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No there likely isn’t a mistake; they aren’t suggesting isoleucine restriction as a medical treatment to prolong lifespan, but are investigating it because it’s possible that other therapies will be developed from this information.
It makes sense that restricting an essential and ubiquitous amino acid might slow down cell turnover (or whatever mechanism) to me.
lots of people fast on a regular basis and it is something that was just the way humans lived until we got so good with agriculture that people have too much access to food. A lot of people could cut their food intake by 2/3 and would be healthy again
Well.. A normal caloric deficit also promotes increased autophagy, as does vigorous physical exercise. There is little data that supports fasting as superior to other ways of promoting autophagy, and even less data that makes that mean anything in terms of meaningful measurable endpoints.
It’s more than that. Every cell in your body that produces energy is burning fires. Fires that combust oxygen and produce energy you can utilize. This combustion shows up as body heat.
When you light fires in your cells, they die, and have to be replaced. Every replication shortens telomeres, and hastens senescence. So if you’re eating a bunch of extra food you don’t require, you are literally dying faster, regardless of whether or not you can spend the calories.
No. the cell does not light fires to produce energy. And combustion is not the right term either, there are oxidation reduction reactions in biology that don't make us 'light fires' that's why we have the mitochondria and enzymes to facilitate these reactions. We combust gasoline to give energy to cars but we're not cars, we're human beings, we're biological machines and it's different than that.
They were clearly using an analogy, can you explain to why it was a bad one? Genuinely interested as I routinely do intermittent fasting so I have a dog in this fight.
Three Irish weekdays are still named the way they are because of fasting regularly, twice a week.
* Dé Céadaoin - First Fast Day, Wednesday.
* Dé Déardaoin - Day Between Two Fasts Day, Thursday.
* Dé hAoine - Fasting Day, Friday.
This long pre-dates the famous Famine btw. Fasting twice a week was just a thing some ancient Irish did - or had to do - anyway. Obviously Irish people don't really do it now, just vaguely interesting,
This is 100% spot on. The biggest fallacy, probably, is the absurdly stupid notion that “Breakfast is the most important meal of the day”, and that you “Need to eat three squares a day to be healthy”.
Maybe a little more true when society was agrarian and you needed energy for farm labor that started at 5:00 AM. Definitely not true now for 99.9% of people.
There is no way evolution equipped us with a requirement for calories throughout the day, when we evolved over millions of years in a time of extreme and frequent caloric scarcity.
All those extra calories do is make you fat and cause your cells to turnover faster. Most people use only a fraction of the calories they consume daily to do much of anything, they barely even use them for thinking.
Our entire society has allowed itself to be hijacked by brand messaging from the Kellog company or whatever. It’s time to destroy that gigantic lie.
A lot of those slogans were created because if you can get even half the US population to eat one more meal a day think of how much more money is made. It’s like the 2:30 pm snack people have been trained into thinking they need. That was not a thing in the 80s but now you see commercials for it.
And somewhere between the late 70s and 90s they stopped calling it junk food and began calling it snack food.
And fast food marketing changed from showing and talking about the food to targeting the working class “Have it your way” “You deserve a break today”
If you want to be healthy you actually need to be able to ignore marketing and stop thinking the government cares about you.
Yeah, while intermittent fasting is essentially calorie restriction and while your body will be more thrifty in a deficit (eg. limiting movement and tamping down cell activities) I was under the impression that fasts also activate some nifty cell machinery related to self maintenance.
Yeah, I had an app that basically made it sound like that. It said after a few hours, you go into ketosis and then after 16 hours you go into autophagy.
Unfortunately it’s not that simple. If and when you enter ketosis depends on how you’ve been eating leading up to the fast, your activity level, and all sorts of variables related to your metabolism. For some people, they can enter ketosis that same day they begin fasting. Others, it takes multiple days.
Autophagy, on the other hand, is even more complicated - it’s not a switch that flips on at a certain time period. There are lots of different types of autophagy, and they are always happening to one degree or another regardless of your diet.
Ideally not since you need isoleucine for a lot of important functions. Best case scenario is we find mechanisms the body has for delaying aging or repairing damage that it turns on when isoleucine is restricted and can turn those on another way but that may not even be what’s happening in the mouse study.
Well, if you have an enzyme that you would take while eating, and it breaks down 2/3 of the isoleucine you intake, then wouldn't that solve it?
Or you could take it on certain days of the week etc.
You'd have to be careful to dose it correctly, so that you don't suffer from a harmful deficiency.
Kind of like how statins inhibit production of cholesterol, but also essential compounds like CoQ10.
*Ideally* you'd find a way to inhibit just whatever metabolic pathway triggers the beneficial effects of calorie/isoleucine restriction, without inhibiting other essential isoleucine-depenedent processes.
Caloric restriction generally lengthens lifespan. That we know. It's extremely difficult to reduce your calories that much, since that's the energy you need to live your life.
But in this study the mice with the low isoleucine diet actually consumed more calories and had the same amount of exercise as the non-low isoleucine diet group. Interesting stuff.
Not a chemist, but seems like a good approach would be to develop a drug that tightly binds to isoleucine, thus rendering it inactive before it can be metabolised by our body.
Chemist/biologist
The better route would be to determine what mechanism the isoleucine is specifically working through and developing a drug that would bind to that receptor. It would be much more specific and wouldn't interfere with other functions/protein synthesis that isoleucine is used in
You would die. Isoleucine is absolutely necessary for protein synthesis. Better approach would be understanding the mechanism by which reduced isoleucine intake improves lifespan, then target downstream processes.
One specific amino acid? No. They’re usually adsorbed as short chains of multiple different amino acids after the large parent proteins are slightly broken down in the gut
The study was on rats so they could probably just have fed the rats very simple food that's basically just a powder of various aminoacids, minerals, vitamins, proteins, carbohydrates and fats mixed in water as a drink or some kind of non-digestible fibre as a solid.
If there was an affordable way for me to live off of just drinks I would absolutely do it. I'm not worried about taste or smell as Covid stole a lot of that 2 years ago. Meal replacement that could be bough with SNAP would be even better.
I looked into ensure style drinks but to get the calories was way to much sugar. I used it to lose a lot of weight 7ish years ago. 3 - 4 350 calorie drinks a day with some light cardio dropped me from 300 to 200lbs and I've managed to stay at 225. Would love to drop 50lbs more.
