that these are related to survival.19 We are only starting to under- stand how both indispensable and dispensable AA intakes contribute to mammalian health and well- being. In 
contrast to the PR and MetR literature, human nutritionists generally seek to supply adequate protein and AAs to promote lean body mass, especially when combined with adequate physical activity.15 Under these conditions, nutritionists seek to then understand how other dietary 
variables and the environment may affect these requirements." 
[ source: Lessons from animal nutritionists: dietary amino acid requirement studies and considerations for healthy aging studies" https://www.researchgate.net/publication/322687412_Lessons_from_animal_nutritionists_Dietary_amino_acid_requirement_studies_and_considerations_for_healthy_aging_studies ] 

This review, presenting data of variable quality makes a case for higher-than RDA requirements in a variety of settings: "Protein for Life: Review of Optimal Protein Intake, Sustainable Dietary Sources and the Effect on Appetite in Ageing Adults" ( 2018) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872778/pdf/nutrients-10-00360.pdf

In contrast, this recent high quality RCT published in JAMA internal medicine found that "changes in lean body mass, muscle strength and power, and physical function did not differ between men who consumed controlled diets containing the recommended dietary allowance and men who consumed a higher amount of protein (1.3 g/kg/d) for 6 months." Source: "Effect of Protein Intake on Lean Body Mass in Functionally Limited Older Men
A Randomized Clinical Trial" ( 2018): https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2673735

And then, finally, there research  - primarily basic and translational on the impact of sub-RDA levels of protein and certain AAa such as Met+Cys or BCAA’s ( as well as tryptophan, which I do not discuss in this thread) - and more on this can be found below and in the references provided in this post throughout.  Among the most comprehensive is the Lancet piece I keep referencing: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(19)30239-7/fulltext

Though ““methionine restriction extended lifespan in mice by nearly 7% [267], rats by 44% [268], and Drosophila by 36% [269]”  [  Source “Amino acids in the regulation of aging and aging-related diseases” https://www.sciencedirect.com/science/article/pii/S2468501119300082 ], it is worth considering how much of the benefits of PR are explained by CR.  

Speakman’s analysis of rodent data concluded that “Our analysis of multiple manipulation experiments in rodents over the past 80 years shows that the food restriction effect on lifespan is due to reduced calories and not reduced protein intake (or sucrose intake, and possibly also fat intake), and hence is correctly called ‘caloric restriction’ or CR. Nev- ertheless, it is also clear that there is an independent impact of dietary protein reduction on lifespan, but it operates over a different range of restriction (50 to 85%: relative to a reference intake of 18–26% protein in the diet) than that over which CR is effective (10–65% relative to ad libitum intake), and has a much smaller impact. Hence, reducing protein levels by 80% (from 20% to 4%) increases median lifespan by about 15%, while reducing calories by half this amount (40%) increases median lifespan by on average twice as much (30%).” [ Source:  “Calories or protein? The effect of dietary restriction on lifespan in rodents is explained by calories alone ( 2016) https://www.abdn.ac.uk/energetics-research/publications/pdf_docs/457.pdf ].   The overlap and relative magnitude of CR vs PR continues to be hotly debated and will be the subject of further research teasing this apart.  Less controversial is the  CR-independent metabolic and cancer risk reduction benefits of PR/BCAA/MetR, etc, as highlighted in multiple reviews cited in this post.


Hence, debates in the scientific community abound, both regarding what is the optimal research protocol to capture our true protein/AA demand, the interpretation of these protocols and methods, and over the fine art and subjective assessment based on limited human data on what might comprise the best balance between (a) avoiding excess AA ( or Met in particular for example) and (b) avoiding deficiency/malnutrition that at a certain level may outweigh the benefits of AA/Met moderation/restriction.

