Calorie-restricted Rats Live 50% Longer - What's Wrong With The Methodology?

[ANDREW CHIN]

Hello Everyone,
I'm not trained at all in methodology in the hard sciences, so I'm hoping someone can help me here.

I've always heard that calorie restriction and slowing down metabolism will extend lifespan. Obviously, Ray Peat believes otherwise - a high metabolism is a sure sign of health, and that eating more while staying trim is actually optimal.

So what exactly is wrong with the methodology on these studies of calorie-restricted rats that live far longer than the control group?

The Calorie-Restriction Experiment

 

[haidut]

Hello Everyone,
I'm not trained at all in methodology in the hard sciences, so I'm hoping someone can help me here.

I've always heard that calorie restriction and slowing down metabolism will extend lifespan. Obviously, Ray Peat believes otherwise - a high metabolism is a sure sign of health, and that eating more while staying trim is actually optimal.

So what exactly is wrong with the methodology on these studies of calorie-restricted rats that live far longer than the control group?

The Calorie-Restriction Experiment

This has been discussed many times on the forum but essentially, fasting lowers endotoxin and (for the first 48 hours) PUFA inside cells. Avoiding endoxotin rise by eating easily digestible foods, using antibiotics, etc has the same effects on lifespan but without the need to starve yourself.
https://raypeatforum.com/community/threads/the-benefits-of-fasting-are-due-to-lowering-endotoxin-lps-not-less-calories.25483/
https://raypeatforum.com/community/threads/low-protein-high-carb-diet-has-the-same-benefits-as-caloric-restriction.26641/

Btw, fasting is nothing special. The same results can be achieve by restricting anti-metabolic nutrients while keeping caloric intake normal. Google for "tryptophan restriction lifespan", or "methionine restriction lifespan", or "cysteine restriction lifespan", and so on. Restricting any of these amino acids has pro-metabolic effects and still reliably increases lifespan as much as fasting, and in the case of tryptophan restriction (serotonin) it actually exceeds benefits of fasting. Speaking of serotonin, using serotonin antagonists also dramatically prolongs lifespan and blocking serotonin increases metabolism.
https://raypeatforum.com/community/threads/serotonin-antagonists-extend-lifespan-ssri-dramatically-shorten-it.6451/
Blocking Serotonin Extends Lifespan By 40%, Triples Youthspan

Btw, you can easily find all of these by simply searching for "extending lifespan" in the forum search box. Many, if not most, questions I have seen from people over the last year can easily be answered by searching. The forum at this point has a wealth of information on pretty much anything Peat-related, including controversial topics that people think contradict Peat.

 

[ANDREW CHIN]

This has been discussed many times on the forum but essentially, fasting lowers endotoxin and (for the first 48 hours) PUFA inside cells. Avoiding endoxotin rise by eating easily digestible foods, using antibiotics, etc has the same effects on lifespan but without the need to starve yourself.
https://raypeatforum.com/community/threads/the-benefits-of-fasting-are-due-to-lowering-endotoxin-lps-not-less-calories.25483/
https://raypeatforum.com/community/threads/low-protein-high-carb-diet-has-the-same-benefits-as-caloric-restriction.26641/

Btw, fasting is nothing special. The same results can be achieve by restricting anti-metabolic nutrients while keeping caloric intake normal. Google for "tryptophan restriction lifespan", or "methionine restriction lifespan", or "cysteine restriction lifespan", and so on. Restricting any of these amino acids has pro-metabolic effects and still reliably increases lifespan as much as fasting, and in the case of tryptophan restriction (serotonin) it actually exceeds benefits of fasting. Speaking of serotonin, using serotonin antagonists also dramatically prolongs lifespan and blocking serotonin increases metabolism.
https://raypeatforum.com/community/threads/serotonin-antagonists-extend-lifespan-ssri-dramatically-shorten-it.6451/
Blocking Serotonin Extends Lifespan By 40%, Triples Youthspan

Btw, you can easily find all of these by simply searching for "extending lifespan" in the forum search box. Many, if not most, questions I have seen from people over the last year can easily be answered by searching. The forum at this point has a wealth of information on pretty much anything Peat-related, including controversial topics that people think contradict Peat.