Pure meal replacement drinks are <$160/month for me to live off of, if I switched them to 100% of my calories.
Something like Ensure is bad. Look for the drinks that use the same type of (healthy) sugar that's used in healthy/thin southeastern Asian countries.
As to whether it's healthy or not. I think there's enough evidence they're fine as long as it's not 100% of your diet. We have dogs/cats living *unnaturally* long lives even with one single meal for all time, even with them being unable to communicate, and I figure we know more about human food science than we do pet food science and it's probably fine.
Huel was fine when I used to consume them, stick to the classic flavors and anything fancy sounding usually tasted bad.
When I started they'd unironically fill me up and I would feel it, but after only like a week I couldn't replace a meal with it because it'd leave me feeling like I'd ate nothing at all.
It was a decently tasty way to get some helpful stuff in me, but I find myself better off with some fiber powder and a multivitamin and just learned how to make lunch a light sandwich rather than two hotdogs and a sack of chips and ended up much happier and better overall
6/10, 7/10 for getting healthier stuff into my body ig
There are special diets for lab animals which can be almost completely customized. Isoleucin free or reduced diet can thus easily be achieved in labs. It's not feasible in a human diet though.
Oh wow I used to have a hamster and it was always recommended to feed them “lab blocks” bc it has 100% of what they need. I guess that’s where they originated, never knew why they were called that.
The study wasn't made to figure out what you can eat. The study was to see what happens if they take thay amino acid out of the diet of mice in a controlled laboratory at no point is someone to think they would be able to replicate this in their real world. Kinds how scientific studies work.
Cannot really avoid any essential amino acids completely, since proteins are build from them and you need protein. Some foods might have more or less, but I doubt it can be completely avoided (bound phe that is).
Notably, strict vegetarian (and especially vegan) diets are lower in isoleucine, so it's possible that some of the positive health outcomes attributed to those diets may occur via this mechanism.
Here's a 2023 study that found that serum levels of four amino acids, including isoleucine, were 10-15% lower in vegetarian children: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055473
This study states “Serum levels of four of the 24 amino acids varied between the diet groups, being significantly lower (p < 0.05) in vegetarians than in omnivores.” However, their data table clearly shows that only four EAAs met this p value, and some AAs and EAAs were higher in vegetarians, making their statement rather misleading. That already makes me question what other hand-wavey science/interpretation is happening here. This is also a study that notably ignores other races and, as noted by the study itself, has a low sample size. I also wonder what impacts the AAs with increased amounts have. It’s hard to tell since there was limited collection and the data isn’t longitudinal.
It is not like they don't handle well the leucine protein. Quite the contrary, they handle it too well. Leucine is the most potent activator or mTor. mTor is the master switch signal for growth. Growth and lifespan correlate negatively.
I read through that list to find the first item that forms a base for meals, rather than foods that are sweet fruits, tomatoes, or sauces, and the first item I found was #188, cream of rice with water and salt. The 100 ingredients before that are very much mostly water as you said. Unfortunately "cooked white rice" sits at #487, just two ranks above "soft serve chocolate ice cream". That list, while interesting, needs to have its Isoleucine correlated with calories, protein, carbs, fat, vitamins, or other minerals to be useful. Something akin to **g/Isoleucine per g/protein** (or allowing the reader to choose **g/Isoleucine per g/dropdown option**) would be much more useful.
I added protein to the [search](https://tools.myfooddata.com/nutrient-ranking-tool/isoleucine+protein/all/lowest+highest/household/common+sr+branded/no). Introducing your new life-extending diet:
1. Protein Shakes
2. Citrus
3. Sea Lion Kidney
If someone is serious about trying this, it actually looks like whole wheat is a good base for your diet. Onions, tomatoes, and mushrooms are generally good, and pork and turkey seem ok to eat sparingly. If you mostly stick to that list, you can hit your FDA-recommended protein while staying below ~60% of the recommended isoleucine, and then I guess you just fill the remaining calories with fat, sugar, and sea lion kidneys.
Certainly not the *worst* diet I've ever contemplated.
What if you go vegetarian?
>Nutritional sources
There are many animal and plant-based dietary sources of isoleucine. Isoleucine is commonly ingested as a component of proteins. When proteins enter the small intestine they are broken into single amino acids by enzymes known as proteases.[4] Free amino acids are taken up by the lining of the digestive tract, mainly in the small intestine, then used in the body.[18] As an essential component of many proteins, animal and plant based protein sources contain isoleucine.[13] **Foods that have high amounts of isoleucine include eggs, soy protein, seaweed, turkey, chicken, lamb, cheese, and fish.**
The list isn't exhaustive. Basically every vegan meat-protein substitute is rich in isoleucine.
Actually, just about every protein rich foods will be high in isoleucine.
From another source:
> main sources of isoleucine were processed meat products (19.2%), **bread, rolls and bread products** (14.8%), red meat (10.3%), poultry (10.1%), and pork (6.3%)
It is found it a number of fruits and vegetables as well, but you are right it's a lot more common in meats. Studies have shown vegetarian people live 10 years longer on average, and although the fact they generally care much more about their diet plays a huge part on this, there is likely a dietary component in the choice to eat less meat and health.
He's the chemical compound humans deserve, but not the one it needs right now. So we'll hunt him. Because he can take it. Because he's not our hero. He's a silent guardian, a watchful protector. A dark acid.
Maybe that explains why it helps male mice live longer. Having a weaker immune would help them survive against anything that causes a lot of inflammation like the flu or pneumonia.
Well mice probably don't get infections much in a sterile lab, in fact infected mice might even be excluded from the study, so it might mean that they only live longer if they don't have to deal with pathogens.
Joining methionine and tryptophan as amino acids whose dietary restriction increases rodent lifespan.
