OP
Thanks for the additional pointers.
I suspect glycine chelates heavy metals, as several amino acids have been shown to do in vivo. Will see if I can find something specific on chelation and post it here.
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Dietary Glycine Supplementation Mimics Lifespan Extension By Dietary Methionine Restriction
- Thread starter haidut
- Start date
Thanks for the additional pointers.
I suspect glycine chelates heavy metals, as several amino acids have been shown to do in vivo. Will see if I can find something specific on chelation and post it here.
Momado965
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LOL
Koveras
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I think your calculations are off - the 8% and 12% figures are g/kg food.
Using a rat diet from a similar study that was ~17% protein...
For a human this equates to
80g protein intake = 27-33g glycine per day
100g protein intake = 35-40g glycine per day
OP
I guess there are two ways of looking at this. If you directly convert into humans based on percentage of calories, and assume protein intake for a human then your calculation would be partially correct. However, even in your conversion I don't think we can say the dose was 8% of protein consumed. It was 8% of total diet, and this is how rat dietary doses are typically given. So, a rat eating about 20g of food per day would mean glycine intake of about 1.6g per day per rat. Most rats used in experiments weigh about 200g so that dose would translate to 8g/kg of bodyweight for a typical lab rat. So, for a human that would be 1.3g/kg of bodyweight, which means 100g+ glycine daily for most people.
There is another formula, which is actually considered more standard and it provides the same final result, which makes me think my approach at least matches what the study intended to convey. So, assuming the percentages glycine given were for total diet and not just protein, an 8% of diet means 80g/kg of food. There are conversion charts for rats that show a given dose in mg/kg of diet can be converted to mg/kg of bodyweight by dividing by 10 (the conversion factor for mice is 6.5 in case you need it for other studies). So, 80g/kg of diet would correspond to 8g/kg of bodyweight, which would be a HED of 1.3g/kg of bodyweight for a human. That matches exactly the other calculation I did above based on assumed rat weight and daily food intake. The advantage of this second approach is that you do not need to know the rat weight or exact food/water intake daily. You just divide the dose per unit of diet by 10 and get a dose per unit of bodyweight.
Anyways, it would be nice if the study design can be replicated with 25g glycine a day even though that would still mean eating about 100g gelatin daily to get that much glycine. If the proline and hydroxyproline in gelatin have largely the same effects as glycine then maybe even a 25g dose gelatin is enough.
Koveras
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Hmm
I converted the %/kg diet to % protein intake - 8% glycine /kg diet equating to 34% of the protein intake (protein itself was 170-200 g/kg and 17-20% of calorie intake)
If you applied your method to any of the amino acids the rats were eating it would lead to some very high numbers - for example the same diet has glutamic acid at 4% , lysine at 1.8%, arginine at 1.2%, etc.
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OP
True. Does the study say it was % of total diet or % of protein intake? I seem to remember it was % of total diet but maybe this study used another formula. In the past, due to the same concerns as you, I emailed a few authors about these percentages (in regards to other studies) and they responded that it was as % of total diet. At some point I was really interested in taurine and studies with taurine in rats commonly use 1% to 2% of diet. So, I thought that this is quite a high dose, just like you did for this study, and emailed a few authors and that's how I got the division by 10 factor for rats, and was told that yes, 1% would be 1g/kg of bodyweight, so 10g-15g for a human daily. Here is a document that one of the authors sent me that shows the conversion charts for mg/kg diet to mg/kg bodyweight for various animal models.
[PDF] The mg/kg/day is converted NOEL of the ppm display, translate from - Free Download PDF
Koveras
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I re-ran the numbers with animal bodyweights and food consumption from the PDF you attached.
If you use the numbers for an adult rat (400g), intake is still high, but almost reasonable.
In my table dark blue squares are the HED using a 400g adult rat (20g food consumption), and dark green squares are young rat numbers (100g BW, 10g food consumption) which is equivalent to your scenario with 200g BW/ 20g food consumption.