Thanks!

 

[Cirion]

Great post Haidut. I am starting to implement many of those strategies you mention and I think I'm finally close to beating my hypothyroid condition.

I vastly under-estimated the impact of some of that, like the amino acid profiles in particular have a massive, massive impact on health that I think most people simply don't appreciate, easily as important as PUFA restriction.

 

[baccheion]

This has been discussed many times on the forum but essentially, fasting lowers endotoxin and (for the first 48 hours) PUFA inside cells. Avoiding endoxotin rise by eating easily digestible foods, using antibiotics, etc has the same effects on lifespan but without the need to starve yourself.
https://raypeatforum.com/community/threads/the-benefits-of-fasting-are-due-to-lowering-endotoxin-lps-not-less-calories.25483/
https://raypeatforum.com/community/threads/low-protein-high-carb-diet-has-the-same-benefits-as-caloric-restriction.26641/

Btw, fasting is nothing special. The same results can be achieve by restricting anti-metabolic nutrients while keeping caloric intake normal. Google for "tryptophan restriction lifespan", or "methionine restriction lifespan", or "cysteine restriction lifespan", and so on. Restricting any of these amino acids has pro-metabolic effects and still reliably increases lifespan as much as fasting, and in the case of tryptophan restriction (serotonin) it actually exceeds benefits of fasting. Speaking of serotonin, using serotonin antagonists also dramatically prolongs lifespan and blocking serotonin increases metabolism.
https://raypeatforum.com/community/threads/serotonin-antagonists-extend-lifespan-ssri-dramatically-shorten-it.6451/
Blocking Serotonin Extends Lifespan By 40%, Triples Youthspan

Btw, you can easily find all of these by simply searching for "extending lifespan" in the forum search box. Many, if not most, questions I have seen from people over the last year can easily be answered by searching. The forum at this point has a wealth of information on pretty much anything Peat-related, including controversial topics that people think contradict Peat.

One nagging thing: doesn't lower serotonin cause (anxiety-ridden) depression?

 

[Cirion]

One nagging thing: doesn't lower serotonin cause (anxiety-ridden) depression?

Excess serotonin / lack of dopamine causes depression. If one is low serotonin and still has depression, it's probably because they concurrently have low dopamine.

There's virtually no such thing as too low serotonin. Low dopamine, however, is quite common.

 

[Hans]

One nagging thing: doesn't lower serotonin cause (anxiety-ridden) depression?

HPA dysregulation has a greater effect on mood than serotonin or dopamine IMO.

Lowering cortisol has a great anti-depressant effect.

For the anxiety, it's more of a hyper HPA responsiveness to stress and low androgens like DHEA.
Excess glutamate and catecholamines are also greatly involved in anxiety.

Serotonin promotes cortisol and glutamate so I'd rather say elevated serotonin is also involved in anxiety and depression.

SSRI drugs promote serotonin receptor downregulation over time and also increases allopregnanolone, which is pro-GABA and anti-anxiety and depression.

 

[Hugh Johnson]

Toxic diet kills you. Less of it kills you slower.

 

[haidut]

One nagging thing: doesn't lower serotonin cause (anxiety-ridden) depression?

So, you have been on the forum for about 2 years and in that time have not heard/read Peat's view on serotonin, or seen the discussions here about serotonin and its role in depression?? Not even once??
https://raypeatforum.com/community/threads/the-dark-side-of-serotonin-exposed-by-haidut-in-70-studies.26016/

 

[baccheion]

So, you have been on the forum for about 2 years and in that time have not heard/read Peat's view on serotonin, or seen the discussions here about serotonin and its role in depression??

No, I don't read the forums extensively.

I mentioned, as MAO-A inhibitors and other serotonin enhancers are often used to treat depression. In addition, higher dopamine and lower serotonin is associated with inner tension, anxiety, suicidal ideation, and depression.

Serotonin is mostly excitatory, hence insomnia at higher levels.