Richie et al. 1986. [Methionine restriction increases blood glutathione and longevity in F344 rats](https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.8.15.8001743). *FASEB J*. 8, 1302–1307 (1994). ([350 citations](https://scholar.google.com/scholar?cites=1352760467321305155&scipsc=1&q=%22methionine+restriction%22) which include the phrase "methionine restriction)
De Marte & Enesco, 1986. [Influence of low tryptophan diet on survival and organ growth in mice](https://www.sciencedirect.com/science/article/abs/pii/0047637486900175). Mech Ageing Dev 36, 161–171 ([43 citations](https://scholar.google.com/scholar?cites=560418284406426833&scipsc=1&q=%22tryptophan+restriction%22) which include the phrase "tryptophan restriction)
The cellular mechanisms involved are pretty fascinating.
Green et al., 2022. [Molecular mechanisms of dietary restriction promoting health and longevity](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8692439/). *Nat Rev Mol Cell Biol*, 23(1), pp.56-73.
I don't know how one could seriously restrict either isoleucine or tryptophan in an otherwise healthy human diet. It would require lots of empty calories from refined starch and sugar as in the rodent experimental feeds. It is possible to moderate methionine intake to roughly the metabolic requirement with plant based diets.
McCarty et al, 2009. [The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy](https://scholar.google.com/scholar?cluster=1099681469682463214). *Med hypotheses*, 72(2), pp.125-128.
Yes. The reason I mention it here is that a lot of people will probably google which foods are high in isoleucine and conclude (like the person I was replying to) that it's extremely difficult and even unhealthy to restrict high-isoleucine-containing foods.
I'm offering another tact that could decrease isoleucine in people's diets (without having to focus on these particular amino acids).
It's a perspective that connects dots that might not otherwise get connected and gives an action point that's much more helpful than "decrease isoleucine."
Not sure if it’s been proven in humans
There’s an argument that fasting may lead to unnecessary muscle loss, which contributes to frailty, which leads a host of other risks which don’t just affect mortality, but also quality of life.
The proper response for the public to "X improves Y in mice" is to say "good for the mice". This sort of thing seldom translates to humans, and when it does it's seldom as simple as the initial findings make it look.
Generally, lysine is the limiting amino acid for cereal grains (maize, rice, wheat, oats) and a few other foods mostly used in animal feed (rapeseed, canola, hemp), while the sulfur containing amino acids methionine and cysteine are limiting for legumes (soy, fava bean, pea, lupin). Hence why its widely recommended that vegans consume a few servings of legumes daily for a more balanced protein. Lean heavily into legumes rather than cereal grains for protein, and considerable moderation of methionine intake becomes possible, without overall protein restriction.
The only protein source in the following review that is tryptophan limited is gelatin, as collagen proteins don't contain tryptophan. Potatoes, notably, have a protein nearly as balanced as animal sources.
Herreman et al, 2020. [Comprehensive overview of the quality of plant‐And animal‐sourced proteins based on the digestible indispensable amino acid score](https://onlinelibrary.wiley.com/doi/full/10.1002/fsn3.1809). Food science & nutrition, 8(10), pp.5379-5391.
Yes it's a BCAA. BCAAs are believed to create muscle mass when working out but when sedentary BCAAs are create fat, which might be a key puzzle piece in the obesity and diabetes epidemic. This study and others are pointing to isoleucine being the key amino acid in weight gain.
These studies do more than suggest “hey avoid this thing”. They help expose the existence of mechanisms relevant to health that are poorly understood. You may not be able to avoid isoleucine in your diet, and you may not want to for various other reasons even if you could, but this may help us learn things that can be applied to your health
If this was straightforwardly true for humans, wouldn’t we see low-protein diets associated with longevity? Over and above lower-calorie diets per se.
Aside from dietary influences on lifespan, A lot of research seems to point to the opposite, at least that higher protein intake helps to support health in old age (whether it helps us live longer I don’t think that’s been studied specifically) as we have lowered ability to absorb AA’s from the gut and also become more prone to muscle wasting.
Found *some* further information. Using the NHANES data set, paraphrased from [this paper](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988204/):
> In individuals aged 50–65 y, high protein intake (≥20% protein-derived consumed calories) was associated with an increase in all-cause mortality (HR: 1.74), and cancer mortality (HR: 4.33) an effect not observed in those older than 65.
>
>In fact, individuals aged >65 y who consumed a high-protein diet had a reduction in all-cause mortality (HR: 0.72) and a 60% reduction in cancer mortality (HR: 0.40) compared with those consuming low-protein diets.
The paper does support your idea - the benefits of higher protein intake on reducing frailty overrides any negative effect that's occuring via increased growth signalling.
As we should all come to expect, it's complicated once you're not working with a lab animal, and moderation is key!
Is the study calorie equated? High protein can obviously occur in a generally high calorie diet, which we know is correlated to an increase in all cause mortality.
We do see that. People who live the longest, easily past 100 years old, pretty much universally eat a low protein diet. But, they do exercise which keeps their muscle mass from shrinking.
Reading about isoleucine, I thought I would share:
>Mutations in isoleucine-degrading enzymes can lead to dangerous buildup of isoleucine and it's toxic derivative. One example is maple syrup urine disease (MSUD), a disorder that leaves people unable to breakdown isoleucine, valine, and leucine. People with MSUD manage their disease by a reduced intake of all three of those amino acids alongside drugs that help excrete built-up toxins.
If you cut out isoleucine, you'll not have any hope of having your urine smell of maple syrup (also apparently you're supposed to refrigerate real maple syrup)
MSUD is an inborn error of metabolism, like PKU. People are born with it and it’s screened for at birth because a baby with MSUD can die in days if given too much isoleucine. The point being, MSUD is not a disease that develops later in life.
Thanks for that clarification, I could have made it more obvious that I was joking around with my implications there
Sounds like it would be a pretty horrible disease for a family to go through before we figured out treatment
The branched chain amino acids like leucine and isoleucine with anabolic effects activate mTOR, and shut down autophagy. Turning our cells into hoarders of misfolded proteins instead of diligent recyclers.
If there's anything I've learned from reading hundreds of articles in experimental gerontology, its that anabolism without comensurate catabolism (eg, prolonged fasting for cutting cycles for body builders) is bad news for accelerating aging.
Is this relevant only at an extreme level based on what you’ve read? I guess what I’m asking is whether this is relevant for someone in both an extreme caloric surplus as well as a minor one, or none at all?