The sample calculation above was provided for illustration purposes only and is not medical advice.  Individuals requirements vary by age, health status and physical activity level and other individual and environmental factors that can effect protein requirements; for example, for an overview of some factors affecting individuals over 40 years old, see:  "Protein for Life: Review of Optimal Protein Intake, Sustainable Dietary Sources and the Effect on Appetite in Ageing Adults," 2018 @ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872778/pdf/nutrients-10-00360.pdf for more).  Given such variation, mccoy has advocated in the past for individualized testing of protein requirements in the past, but regardless, where you stand on this, consultation with a knowledgeable and competent nutritionist, dietitian, or medical doctor specializing in this area would be best for significant nutritional interventions.

Another metric is that moderated protein diet tend to average only  around 7-9% calories from protein  ( Dr. Fontana tends to use these numbers) , while in the U.S. the interquartile range ( IQR) is more like 10%-20% with most in the 1.0-1.5 mg/kg/day of protein [ Source: "A word of caution against excessive protein intake" 2019: https://www.nature.com/articles/s41574-019-0274-7

Again, requirements vary greatly, and these numbers are not set in stone: For example, Fontana examined a little less than 0.8g/kg/day ( ie 0.76 g/kg/day) total protein in humans relative to 1.73 g/kg/day and found a reduction in serum IGF-1 from 194 ng mL −1 to 152 ng mL  with a concomittant elevation in IGFBP3 ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673798/ ) which we have reliably reproduced  in follow-up studies ( esp. the rise in IGFBP3).  

Refer to my link in this paragraph for a review of some of the problems with excess protein - the data is based on various study designs and variable in quality - everything from epidemiological studies in man, to short-term RCTs focusing on surrogate markers of health and longevity, to well-controlled animal model . 

Something Michael emphasized in his long, well-documented thread above is that “based on data from both the Nurses’ Health Study (followed up from 1980 to June 1, 2012) and the all-male Health Professionals Follow-up Study (followup 1986 to January 31, 2012)” - and here Michael quotes the review: "The median protein intake, as assessed by percentage of energy, was 14%for animal protein (5th-95th percentile, 9%-22%) and 4%for plant protein (5th-95th percentile, 2%-6%). After adjusting for major lifestyle and dietary risk factors, animal protein intake was weakly associated with higher mortality, particularly cardiovascular mortality (HR, 1.08 per 10% energy increment; 95%CI, 1.01-1.16; P for trend = .04), whereas plant protein was associated with lower mortality (HR, 0.90 per 3% energy increment; 95%CI, 0.86-0.95; P for trend < .001). These associations were confined to participants with at least 1 unhealthy lifestyle factor based on smoking, heavy alcohol intake, overweight or obesity, and physical inactivity, but not evident among those without any of these risk factors."

So that's the background, but how about BCAA ( leucine, isoleucine, valine) specifically?  Just as we have seen for total protein - where  definitions vary in intake threshold, organism, outcome of interest, and theoretical grounding ( e.g. g/kg vs. % calories vs. carbohydrate to protein ratio [ e.g., nutritional geometry framework ]  vs. percentile of RDA or RDI, vs. percentile of measures observed in in the ad libitum population ),  BCAA data is also all over the map.  So the answer depends on what outcome you care most about, and how you feel about their methodology as well as the suitability extrapolating your goals in that domain. 

From the review I directed your attention to at the very top of this post, references 10, 12, and 75-84 focus most on this issue and you can read section 5.1 of the review to follow along depending on what benefits and protocols interest and suit you the most.   In particular, you may find Fontana's work  - whereby reducing total protein to only ~ 7-9% calories ( vs. ~50% more in the ad libitum controls) in humans improves metabolic markers, while in mice reducing BCAA's in particular by about 2/3  ( ie from 21% to 7%) recapitulated most of the metabolic benefits observed via 2/3 overall total protein  reduction - pertinent : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947548/pdf/nihms-800719.pdf ( "Decreased consumption of branched chain amino acids improves metabolic health"). 