Said about 5-HT1A, the main serotonin receptor:

5-HT1A receptor activation has been shown to increase dopamine release in the medial prefrontal cortex, striatum, and hippocampus, and may be useful for improving the symptoms of schizophrenia and Parkinson's disease.[38][39] As mentioned above, some of the atypical antipsychotics are 5-HT1A receptor partial agonists, and this property has been shown to enhance their clinical efficacy.[38][40][41] Enhancement of dopamine release in these areas may also play a major role in the antidepressant and anxiolytic effects seen upon postsynaptic activation of the 5-HT1A receptor.[42][43]

Also:

5-HT1A receptor activation induces the secretion of various hormones including cortisol, corticosterone, adrenocorticotropic hormone (ACTH), oxytocin, prolactin, growth hormone, and β-endorphin.[61][62][63][64] The receptor does not affect vasopressin or renin secretion, unlike the 5-HT2 receptors.[61][62] It has been suggested that oxytocin release may contribute to the prosocial, antiaggressive, and anxiolytic properties observed upon activation of the receptor.[30] β-Endorphin secretion may contribute to antidepressant, anxiolytic, and analgesic effects.[65]

Both from 5-HT1A receptor - Wikipedia.

I suppose if it is the associated dopamine release that counters depression, then directly increasing dopamine would be sufficient. On the other hand, based on personal experience, dopamine precursors (L-phenylalanine, L-tyrosine, N-acetyl L-tyrosine) eventually increased anxiety. Further, it's commonly recommended that L-tryptophan be taken at night if taking a dopamine precursor in the AM.

There's a common trend on this forum of favoring L-tryptophan depletion, so maybe it's not seen as problematic.

I see a lot of "bad" hormones released (eg, cortisol and prolactin), but some of each are required. In general, I can see how (but it's mostly excess) serotonin could be held in poor regard.

In one post, 40% carb + 40% fat + 20% protein is mentioned. In another, low fat is better due to lowered serotonin.

In any event, the constant cycling between the same thing being good and then bad both annoys and confuses me.

 

[haidut]

No, I don't read the forums extensively.

I mentioned, as MAO-A inhibitors and other serotonin enhancers are often used to treat depression. In addition, higher dopamine and lower serotonin is associated with inner tension, anxiety, suicidal ideation, and depression.

Serotonin is mostly excitatory, hence insomnia at higher levels.

Said about 5-HT1A, the main serotonin receptor:



Also:



Both from 5-HT1A receptor - Wikipedia.

I suppose if it is the associated dopamine release that counters depression, then directly increasing dopamine would be sufficient. On the other hand, based on personal experience, dopamine precursors (L-phenylalanine, L-tyrosine, N-acetyl L-tyrosine) eventually increased anxiety. Further, it's commonly recommended that L-tryptophan be taken at night if taking a dopamine precursor in the AM.

There's a common trend on this forum of favoring L-tryptophan depletion, so maybe it's not seen as problematic.

I see a lot of "bad" hormones released (eg, cortisol and prolactin), but some of each are required. In general, I can see how (but it's mostly excess) serotonin could be held in poor regard.

In any event, the constant cycling between the same thing being good and then bad both annoys and confuses me.

OK, you don't read the forum much but what about Peat's writing/interviews? If you have not come across something so central in his views on health as serotonin, then I am not sure how much help would be to browse a forum that mostly focuses on discussing those views...
I don't think, or heard/read, anybody saying here that you should be dropping your serotonin to zero. But if there is "depression", then elevated serotonin/cortisol are likely involved as causative factors, and I am not even sure through what mechanism LOW serotonin would cause depression. Again, without getting familiar with Peat's writings on serotonin, there is not much point discussing the mechanisms but a TLDR would be that depression is essentially brain energy deficiency, so the mediators of stress (serotonin, cortisol, prolactin, NO, adrenaline, etc), which inhibit energy production, would be prime suspects as causes of depression, not its cures.
Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response. - PubMed - NCBI
https://raypeatforum.com/community/threads/serotonin-injection-induces-a-dramatic-fall-in-brain-atp-levels.26031/

 

[Kelj]

There must be an essential difference between rats and humans. The anecdotes of Okinawans routinely eating up to a certain percentage of fullness, (which seems nebulous) aside, what else is there in human experiments? These are the ideas that spring to my mind. From research: the men in the Minnesota Starvation experiment were not physically benefited by a calorie intake of 1,650 calories per day. They had many physical and psychological problems from that restriction of calories. Their full recovery, which all achieved, was brought about by unrestricted calorie access. My personal experience with eating disorder: eating too low one day and more the next causes obesity. Eating consistently low results in slimness with health problems like low thyroid, rosacea, digestive issues, female issues, spleen troubles, eye troubles, joint degeneration and more. All these were caused by calorie restriction, not calorie absence and cured by unrestricted calorie intake. "There's something rotten" in the state of calorie restricted rat studies

 

[tankasnowgod]

Hello Everyone,
I'm not trained at all in methodology in the hard sciences, so I'm hoping someone can help me here.