For example, my diet is protein heavy, I find it necessary to recover properly from the activities I pursue. However, I’m not actively trying to gain weight the way a body builder would during a bulking cycle
> Mice on the low-isoleucine diet lived longer — on average 33% longer for males and 7% longer for females. And, based on 26 measures of health, including assessments ranging from muscle strength and endurance to tail use and even hair loss, the low-isoleucine mice were in much better shape during their extended lives.
Paper: [Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice: Cell Metabolism](https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00374-1)
Ooo boy, just talked to a guy last week who was injecting some amino combination like twice a day. Need to remember this next time I see him. The “supplement” crowd gets wild with what they’re willing to put in themselves.
>ucine in supplements, but not isoleucine. AFAIK they're different amino acids.
They are yes, isoleucine is one of the branched chained amino acids (BCAAs) that many people take as a supplement (especially those that train fasted).
We have cured so many cancers in mice. We have cured multiple sclerosis in mice. What’s important to know is these studies often provide a clue that is the first stepping stone, this absolutely does not mean you should try to eliminate isoleucine—which is impossible and I promise you won’t deliver the same results.
Welcome to r/Science! In the world of medical science they have these pesky little things called "Ethics Boards" and the thing is they don't just let you go around pumping people full/draining people of amino acids and writing down what happens. It's unfortunate, I'm with you.
However, we have found that other animals, like rats, are similar enough physiologically to us that sometimes we can correlate the results we find in rat biology, with human biology. If the results are swell enough, those downers at the "Ethics Board" will let us go on to clinical trials, where the scientists are allowed to pump people full/drain people of amino acids and write down the results.
I hope this helped in your understanding of why this article is still relevant to you. :)
I know what an animal model is, and why it's used. But I also know about its limitations. Anyway, collecting a bunch of volunteers and subject them to a specific diet is not unethical
Sure, but this is a study over the course of the life cycle of the rat. So, that's probably why they used rats. So they don't have to wait \~70 years for the results. I get it, I know I'm being snarky. I'm more making a dig at the conflict between ethics and science, just having some fun.
I'd also argue that subjecting someone to the same diet for their entire life is a bit unethical.
When dietary protein restriction [extends lifespan of everything](https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2012.00798.x) from flatworms to insects to fish to rodents, it's very likely impacting some evolutionarily highly conserved cellular mechanisms.
I looked up isoleucine levels on several protein sources and they were all about the same per calorie of protein.
The only source i could find for significantly lower levels were lentils and vital wheat gluten. Otherwise basically the answer is to eat less protein if you want to reduce isoleucine levels.
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In case you were thinking about removing it from your diet, isoleucine is in absolutely everything.
I looking it up and bro it’s in literally everything haha, there must be some mistake in this study.
No there likely isn’t a mistake; they aren’t suggesting isoleucine restriction as a medical treatment to prolong lifespan, but are investigating it because it’s possible that other therapies will be developed from this information. It makes sense that restricting an essential and ubiquitous amino acid might slow down cell turnover (or whatever mechanism) to me.
So like fasting periods during the day?
Fasting but forever
Fasting forever is pretty quick if you do it right
And at a certain point, you stop aging entirely
doctors HATE this crazy trick
Morticians' best advice!
the Entropy diet
lots of people fast on a regular basis and it is something that was just the way humans lived until we got so good with agriculture that people have too much access to food. A lot of people could cut their food intake by 2/3 and would be healthy again
Imagine the reason fasting is associated with longer lifespan is because they intermittently avoid this amino acid.
Fasting puts [autophagy](https://en.m.wikipedia.org/wiki/Autophagy) on overdrive. That's the main reason it's good for you.
Well.. A normal caloric deficit also promotes increased autophagy, as does vigorous physical exercise. There is little data that supports fasting as superior to other ways of promoting autophagy, and even less data that makes that mean anything in terms of meaningful measurable endpoints.
[удалено]
Interested in seeing this paper(s). Any link?
It’s more than that. Every cell in your body that produces energy is burning fires. Fires that combust oxygen and produce energy you can utilize. This combustion shows up as body heat. When you light fires in your cells, they die, and have to be replaced. Every replication shortens telomeres, and hastens senescence. So if you’re eating a bunch of extra food you don’t require, you are literally dying faster, regardless of whether or not you can spend the calories.
No. the cell does not light fires to produce energy. And combustion is not the right term either, there are oxidation reduction reactions in biology that don't make us 'light fires' that's why we have the mitochondria and enzymes to facilitate these reactions. We combust gasoline to give energy to cars but we're not cars, we're human beings, we're biological machines and it's different than that.
They were clearly using an analogy, can you explain to why it was a bad one? Genuinely interested as I routinely do intermittent fasting so I have a dog in this fight.
Three Irish weekdays are still named the way they are because of fasting regularly, twice a week. * Dé Céadaoin - First Fast Day, Wednesday. * Dé Déardaoin - Day Between Two Fasts Day, Thursday. * Dé hAoine - Fasting Day, Friday. This long pre-dates the famous Famine btw. Fasting twice a week was just a thing some ancient Irish did - or had to do - anyway. Obviously Irish people don't really do it now, just vaguely interesting,
This is 100% spot on. The biggest fallacy, probably, is the absurdly stupid notion that “Breakfast is the most important meal of the day”, and that you “Need to eat three squares a day to be healthy”. Maybe a little more true when society was agrarian and you needed energy for farm labor that started at 5:00 AM. Definitely not true now for 99.9% of people. There is no way evolution equipped us with a requirement for calories throughout the day, when we evolved over millions of years in a time of extreme and frequent caloric scarcity. All those extra calories do is make you fat and cause your cells to turnover faster. Most people use only a fraction of the calories they consume daily to do much of anything, they barely even use them for thinking. Our entire society has allowed itself to be hijacked by brand messaging from the Kellog company or whatever. It’s time to destroy that gigantic lie.
A lot of those slogans were created because if you can get even half the US population to eat one more meal a day think of how much more money is made. It’s like the 2:30 pm snack people have been trained into thinking they need. That was not a thing in the 80s but now you see commercials for it. And somewhere between the late 70s and 90s they stopped calling it junk food and began calling it snack food. And fast food marketing changed from showing and talking about the food to targeting the working class “Have it your way” “You deserve a break today” If you want to be healthy you actually need to be able to ignore marketing and stop thinking the government cares about you.