Using your scenario, they have an HED of 3.8g PROTEIN/kg-BW/day and an HED of 1.3g GLYCINE/kg-BW/day
Using the PDF's adult rat numbers, they have the more reasonable HED of 1.9g PROTEIN/kg-BW/day and an HED of 0.6 g GLYCINE/kg-BW/day.
Either way across the board the 8% dietary glycine figure equates to roughly 33% of protein intake or maybe another metric would be a 10:1 glycine:methionine ratio.
The animal's control diet was 17.2% protein, 64.8% carbohydrates, and 18.0% fat by CALORIES.
---
Keeping in mind that the ratios of amino acids seem to be important, I would be more tempted to set my own protein intake at whatever I felt was important - say 1 g/kg-BW/day for a weight training individual, or for the non-training Peat crowd maybe 20% calories or 80-120g total
...then using whatever protein target you set and aiming for that ~33% glycine
OR keeping in mind that reducing methionine intake would reduce glycine needs, maybe the 10:1 glycine:methionine is a better target.
Still extrapolating some things here so I wouldn't get too attached to the exact numbers.
---
Also the lead author of these studies, Joel Brind, seems slightly controversial and sells glycine supplements.
According to this paper
"In rats fed a high methionine diet, the hepatic methionine level was significantly increased with a concomitant decrease in the levels of glycine, serine, and threonine."
"The addition of glycine to the high methionine diet effectively suppressed the enhancement of the hepatic methionine level and almost completely restored the glycine level, but it only partially restored the serine level and further decreased the threonine level."
"The addition of glycine to the high methionine diet effectively suppressed the enhancement of the hepatic methionine level and almost completely restored the glycine level, but it only partially restored the serine level and further decreased the threonine level."
...I should probably get around to reading this
I'd be tempted to think that overall you'd be better off keeping methionine and total protein on the lower side for longevity ...and not supplementing with very high amounts of any one.
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OP
Thanks, very detailed work!
BCAA and aspirin inhibit methionine absorption from diet, and aspirin inhibits tryptophan absorption as well. Some studies found BCAA also inhibit tryptophan absorption from diet by competition for active transport but the results were not consistent. Maybe one reason why both BCAA and aspirin extend lifespan by mimicking methionine/tryptophan restriction. Glycine extends lifespan in other models when used in much smaller doses equivalent to 2g-3g daily in humans, and in 5g-6g doses it reverses aging in human cells (in vitro). Proline/hydroxyproline in gelatin have also been shown to extend lifespan so maybe able to fill in for glycine and thus may be able to get the health/lifespan benefits even from much smaller doses like 1 spoon gelatin daily.
Amazoniac
Member
I guess there are a few problems in the approaches above. It's an assumption that animals of all groups develop normally regardless of their diet and that extreme manipulations in what they eat won't affect food intake.
This can also impact the human equivalent dose because the weight that the gurus had in mind is outside of the working range for rat standard (and mouse as well); they might grow disproportionately due to the interventions, ending up with a body surface area that's closer to normal than the weight, making the correction factor off.
For a fixed amount of food (as 100%), when you increase a single element of the composition, the expected consequence is that everything else will decrease to give space for it, but we know from the abstract that this didn't happen because the methionine remained the same no matter how the glycine content varied.
(those are quality issues after upload)
They can imply that they is isocaloric diets (as they did in one of the experiments below) where energy wasn't modified, with carbs decreasing as compensation; this way, at least the proportion of other amino acids relative to methionid stays the same, however it's an admission that all glycine is being burn'd for energy.
Protein content could have increased from 20% to 30% of diet due to the glycine addition, and since Koveras' calculations are based on this, the figures can be far from what happened in the experiment.
That's why food intake has to be reported. To make it fairer, as supplemental glycine increased, food intake has to increase along:
Otherwise the animals getting more glycine might be on a diet that's being restrictive in usable calories in spite of them looking similar in theory.
There are a lot of confounders that make such extrapolation challenging.