I've always heard that calorie restriction and slowing down metabolism will extend lifespan. Obviously, Ray Peat believes otherwise - a high metabolism is a sure sign of health, and that eating more while staying trim is actually optimal.

So what exactly is wrong with the methodology on these studies of calorie-restricted rats that live far longer than the control group?

The Calorie-Restriction Experiment

Maybe nothing is wrong with them..... if you are a rat or other animal living in captivity. But the fact remains that calorie restriction has NEVER been shown to extend the life of ANY animal (even an insect or worm) that isn't in a 100% controlled and protected environment. Which, makes sense. Weakness due to starvation would likely make you easy prey for any predator.

As for the captive experiments, all sorts of toxins (and potentially toxic elements of food) are also restricted, such as PUFA, iron, methionine, and so on, and many (including Ray Peat) have suggested that restriction of some or all of these substances is responsible for any apparent "life extension."

Lastly, if you are thinking of applying this to your own life..... well, are you more dedicated than calorie restriction proponent and pioneer Roy Walford? Roy Walford - Wikipedia

He died in 2004 at age 79, which is less than the average life span, and a full five years before that New York Times article, but strangely, he isn't mentioned in the article at all. So, if a leading proponent of calorie restriction, who worked with some of the original mouse studies, couldn't use that method to extend his own lifespan, well, then I don't know why anyone else would think they would have success.

 

[tankasnowgod]

No, I don't read the forums extensively.

Well, Peat's view that Serotonin is especially problematic isn't something he just mentioned once or twice.... It's basically a central tenant of his work. As can easily be seen in articles such as this-

Serotonin: Effects in disease, aging and inflammation

Serotonin, depression, and aggression - The problem of brain energy.

 

[baccheion]

OK, you don't read the forum much but what about Peat's writing/interviews? If you have not come across something so central in his views on health as serotonin, then I am not sure how much help would be to browse a forum that mostly focuses on discussing those views...
I don't think, or heard/read, anybody saying here that you should be dropping your serotonin to zero. But if there is "depression", then elevated serotonin/cortisol are likely involved as causative factors, and I am not even sure through what mechanism LOW serotonin would cause depression. Again, without getting familiar with Peat's writings on serotonin, there is not much point discussing the mechanisms but a TLDR would be that depression is essentially brain energy deficiency, so the mediators of stress (serotonin, cortisol, prolactin, NO, adrenaline, etc), which inhibit energy production, would be prime suspects as causes of depression, not its cures.
Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response. - PubMed - NCBI
https://raypeatforum.com/community/threads/serotonin-injection-induces-a-dramatic-fall-in-brain-atp-levels.26031/

Peat's writings are sometimes sensible (to me) and at other times make no sense.

Melatonin messed with me for a while, until I understood it as staying in bright light until bedtime to avoid premature melatonin release rather than avoiding it altogether.

Well, Peat's view that Serotonin is especially problematic isn't something he just mentioned once or twice.... It's basically a central tenant of his work. As can easily be seen in articles such as this-

Serotonin: Effects in disease, aging and inflammation

Serotonin, depression, and aggression - The problem of brain energy.

Interesting. I assumed his main thing was progesterone. But then maybe it's due to lowering of serotonin.

I'm generally aware serotonin can be bad. The higher amount leading to depression is new. Even when serotonin-induced depression is described, it sounds different:

"The depression associated with high serotonin is of a different variety from the classical depression, which is most familiar. The typical symptoms of anxiety, low mood, pessimism, sadness, emotional instability, etc. are missing. For that reason it often overlooked, and nothing is done about it." - Symptoms of High Serotonin

I'm also aware of serotonin inducing anxiety, but that's mainly said to be social rather than generalized anxiety.