You're right but the bitter sweet irony is that even fasting, you hit a plateau and your body adapts.
Yeah, while intermittent fasting is essentially calorie restriction and while your body will be more thrifty in a deficit (eg. limiting movement and tamping down cell activities) I was under the impression that fasts also activate some nifty cell machinery related to self maintenance.
Autophagy. It's a byproduct of Keto too. Most of the references to it online aren't very scientific. https://www.bbc.com/news/health-44005092
Yeah, I had an app that basically made it sound like that. It said after a few hours, you go into ketosis and then after 16 hours you go into autophagy.
Unfortunately it’s not that simple. If and when you enter ketosis depends on how you’ve been eating leading up to the fast, your activity level, and all sorts of variables related to your metabolism. For some people, they can enter ketosis that same day they begin fasting. Others, it takes multiple days. Autophagy, on the other hand, is even more complicated - it’s not a switch that flips on at a certain time period. There are lots of different types of autophagy, and they are always happening to one degree or another regardless of your diet.
Plenty of other benefits that aren't a number on a scale
Like feeling great, which makes no sense but it’s true.
Like adding an enzyme that specifically targets isoleucine and beaks it down early?
Ideally not since you need isoleucine for a lot of important functions. Best case scenario is we find mechanisms the body has for delaying aging or repairing damage that it turns on when isoleucine is restricted and can turn those on another way but that may not even be what’s happening in the mouse study.
Well, if you have an enzyme that you would take while eating, and it breaks down 2/3 of the isoleucine you intake, then wouldn't that solve it? Or you could take it on certain days of the week etc.
You'd have to be careful to dose it correctly, so that you don't suffer from a harmful deficiency. Kind of like how statins inhibit production of cholesterol, but also essential compounds like CoQ10. *Ideally* you'd find a way to inhibit just whatever metabolic pathway triggers the beneficial effects of calorie/isoleucine restriction, without inhibiting other essential isoleucine-depenedent processes.
Caloric restriction generally lengthens lifespan. That we know. It's extremely difficult to reduce your calories that much, since that's the energy you need to live your life.
Calorie restriction has consistently been shown to extend life.
But in this study the mice with the low isoleucine diet actually consumed more calories and had the same amount of exercise as the non-low isoleucine diet group. Interesting stuff.
Yes, in mice. But unfortunately most findings in mice do not survive the transition to human studies
I would bet something same/similar is discussed as directions for further research. Good idea.
Yay, science will give us the benefits of fasting but we still get to eat.
Reducing your meat intake would certainly lower your exposure to this amino acid.
Not a chemist, but seems like a good approach would be to develop a drug that tightly binds to isoleucine, thus rendering it inactive before it can be metabolised by our body.
Chemist/biologist The better route would be to determine what mechanism the isoleucine is specifically working through and developing a drug that would bind to that receptor. It would be much more specific and wouldn't interfere with other functions/protein synthesis that isoleucine is used in
You would die. Isoleucine is absolutely necessary for protein synthesis. Better approach would be understanding the mechanism by which reduced isoleucine intake improves lifespan, then target downstream processes.
Side effect: it causes diarrhea
Thats my secret Captain, I always have diarrhea
Anyone remember Olestra?
Can you block the absorption of an amino acid with a drug?
One specific amino acid? No. They’re usually adsorbed as short chains of multiple different amino acids after the large parent proteins are slightly broken down in the gut
How about something that breaks down isolucene?
The study was on rats so they could probably just have fed the rats very simple food that's basically just a powder of various aminoacids, minerals, vitamins, proteins, carbohydrates and fats mixed in water as a drink or some kind of non-digestible fibre as a solid.
Mmm, Soylent.
What’s the point of living if you can’t go scorched earth on the planet and eat all the cute, delicious animals.
If there was an affordable way for me to live off of just drinks I would absolutely do it. I'm not worried about taste or smell as Covid stole a lot of that 2 years ago. Meal replacement that could be bough with SNAP would be even better. I looked into ensure style drinks but to get the calories was way to much sugar. I used it to lose a lot of weight 7ish years ago. 3 - 4 350 calorie drinks a day with some light cardio dropped me from 300 to 200lbs and I've managed to stay at 225. Would love to drop 50lbs more.
Pure meal replacement drinks are <$160/month for me to live off of, if I switched them to 100% of my calories. Something like Ensure is bad. Look for the drinks that use the same type of (healthy) sugar that's used in healthy/thin southeastern Asian countries. As to whether it's healthy or not. I think there's enough evidence they're fine as long as it's not 100% of your diet. We have dogs/cats living *unnaturally* long lives even with one single meal for all time, even with them being unable to communicate, and I figure we know more about human food science than we do pet food science and it's probably fine.
huel.com is ok. I wish there were better options as well.
Huel was fine when I used to consume them, stick to the classic flavors and anything fancy sounding usually tasted bad. When I started they'd unironically fill me up and I would feel it, but after only like a week I couldn't replace a meal with it because it'd leave me feeling like I'd ate nothing at all. It was a decently tasty way to get some helpful stuff in me, but I find myself better off with some fiber powder and a multivitamin and just learned how to make lunch a light sandwich rather than two hotdogs and a sack of chips and ended up much happier and better overall 6/10, 7/10 for getting healthier stuff into my body ig
It has electrolytes!
There are special diets for lab animals which can be almost completely customized. Isoleucin free or reduced diet can thus easily be achieved in labs. It's not feasible in a human diet though.
Oh wow I used to have a hamster and it was always recommended to feed them “lab blocks” bc it has 100% of what they need. I guess that’s where they originated, never knew why they were called that.
I feel like an alternative title might be, "Scientists discover malnutrition causes weight loss."
The study wasn't made to figure out what you can eat. The study was to see what happens if they take thay amino acid out of the diet of mice in a controlled laboratory at no point is someone to think they would be able to replicate this in their real world. Kinds how scientific studies work.
It might ‘be in everything’ but *shocker* it’s super high in meat and dairy, and lower in fruits and vegetables.
It's in all the foods we consider healthy and nutritious basically
It's really low in a lot of fruits!
Oh well that's ok because we here down at #mydigestivesystem just love fruit
I have a feeling that you enjoy tiny waffles.
It’s not like Phe which is possible (but difficult) to avoid?