Due to this, I contact'd Joel "The Author" Brind, who kindly replied that the experiment in question was published only as an abstract, but that he had a poster of it from a conference with more details.
- Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats (attach'd)
Extra glycine is not a substitute for methionine restriction, it only mitigates some of the issues when the amounts are high enough.
He has a recent publication as well:
- Glycine supplementation extends lifespan of male and female mice
This can also impact the human equivalent dose because the weight that the gurus had in mind is outside of the working range for rat standard (and mouse as well); they might grow disproportionately due to the interventions, ending up with a body surface area that's closer to normal than the weight, making the correction factor off.
For a fixed amount of food (as 100%), when you increase a single element of the composition, the expected consequence is that everything else will decrease to give space for it, but we know from the abstract that this didn't happen because the methionine remained the same no matter how the glycine content varied.
(those are quality issues after upload)
They can imply that they is isocaloric diets (as they did in one of the experiments below) where energy wasn't modified, with carbs decreasing as compensation; this way, at least the proportion of other amino acids relative to methionid stays the same, however it's an admission that all glycine is being burn'd for energy.
Protein content could have increased from 20% to 30% of diet due to the glycine addition, and since Koveras' calculations are based on this, the figures can be far from what happened in the experiment.
That's why food intake has to be reported. To make it fairer, as supplemental glycine increased, food intake has to increase along:
Otherwise the animals getting more glycine might be on a diet that's being restrictive in usable calories in spite of them looking similar in theory.
There are a lot of confounders that make such extrapolation challenging.
Due to this, I contact'd Joel "The Author" Brind, who kindly replied that the experiment in question was published only as an abstract, but that he had a poster of it from a conference with more details.
- Dietary glycine supplementation mimics lifespan extension by dietary methionine restriction in Fisher 344 rats (attach'd)
"Male F344 rats (7w) were fed purified diets containing 0.43% met (control-fed; CF), 0.17% met (methionine-restricted; MR), or CF supplemented with gly (GS) to yield total gly contents of 4%, 8%, 12%, or 20% by wt. Gly content of CF and MR diets was 2.3% by wt. All diets were devoid of L-cys. Animals were allowed food and water ad lib and remained on diet until death, except where noted. Food and body weight were monitored weekly."
Extra glycine is not a substitute for methionine restriction, it only mitigates some of the issues when the amounts are high enough.
He has a recent publication as well:
- Glycine supplementation extends lifespan of male and female mice
"A small study using glycine supplementation in Fisher 344 rats showed significant lifespan extension at levels of 8%, 12%, and 20% (Brind, 2011), although the higher glycine levels led to weight loss compared to control rats. Maximum lifespan, evaluated by the Wang/Allison method, was significantly increased (p = 0.03) only at the 8% supplementation level. In this earlier experiment, glycine treatment did not elevate plasma methionine levels, suggesting that the effect was not due to minimizing methionine toxicity, but to some other, unknown, mechanism."
"Our most interesting new finding is that glycine‐supplemented diets extend lifespan of male and female UM‐HET3 mice, including significant benefits in lifespan to mice at the 90th percentile age. This supplementation leads to significant effects at each of the three test sites. The result is consistent with an earlier report (Brind, 2011) showing a beneficial effect of glycine on lifespan (including maximal lifespan) in small groups of Fisher 344 rats. The effect in mice, although consistent with this prior rat study, is quite small and does not much alter median survival age. We speculate that variations in this protocol, for example, in which glycine supplementation is started earlier or terminated once mice are fully grown, might have improved effects on health and lifespan."