For comparison,  recall that the traditional Okinawan diet has ~9% kcal from protein with a C:P ratio of around 10:1, dubbed as the "Okinawan Ratio" by Simpson et. al. using their yet-controversial nutritional geometry framework: https://academic.oup.com/ageing/article/45/4/443/1680839

Having said that, why is there a relative dearth of BCAA standardized geroscience protocols compared to MetR despite the comparatively robust literature on BCAA and its anabolic effects of muscle hypertrophy?  Partly because MetR -  in contrast with BCAA - at least for synthetic diets with dramatically lower met+cys (ie MetR) protocols empirically have been observed to have a fairly consistent and robust impact on life extension.  So BCAA work has focused more on moderating  rather than restricting, and disease prevention rather than true life extension per se.    There is lots more to it ( e.g., adding back Met specifically to CR diet abrogating the benefit of CR in at least one model), these are some of the highlights.

Edited by Mechanism

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Glad it was helpful Clinton.  I did some polishing and just added a couple new sections and sample calculations.

Edited by Mechanism

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Mechanism, thank you for the great post! It really helps sort it all out in one place and make better sense of it all.

I am not sure I have any hope of getting my protein intake down to the levels discussed, while still getting a balanced diet. Here is a snapshot of my protein intake over the last three months:

1013694526_ScreenShot2020-02-10at14_48_04.png.b5a2f83a86eab684eee88cb9bfa1d488.png


Virtually all of my protein is from plant sources (I eat cheese very rarely) and mostly from flax, nuts and seeds, legumes and cacao nibs.

But, I average close to 70g of fiber daily, so I wonder if having a diet high in fiber reduces the absorption of plant protein, which I believe is a little less bioavailable than animal protein anyway?

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Hi Ron indeed this is what Michael argues, that it is not possible for natural diets and is more the purview of synthetic diet to achieve true SAAR.

As I stated, more realistic Is methionine moderation to RDAish levels ( and as Michael warms and I caution below-RDA levels are not without risk) rather than striving for research protocol level restriction with the full caveat on morbidity prevention associated with the former vs. potential life extension suggested in animal models for the latter.  Indeed, RDA may be too low depending on your age, health, and circumstances.  Everything posted is not medical advice, but only for information purposes - Consult with your health professional!   🙂

if there is any rule of thumb take away, it is simply that a balanced, moderated calorie, yet high nutrient whole foods based diet and sound lifestyle is more important than precise protein levels as long as you don’t overdo it.

Vegetable  protein quality is generally lower from most sources, which is good for most people and indeed fiber can reduce absorption though not tremendously.

Getting down to RDA levels of methionine is definitely possible.   Playing around with cronometer it is possible to isolate the highest and lowest sources of methionine which can be readily identified.  For example, it is possible to consume up to 3000-4500 kcal with 100-150% total protein requirements yet with (Met+Cys) in the 50%-120% range.   That also implies <50% range for moderated calorie or FMD-like semi-fasting days of similar dietary composition and Of course 0% with a complete water fast.   Keep in mind this may be helpful or harmful in humans and the jury is still out there; the most conservative approach would be to aim for 100% met+cys but not necessarily above that unless your background and circumstances indicate you would personally benefit from more.
 

While leucine levels remain quite stable during fasts, Met drops like a rock and is one input for lower IIS signaling and mTOR inhibition with downstream autophagy - which in turn helps recycle AAs.
 

Not advocating that example, just speaking from experience that it is possible for most people to get methionine down to RDA-ish levels provided that  they are data-oriented with flexible preferences and permissive circumstances.
 

As a rule of thumb, legume-heavy and vegan / near-vegan diets, and dilution by non-protein sources ( like healthy fats and/or carbs) tend to have lower methionine levels.

For your interest, see the charts here on methionine levels by food ( through remember it is really C+M so not 100% accurate): https://www.brendadavisrd.com/methionine-restricted-diet/

Or really drill down with cronometer coupled with isolating low Met and Cys ratios with this nifty tool: https://tools.myfooddata.com/nutrient-ranking-tool.php

Of course it depends in your dietary preferences.  I personally enjoy giant whole foods based meals centered around diverse non-starchy vegetables and nuts.  