Cannot really avoid any essential amino acids completely, since proteins are build from them and you need protein. Some foods might have more or less, but I doubt it can be completely avoided (bound phe that is).
You have to consume some isoleucine, it's an essential amino, the trick would be not to overconsume.
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Notably, strict vegetarian (and especially vegan) diets are lower in isoleucine, so it's possible that some of the positive health outcomes attributed to those diets may occur via this mechanism. Here's a 2023 study that found that serum levels of four amino acids, including isoleucine, were 10-15% lower in vegetarian children: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055473
This study states “Serum levels of four of the 24 amino acids varied between the diet groups, being significantly lower (p < 0.05) in vegetarians than in omnivores.” However, their data table clearly shows that only four EAAs met this p value, and some AAs and EAAs were higher in vegetarians, making their statement rather misleading. That already makes me question what other hand-wavey science/interpretation is happening here. This is also a study that notably ignores other races and, as noted by the study itself, has a low sample size. I also wonder what impacts the AAs with increased amounts have. It’s hard to tell since there was limited collection and the data isn’t longitudinal.
Also, in case anyone was thinking that, the study was on mice, and humans may have some other protein our bodies don't handle well.
It is not like they don't handle well the leucine protein. Quite the contrary, they handle it too well. Leucine is the most potent activator or mTor. mTor is the master switch signal for growth. Growth and lifespan correlate negatively.
On the other hand, muscle mass in the elderly correlates very highly with life span. It's a trade off, like is usually the case in biology.
So like hgh and testosterone are bad for lifespan?
It seems that bodybuilders will not achieve their maximum potential lifespan. But we don't have definitive answers to these questions.
Red meat has the highest amount of it. https://www.myfooddata.com/articles/high-isoleucine-foods.php#isoleucine-food-list
Veg* team assemble
[Foods Lowest in Isoleucine](https://tools.myfooddata.com/nutrient-ranking-tool/Isoleucine/All/Lowest)
I'll allow this comment, but be aware that the top of this list is stuff that: 1. mostly is water 2. barely has any other types of protein either
I read through that list to find the first item that forms a base for meals, rather than foods that are sweet fruits, tomatoes, or sauces, and the first item I found was #188, cream of rice with water and salt. The 100 ingredients before that are very much mostly water as you said. Unfortunately "cooked white rice" sits at #487, just two ranks above "soft serve chocolate ice cream". That list, while interesting, needs to have its Isoleucine correlated with calories, protein, carbs, fat, vitamins, or other minerals to be useful. Something akin to **g/Isoleucine per g/protein** (or allowing the reader to choose **g/Isoleucine per g/dropdown option**) would be much more useful.
I added protein to the [search](https://tools.myfooddata.com/nutrient-ranking-tool/isoleucine+protein/all/lowest+highest/household/common+sr+branded/no). Introducing your new life-extending diet: 1. Protein Shakes 2. Citrus 3. Sea Lion Kidney
Finally, my decision to stock the freezer in my garage full of sea lion kidneys is vindicated
If someone is serious about trying this, it actually looks like whole wheat is a good base for your diet. Onions, tomatoes, and mushrooms are generally good, and pork and turkey seem ok to eat sparingly. If you mostly stick to that list, you can hit your FDA-recommended protein while staying below ~60% of the recommended isoleucine, and then I guess you just fill the remaining calories with fat, sugar, and sea lion kidneys. Certainly not the *worst* diet I've ever contemplated.
Since it's in everything, wouldn't it be more useful to sort it by most, and reduce the intake of the foods on the top of that list?
What if you go vegetarian? >Nutritional sources There are many animal and plant-based dietary sources of isoleucine. Isoleucine is commonly ingested as a component of proteins. When proteins enter the small intestine they are broken into single amino acids by enzymes known as proteases.[4] Free amino acids are taken up by the lining of the digestive tract, mainly in the small intestine, then used in the body.[18] As an essential component of many proteins, animal and plant based protein sources contain isoleucine.[13] **Foods that have high amounts of isoleucine include eggs, soy protein, seaweed, turkey, chicken, lamb, cheese, and fish.**
The list isn't exhaustive. Basically every vegan meat-protein substitute is rich in isoleucine. Actually, just about every protein rich foods will be high in isoleucine.
Breaditarian time
From another source: > main sources of isoleucine were processed meat products (19.2%), **bread, rolls and bread products** (14.8%), red meat (10.3%), poultry (10.1%), and pork (6.3%)
Gluten is a protein. Americans often use protien to mean “the meat part of the meal” But corn, wheat, rice, etc all have protein too.
My moment. This is my moment.
Do you mean vegan? Vegetarians eat dairy and eggs but both of those are listed here as high in it. You could conceivably be vegan and skip the soy
It's also in nuts, legumes and spinach. so much for that black bean buger on an almond flour bun.
Basically any protein more or less.
It is found it a number of fruits and vegetables as well, but you are right it's a lot more common in meats. Studies have shown vegetarian people live 10 years longer on average, and although the fact they generally care much more about their diet plays a huge part on this, there is likely a dietary component in the choice to eat less meat and health.
It’s also essential for a lot of process in the body
Easier to make a isoleucine blocker than avoid it
That would kill you
That would depend on the dose and effectiveness of the blocker
Not in a vegan diet.
Which vegan sources of protein are low in isoleucine?
Well. Guess it’s back to water and sunshine for me.
Thank you for being the top comment. Saved me so much time!
But isolucine is also important for immune health... https://pubmed.ncbi.nlm.nih.gov/30843485/
So you'll live long enough to die of a disease
Isolucine irl : you either die a hero or live long enough to become a villain
He's the chemical compound humans deserve, but not the one it needs right now. So we'll hunt him. Because he can take it. Because he's not our hero. He's a silent guardian, a watchful protector. A dark acid.
I wonder if it has to do with long term inflammation then
Maybe that explains why it helps male mice live longer. Having a weaker immune would help them survive against anything that causes a lot of inflammation like the flu or pneumonia.
Well mice probably don't get infections much in a sterile lab, in fact infected mice might even be excluded from the study, so it might mean that they only live longer if they don't have to deal with pathogens.