 

[SOMO]

Peat's writings are sometimes sensible (to me) and at other times make no sense.

Melatonin messed with me for a while, until I understood it as staying in bright light until bedtime to avoid premature melatonin release rather than avoiding it altogether.

Interesting. I assumed his main thing was progesterone. But then maybe it's due to lowering of serotonin.

I'm generally aware serotonin can be bad. The higher amount leading to depression is new. Even when serotonin-induced depression is described, it sounds different:

"The depression associated with high serotonin is of a different variety from the classical depression, which is most familiar. The typical symptoms of anxiety, low mood, pessimism, sadness, emotional instability, etc. are missing. For that reason it often overlooked, and nothing is done about it." - Symptoms of High Serotonin

I'm also aware of serotonin inducing anxiety, but that's mainly said to be social rather than generalized anxiety.

There is a genuine toxicity attributed to Serotoning. I can vouch that high serotonin is a medical emergency.

You can actually die from OVERHEATING when there is too much serotonin in the body: UpToDate

 

[ANDREW CHIN]

There must be an essential difference between rats and humans. The anecdotes of Okinawans routinely eating up to a certain percentage of fullness, (which seems nebulous) aside, what else is there in human experiments? These are the ideas that spring to my mind. From research: the men in the Minnesota Starvation experiment were not physically benefited by a calorie intake of 1,650 calories per day. They had many physical and psychological problems from that restriction of calories. Their full recovery, which all achieved, was brought about by unrestricted calorie access. My personal experience with eating disorder: eating too low one day and more the next causes obesity. Eating consistently low results in slimness with health problems like low thyroid, rosacea, digestive issues, female issues, spleen troubles, eye troubles, joint degeneration and more. All these were caused by calorie restriction, not calorie absence and cured by unrestricted calorie intake. "There's something rotten" in the state of calorie restricted rat studies

Mice and humans share 90% of the same DNA. I'm guessing it's about the same with rats and humans. However, that remaining 10% difference could be huge in some ways, right? I mean, we've seen from Robert Lustig's work on fructose that we can't take scientific findings at face value. His findings sounded great on paper, until we realized that carbohydrate metabolism in mice vs. humans is very different, and that the amount of fructose being consumed by the mice was the human equivalent of drinking five liters of Coke per day.

I believe the mice in this study were full of vim and vigor. Not so much in Ancel Keys' Minnesota Starvation Experiment.

 

[LuMonty]

There is a genuine toxicity attributed to Serotoning. I can vouch that high serotonin is a medical emergency.

You can actually die from OVERHEATING when there is too much serotonin in the body: UpToDate

I can vouch for it as well. When 90F with high humidity feels cool, it's not a fun time.

 

[haidut]

Melatonin messed with me for a while, until I understood it as staying in bright light until bedtime to avoid premature melatonin release rather than avoiding it altogether.

Peat cautioning against melatonin was in regards to supplements as the doses commonly sold/used are massive and likely dangerous. He did say that people with good metabolism have high melatonin response upon onset of darkness and that melatonin is basically the body's way to channel the rise of serotonin with darkness into less problematic pathways. The synthesis of melatonin from serotonin depends on thyroid, so a hypo person will likely have higher than optimal serotonin and lower than optimal melatonin. In such a person, supplementing with more melatonin is one of the worst things that person can do because then both melatonin and serotonin would be higher than optimal and both of them powerfully suppress metabolism, immunity, gonadal function, etc and activate adrenal function (mostly cortisol).
I agree that sometimes his writings are confusing but IMO he has been pretty clear on the serotonin/melatonin topic and there is plenty of evidence to support those views.

 

[Kelj]

He died in 2004 at age 79, which is less than the average life span, and a full five years before that New York Times article, but strangely, he isn't mentioned in the article at all.
Maybe because he died of complications of ALS?
Calorie Restriction Pioneer Roy Walford: Where Did He Go Wrong? – Michael Lustgarten
That is a blow to those who feel calorie restriction is healthy. I think it is just the sort of thing that will happen if you calorie restrict.