"A preliminary life‐span study in rats using glycine supplementation (Brind, 2011) was originally conceived as an approach to mimic the well‐established life‐extending effect of methionine restriction (Brown‐Borg et al., 2014; Miller et al., 2005; Orentreich, 1993; Richie et al., 2004; Sun, 2009). The strategy was based on the understanding that glycine is the only acceptor for methyl groups by the action of glycine‐N‐methyl transferase (GNMT), and that in turn GNMT represents the only pathway for the clearance of excess methionine in mammals (Luka et al., 2009). Supplemental glycine, however, was found (Brind, 2011) not to reduce plasma methionine levels, in contrast to the 60% reduction in plasma methionine levels seen in rats on a low methionine diet. This result suggested that elevated glycine levels, in plasma or tissues, might in themselves produce health benefits and increased longevity. Glycine receptors are gated chloride channels that hyperpolarize plasma membranes and can inhibit cell activation; although they were originally thought to be restricted to the nervous system, more recent work has demonstrated glycine receptors on many cell types, including macrophages of lung and liver, and platelets (Schemmer et al., 2013; Wheeler, 1999). Glycine promotes chloride influx largely at concentrations (0.5–1 mM) that are considerably higher than those needed for protein synthesis and one‐carbon transfer reactions. Prevention of cell activation and depolarization by maintenance of resting membrane potentials may help to limit macrophage activation (Zhong et al., 2003)."
"The present study provides support for the hypothesis that consumption of glycine in the normal diet may be suboptimal for longevity, and that higher levels might be beneficial, perhaps through moderation of inflammatory processes. The limited data from the rat study (Brind, 2011) suggest that higher glycine doses might not produce higher benefits, but it is possible that initiation of glycine supplementation at an earlier age might be worth testing."
"We considered the possibility that extended longevity in the glycine‐treated mice might reflect low food intake. This seems unlikely, because male mice show extended longevity without small body size. Food intake is very difficult to measure accurately, because of complications from food wastage into cage bedding, caloric loss in feces, and variability among mice in the same cage. In addition, small mice eat less food than large mice, because they have diminished the need for thermogenesis; thus, an association between size and food intake does not demonstrate a causal connection in either direction. We cannot, however, rule out the possibility that glycine supplementation might have led to low food intake and to extended longevity in female mice. Incorporation of glycine into the diet lowers its calorie density by <1%, which is unlikely to lead to any alteration in nutritional status or health."
"The ITP protocol for longevity studies [used] has been described extensively elsewhere (Miller et al., 2014; Strong, 2016), with details on source of food, bedding, cage changes, light/dark cycle, and other husbandry details. In brief, mice are bred as the progeny of (BALB/cByJ × C57BL/6J)F1 mothers and (C3H/HeJ × DBA/2J)F1 fathers, so that each mouse is genetically unique and a full sib to all other mice with respect to segregating nuclear alleles. Mice are housed at three males or four females per cage from weaning, without replacement as mice die at older ages. They are given free access to food and water. Purina 5LG6 [*] is used as the base diet from weaning, with drugs and supplements given at the concentrations shown in Supporting Information Table S1."
"Our most interesting new finding is that glycine‐supplemented diets extend lifespan of male and female UM‐HET3 mice, including significant benefits in lifespan to mice at the 90th percentile age. This supplementation leads to significant effects at each of the three test sites. The result is consistent with an earlier report (Brind, 2011) showing a beneficial effect of glycine on lifespan (including maximal lifespan) in small groups of Fisher 344 rats. The effect in mice, although consistent with this prior rat study, is quite small and does not much alter median survival age. We speculate that variations in this protocol, for example, in which glycine supplementation is started earlier or terminated once mice are fully grown, might have improved effects on health and lifespan."