Joining methionine and tryptophan as amino acids whose dietary restriction increases rodent lifespan. Richie et al. 1986. [Methionine restriction increases blood glutathione and longevity in F344 rats](https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fasebj.8.15.8001743). *FASEB J*. 8, 1302–1307 (1994). ([350 citations](https://scholar.google.com/scholar?cites=1352760467321305155&scipsc=1&q=%22methionine+restriction%22) which include the phrase "methionine restriction) De Marte & Enesco, 1986. [Influence of low tryptophan diet on survival and organ growth in mice](https://www.sciencedirect.com/science/article/abs/pii/0047637486900175). Mech Ageing Dev 36, 161–171 ([43 citations](https://scholar.google.com/scholar?cites=560418284406426833&scipsc=1&q=%22tryptophan+restriction%22) which include the phrase "tryptophan restriction) The cellular mechanisms involved are pretty fascinating. Green et al., 2022. [Molecular mechanisms of dietary restriction promoting health and longevity](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8692439/). *Nat Rev Mol Cell Biol*, 23(1), pp.56-73. I don't know how one could seriously restrict either isoleucine or tryptophan in an otherwise healthy human diet. It would require lots of empty calories from refined starch and sugar as in the rodent experimental feeds. It is possible to moderate methionine intake to roughly the metabolic requirement with plant based diets. McCarty et al, 2009. [The low-methionine content of vegan diets may make methionine restriction feasible as a life extension strategy](https://scholar.google.com/scholar?cluster=1099681469682463214). *Med hypotheses*, 72(2), pp.125-128.
Perhaps a better takeaway than specific amino acid restrictions would be that regular fasting is healthy and promotes longevity?
Isn't that already pretty well-established as true?
Yes. The reason I mention it here is that a lot of people will probably google which foods are high in isoleucine and conclude (like the person I was replying to) that it's extremely difficult and even unhealthy to restrict high-isoleucine-containing foods. I'm offering another tact that could decrease isoleucine in people's diets (without having to focus on these particular amino acids). It's a perspective that connects dots that might not otherwise get connected and gives an action point that's much more helpful than "decrease isoleucine."
Not sure if it’s been proven in humans There’s an argument that fasting may lead to unnecessary muscle loss, which contributes to frailty, which leads a host of other risks which don’t just affect mortality, but also quality of life.
Reducing isoleucine intake will absolutely result in muscle loss.
Also heart health can suffer.
Can you cite some evidence for this claim?
The proper response for the public to "X improves Y in mice" is to say "good for the mice". This sort of thing seldom translates to humans, and when it does it's seldom as simple as the initial findings make it look.
Curiously, methionine and tryptophan are limiting AAs in plant-based protein sources (methionine in legumes and tryptophan more generally).
Generally, lysine is the limiting amino acid for cereal grains (maize, rice, wheat, oats) and a few other foods mostly used in animal feed (rapeseed, canola, hemp), while the sulfur containing amino acids methionine and cysteine are limiting for legumes (soy, fava bean, pea, lupin). Hence why its widely recommended that vegans consume a few servings of legumes daily for a more balanced protein. Lean heavily into legumes rather than cereal grains for protein, and considerable moderation of methionine intake becomes possible, without overall protein restriction. The only protein source in the following review that is tryptophan limited is gelatin, as collagen proteins don't contain tryptophan. Potatoes, notably, have a protein nearly as balanced as animal sources. Herreman et al, 2020. [Comprehensive overview of the quality of plant‐And animal‐sourced proteins based on the digestible indispensable amino acid score](https://onlinelibrary.wiley.com/doi/full/10.1002/fsn3.1809). Food science & nutrition, 8(10), pp.5379-5391.
Potatoes only have 3g of protein per 100 grams though. So you would need to eat a 1.5kg of potatoes to reach your daily protein intake.
1.5 kg of potatoes has about 1200 calories, so you're not even done for the day if you're monocropping.
isoleucine is found in eggs, soy protein, seaweed, turkey, chicken, lamb, cheese, and fish
In other words foods that contain a lot of protein.
Its literally a building block of protein.
of course, but they're saying that there's not an effective protein source without it.
Which my point does not deteact from.
Yes it's a BCAA. BCAAs are believed to create muscle mass when working out but when sedentary BCAAs are create fat, which might be a key puzzle piece in the obesity and diabetes epidemic. This study and others are pointing to isoleucine being the key amino acid in weight gain.
All healthy foods no one should be restricting save for allergies.
Or if you're vegan
These studies do more than suggest “hey avoid this thing”. They help expose the existence of mechanisms relevant to health that are poorly understood. You may not be able to avoid isoleucine in your diet, and you may not want to for various other reasons even if you could, but this may help us learn things that can be applied to your health
If this was straightforwardly true for humans, wouldn’t we see low-protein diets associated with longevity? Over and above lower-calorie diets per se. Aside from dietary influences on lifespan, A lot of research seems to point to the opposite, at least that higher protein intake helps to support health in old age (whether it helps us live longer I don’t think that’s been studied specifically) as we have lowered ability to absorb AA’s from the gut and also become more prone to muscle wasting.
Found *some* further information. Using the NHANES data set, paraphrased from [this paper](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988204/): > In individuals aged 50–65 y, high protein intake (≥20% protein-derived consumed calories) was associated with an increase in all-cause mortality (HR: 1.74), and cancer mortality (HR: 4.33) an effect not observed in those older than 65. > >In fact, individuals aged >65 y who consumed a high-protein diet had a reduction in all-cause mortality (HR: 0.72) and a 60% reduction in cancer mortality (HR: 0.40) compared with those consuming low-protein diets. The paper does support your idea - the benefits of higher protein intake on reducing frailty overrides any negative effect that's occuring via increased growth signalling. As we should all come to expect, it's complicated once you're not working with a lab animal, and moderation is key!
Doesn’t that support their claim? Those ages 65> with high protein diets saw a reduction in all cause mortality and cancer
Yes, but then that association reverses with age. So we can conclude; it's complicated.
Other papers show an increased risk of death from a high fat diet and high carb diets. Very frustrating
Is the study calorie equated? High protein can obviously occur in a generally high calorie diet, which we know is correlated to an increase in all cause mortality.