 Remember, macadamia nuts are your friend! 

good luck,

-Mechanism

 

Update:  The should be interpreted with caution: Not only is this study based on observational data but cross-sectional too!  Though NHANES is a high quality study from a descriptive epidemiology vantagepoint, even with statistical adjustment we cannot infer causality.   Cross-section data is much better at generating hypotheses than anything else.   Nevertheless, I found this interesting enough to post.   

Source: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(19)30257-3/fulltext ( Association of sulfur amino acid consumption with cardiometabolic risk factors: Cross-sectional findings from NHANES III ). 

Recall ( and in quotes from this study) "Estimated Average Requirement (EAR) of 15 mg/kg/day (required for meeting the needs of half of the population of healthy adults) and Recommended Daily Allowance (RDA) of 19 mg/kg/day (12.2 mg/kg/day for methionine (Met) and 6.6 mg/kg/day for cysteine (Cys)) (required for meeting the needs of 97%–98% of the population of healthy adults) ."

In this study they found Q1 (quintile 1) had on average only 1.50 g/day SAA on average  ( in the 0.7-1.8 g/day of SAA range); alternatively Q1 had an average of 20.1 mg/kg/day (or range of 15.0-24.1 SAA mg/kg/d).  Relative to this lowest quintile, they found "After multivariable adjustment, higher intake of SAA, Met, and Cys were associated with significant increases in composite cardiometabolic disease risk scores, independent of protein intake, and with several individual risk factors including serum cholesterol, glucose, uric acid, BUN, and insulin and glycated hemoglobin (p < 0.01)."  

Although they interpreted "[other studies] together with our present findings, provide support for optimal dietary SAA levels being as close to, but not below, dietary requirements (EAR). Since we observed significantly lower risk values in the first quintile compared with the fourth and fifth quintiles as well as a significant overall trend, we make the assumption that the lowest quintile represents optimal SAA intake."  they nevertheless cautioned ( as do I ) that "It is important to note that the EAR represents an average for the population and that some individuals may have somewhat higher requirements for maintenance of nitrogen balance. For this reason, the RDA value, which is designed to meet the needs of 97%–98% of the population may be a more appropriate target for the population at large."  And I would add or potentially higher requirements at the individual level, depending on age, comorbidities, diet/absorption, genetics and other bio-individual factors.

Edited by Mechanism

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Thanks, Mechanism! Macadamia nuts are on order, next to my walnuts, almonds and Brazil nuts (one a day)

I like MyFoodData, the top item for vegan foods lowest in methionine is Beer! :)

I just ran across this, which among other things discusses median protein and specifically, leucine, intake:

Knowledge Gained from Studies of Leucine Consumption in Animals and Humans
"Food intake surveys underestimate nutrient intakes because of underreporting and my analysis of the UK adult National Diet and Nutrition Survey (8), trimmed of under-reporters (i.e., energy intakes <1.35 × predicted basal metabolic rate), indicates median and 90th percentile intake values for protein of 1.25 and 1.61 g · kg−1 · d−1(14.2 and 17.3% energy) and 108 and 138 mg/kg leucine at 8.3% (9) of the protein intake. Modeling the more recent UK National Diet and Nutrition Survey protein intakes of 17.6% food energy (10) for a physically active 70-kg young man (physical activity level = 2.2) indicates a protein intake of 2.41 g · kg−1 · d−1 or 200 mg · kg−1 · d−1of leucine. Our studies of 90-kg body builders (11) indicated protein intakes up to 3.05 g · kg−1 · d−1(28% protein calories) of a mainly animal protein diet [8.6% leucine (9)]; i.e., a food leucine intake of 262 mg · kg−1 · d−1(∼7 × the recommended dietary allowance). Although little is known about the long-term health impact of these high-protein intakes, it can be assumed that such intakes are widespread."

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