"A preliminary life‐span study in rats using glycine supplementation (Brind, 2011) was originally conceived as an approach to mimic the well‐established life‐extending effect of methionine restriction (Brown‐Borg et al., 2014; Miller et al., 2005; Orentreich, 1993; Richie et al., 2004; Sun, 2009). The strategy was based on the understanding that glycine is the only acceptor for methyl groups by the action of glycine‐N‐methyl transferase (GNMT), and that in turn GNMT represents the only pathway for the clearance of excess methionine in mammals (Luka et al., 2009). Supplemental glycine, however, was found (Brind, 2011) not to reduce plasma methionine levels, in contrast to the 60% reduction in plasma methionine levels seen in rats on a low methionine diet. This result suggested that elevated glycine levels, in plasma or tissues, might in themselves produce health benefits and increased longevity. Glycine receptors are gated chloride channels that hyperpolarize plasma membranes and can inhibit cell activation; although they were originally thought to be restricted to the nervous system, more recent work has demonstrated glycine receptors on many cell types, including macrophages of lung and liver, and platelets (Schemmer et al., 2013; Wheeler, 1999). Glycine promotes chloride influx largely at concentrations (0.5–1 mM) that are considerably higher than those needed for protein synthesis and one‐carbon transfer reactions. Prevention of cell activation and depolarization by maintenance of resting membrane potentials may help to limit macrophage activation (Zhong et al., 2003)."
"The present study provides support for the hypothesis that consumption of glycine in the normal diet may be suboptimal for longevity, and that higher levels might be beneficial, perhaps through moderation of inflammatory processes. The limited data from the rat study (Brind, 2011) suggest that higher glycine doses might not produce higher benefits, but it is possible that initiation of glycine supplementation at an earlier age might be worth testing."
"We considered the possibility that extended longevity in the glycine‐treated mice might reflect low food intake. This seems unlikely, because male mice show extended longevity without small body size. Food intake is very difficult to measure accurately, because of complications from food wastage into cage bedding, caloric loss in feces, and variability among mice in the same cage. In addition, small mice eat less food than large mice, because they have diminished the need for thermogenesis; thus, an association between size and food intake does not demonstrate a causal connection in either direction. We cannot, however, rule out the possibility that glycine supplementation might have led to low food intake and to extended longevity in female mice. Incorporation of glycine into the diet lowers its calorie density by <1%, which is unlikely to lead to any alteration in nutritional status or health."
Was is food efficiency?
"The ITP protocol for longevity studies [used] has been described extensively elsewhere (Miller et al., 2014; Strong, 2016), with details on source of food, bedding, cage changes, light/dark cycle, and other husbandry details. In brief, mice are bred as the progeny of (BALB/cByJ × C57BL/6J)F1 mothers and (C3H/HeJ × DBA/2J)F1 fathers, so that each mouse is genetically unique and a full sib to all other mice with respect to segregating nuclear alleles. Mice are housed at three males or four females per cage from weaning, without replacement as mice die at older ages. They are given free access to food and water. Purina 5LG6 [*] is used as the base diet from weaning, with drugs and supplements given at the concentrations shown in Supporting Information Table S1."
Last edited:
GelatinGoblin
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Good thread. Bump
Amazoniac
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Wasn't is ripofflavin, won't is buffer, will is drain.
- Dimethylglycine supplementation does not affect plasma homocysteineconcentrations in pre-dialysis chronic renal failure patients
- Dimethylglycine supplementation does not affect plasma homocysteineconcentrations in pre-dialysis chronic renal failure patients
I know this is old. I was wondering if you still had this source?. The link is broken and the link does not contain title or author info so couldn't find it. Thanks.
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LadyRae
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I am currently ingesting such levels-
.... 200 grams of gelatin per day actually.... Maybe a bit more if you count the collagen powder I put in my coffee in the morning before breakfast.For the last 3 weeks I have been experimenting with a methionine restricted diet. I do have about 20 to 30 g of animal protein for breakfast, usually either beef heart or liver, eggs or pork loin or oysters, along with fresh fruit like pineapple or melon.
In the morning I make two large bowls of jello with blended fruit(bananas, strawberries, peaches, melon, or pear) and three scoops each of hydrolyzed beef gelatin powder. Zen principle brand. When these are ready to go I put a coconut whip on top and a bunch of salt. They are big and thus very satisfying!
I do not use a scale but instead measure myself. I have lost about an inch or so around my middle and I have to tighten all of my belts an extra notch. My sleep has improved and I notice that my cheeks are warmer and my fingers are never cold...
Has anyone else been experimenting with methionine restriction?
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