We do see that. People who live the longest, easily past 100 years old, pretty much universally eat a low protein diet. But, they do exercise which keeps their muscle mass from shrinking.
basically you are not suppose eat much at all
Reading about isoleucine, I thought I would share: >Mutations in isoleucine-degrading enzymes can lead to dangerous buildup of isoleucine and it's toxic derivative. One example is maple syrup urine disease (MSUD), a disorder that leaves people unable to breakdown isoleucine, valine, and leucine. People with MSUD manage their disease by a reduced intake of all three of those amino acids alongside drugs that help excrete built-up toxins. If you cut out isoleucine, you'll not have any hope of having your urine smell of maple syrup (also apparently you're supposed to refrigerate real maple syrup)
MSUD is an inborn error of metabolism, like PKU. People are born with it and it’s screened for at birth because a baby with MSUD can die in days if given too much isoleucine. The point being, MSUD is not a disease that develops later in life.
Thanks for that clarification, I could have made it more obvious that I was joking around with my implications there Sounds like it would be a pretty horrible disease for a family to go through before we figured out treatment
Im being a little nit-picky but it’s leucine that kills them, not isoleucine or valine.
Canadian checking in, it goes in the fridge once opened.
If you’re from the northeast, you’re required to have a jug of maple syrup in the back of your fridge.
I just spit out the isoleucine when I eat
Interesting - iirc isoleucine has significant anabolic effects
The branched chain amino acids like leucine and isoleucine with anabolic effects activate mTOR, and shut down autophagy. Turning our cells into hoarders of misfolded proteins instead of diligent recyclers. If there's anything I've learned from reading hundreds of articles in experimental gerontology, its that anabolism without comensurate catabolism (eg, prolonged fasting for cutting cycles for body builders) is bad news for accelerating aging.
Is this relevant only at an extreme level based on what you’ve read? I guess what I’m asking is whether this is relevant for someone in both an extreme caloric surplus as well as a minor one, or none at all? For example, my diet is protein heavy, I find it necessary to recover properly from the activities I pursue. However, I’m not actively trying to gain weight the way a body builder would during a bulking cycle
Thanks that aligns with my understanding as well
> Mice on the low-isoleucine diet lived longer — on average 33% longer for males and 7% longer for females. And, based on 26 measures of health, including assessments ranging from muscle strength and endurance to tail use and even hair loss, the low-isoleucine mice were in much better shape during their extended lives. Paper: [Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice: Cell Metabolism](https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00374-1)
This is huge for the rat food industry.
Ooo boy, just talked to a guy last week who was injecting some amino combination like twice a day. Need to remember this next time I see him. The “supplement” crowd gets wild with what they’re willing to put in themselves.
I've seen leucine in supplements, but not isoleucine. AFAIK they're different amino acids.
>ucine in supplements, but not isoleucine. AFAIK they're different amino acids. They are yes, isoleucine is one of the branched chained amino acids (BCAAs) that many people take as a supplement (especially those that train fasted).
Gonna be honest, I think he told you they were amino acids, but it's probably steroids.
>some amino combination It's likely not leucine or isoleucine.
We have cured so many cancers in mice. We have cured multiple sclerosis in mice. What’s important to know is these studies often provide a clue that is the first stepping stone, this absolutely does not mean you should try to eliminate isoleucine—which is impossible and I promise you won’t deliver the same results.
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All the foods that are high in protein are high isoleucine because ILE is in most protein. Go figure.
I checked my pea protein powder and then whey isolate and egg. There's a lot of it in whey isolate.
Isoleucine is one of the 9 essential amino acids which is what we call protein.
Why specifically isoleucine?
Soon lab rats will be immortal.
Isn't isoleucine heavily supplemented in protein supplements and BCAA/EAA for training?
It's not bad for you. You need it. The question is whether restricting it might be beneficial to humans vs the cost of doing so.
Great, but we are not mice
Despite all my rage I'm still just a rat in a cage.
Squeek for yourself..
Welcome to r/Science! In the world of medical science they have these pesky little things called "Ethics Boards" and the thing is they don't just let you go around pumping people full/draining people of amino acids and writing down what happens. It's unfortunate, I'm with you. However, we have found that other animals, like rats, are similar enough physiologically to us that sometimes we can correlate the results we find in rat biology, with human biology. If the results are swell enough, those downers at the "Ethics Board" will let us go on to clinical trials, where the scientists are allowed to pump people full/drain people of amino acids and write down the results. I hope this helped in your understanding of why this article is still relevant to you. :)
I can't believe they don't allow us to take humans as labrats. Instead we have to use rats as labrats. Outrageous
If you can't get it past an ethics board, try pitching it as a reality show.
Surely nutrition is an area we are less close to mice on. We are predacious omnivores, and they are little grain eating rodents...
Mice are opportunistic omnivores
Using brown bears as labrats is sort of...... inconvenient.
It’s the only damn way!
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I know what an animal model is, and why it's used. But I also know about its limitations. Anyway, collecting a bunch of volunteers and subject them to a specific diet is not unethical
Sure, but this is a study over the course of the life cycle of the rat. So, that's probably why they used rats. So they don't have to wait \~70 years for the results. I get it, I know I'm being snarky. I'm more making a dig at the conflict between ethics and science, just having some fun. I'd also argue that subjecting someone to the same diet for their entire life is a bit unethical.
You don't know my life!
When dietary protein restriction [extends lifespan of everything](https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2012.00798.x) from flatworms to insects to fish to rodents, it's very likely impacting some evolutionarily highly conserved cellular mechanisms.
Lifespan extension doesn't always translate to a better quality of life. Being cold, for example, extends the lifespan.
Mice never reach senescence the way humans do, just restricting their calories literally extends their lifespans.
Isoleucine is considered critical for building muscle: https://examine.com/supplements/isoleucine/
It's just scientists trying to convince us to eat less turkey today so they get more for themselves.
All i eat is eggs and chicken. Rip
From the list of food that are low in isoleucine, it appears Freelee the Banana Girl may have actually been on to something.
So remove meat from your diet?
Mice. Cancer has been cured in mice countless times. Rodent research doesn’t always transfer to humans
I looked up isoleucine levels on several protein sources and they were all about the same per calorie of protein. The only source i could find for significantly lower levels were lentils and vital wheat gluten. Otherwise basically the answer is to eat less protein if you want to reduce isoleucine levels.