Mice eating less isoleucine live longer, healthier | Hacker News Reader

Mice eating less isoleucine live longer, healthier

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102 pointsgardenfelder72 comments

Good follow-up would be with Furanomycin, an isoleucine antagonist [1].

[1] https://pubs.acs.org/doi/abs/10.1021/jm00318a035

Except that the mTOR pathway also promotes growth and preservation of muscle tissue, and we know that muscle tissue is rather important to quality of life and avoidance of injury in old age.

Manipulating the mTOR pathway involves making a trade-off based on your preferred type of death: on the one hand we have frailty, hip fractures, muscle wasting, etc, and in the other metabolic diseases, cancer, CVD, alzheimer's, diabetes etc.

But, you can probably still grow strong enough from life-long resistance training a few times a week+eating enough other (plant) protein. I believe that this is the modern longevity recipe from what we have learned so far from the mTOR/fasting/leucine/isoleucine/methionine research. I hope we soon learn more about optimizing anabolism/autophagy in a targeted way instead of the entire body, that's what it all seems to boil down to.

There is a statistically inverse relationship between diameter of the muscle mass of the legs and dementia[1]. Higher muscle mass has more capacity to store glycogen and in a higher priority than insulin-activated GLUT receptors which in tern means less glucose and insulin spikes. And we do know that high glucose levels are inflammatory.

Point being, a more anabolic lifestyle with higher muscle mass has direct benefits in metabolic syndrome and cognitive decline, so your trade-off is incorrect.

[1] https://jamanetwork.com/journals/jamanetworkopen/fullarticle...

The study you linked to doesn’t support the conclusion you claimed. It provides evidence that low muscle mass is associated with cognitive decline. But it’s presented as a binary - low muscle mass vs not low. There is no talk of a “statistically inverse relationship”, as if adding more and more muscle results in less and less cognitive decline. Intuitively, it shouldn’t be too surprising that critically low muscle mass is associated with issues. Either because it causes decline in other areas or because it is correlated with it (or both). Indeed, from that paper: “Whether low muscle mass is an early marker or a causal factor of executive cognitive decline, and elucidation of mechanisms linking muscle mass to cognitive functions remain to be determined.”

As a daily runner that makes a LOT of sense. I wouldn't have been able to put my finger on it and express it but a similar idea has already been told to me, in another context, in another form.

I also think the conclusion of the research and the poster you responded to is rather wrong. It doesn't matter how long you live if that longevity isn't pleasantly usable. From the elderly I take care of around me, I would rather die sooner from some random disease than live longer and be as useless as they are (both physically and cognitively).

>I also think the conclusion of the research and the poster you responded to is rather wrong. It doesn't matter how long you live if that longevity isn't pleasantly usable.

Agreed. The "human body is a battery" type of arguments are a common misconception and have their roots on the fact that the only positive thing we've found about inflammation so far is that it's an integral part of muscle growth as a response to exercise stimuli/stress via the mtor pathways. But that's a one-off you don't need continuous inflammation to maintain your muscle and enjoy the long term benefits of it.

Oh and the plant based protein is also wrong as that protein is 99% of the time incomplete. You need multiple sources.

A fact that is often overlooked is that the mTOR pathway is activated through resistance exercise.

Interestingly, autophagy and mTOR have an inverse relationship.

In nature there is no free lunch, your suggestion would focus on longevity rather then maximum muscle strength and size.

Although intressestingly enough there also is some research stating muscle size and all cause mortality are linked.

Personally I think cycling nutrition over periods could give the better overall results by not overfitting to one diet and lifestyle.

Very well articulated, You’ve given me that strange feeling that happens when some once expresses cohesively a set of ideas you’re still trying to map

There are also dose-size and age-related dependent components to protein intake.

You want to ingest a decent sized amount of protein to stimulate mTOR instead of ingesting small amounts of protein multiple times throughout the day.

As one gets older, you may need more protein to stimulate/kick off mTOR.

from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882708/ (ref numbers removed from text for better legibility):

"Skeletal muscle mass and functional capacity are controlled by the dynamic interaction of numerous factors, also encompassing diet and nutrition. An adverse yet typical consequence of the aging process is the progressive loss of muscle mass and physical function, named sarcopenia. Although the onset and progression of sarcopenia can be influenced by many factors, a compromised capacity to maintain the anabolic response after dietary protein intake has become a key target for researchers.

Independent of the type of protein and its source, it is important to underline that meals should include an appropriate amount of high-quality protein. In recent years, consensus statements and opinion articles have asserted that protein intake above 0.8 g/kg/day may confer muscle health benefits greater than those conferred by the current RDA.

As such, a protein intake of 1.0–1.2 g/kg/day has been recommended for the preservation of healthy aging muscles, while 1.2–1.5 g/kg/day of protein may be necessary in older patients with acute or chronic diseases. Elderly people with severe illness or malnutrition may need as much as 2.0 g/kg/day of protein.

In young individuals, slowly digested proteins (e.g., casein) may produce greater protein retention than those that are more quickly digested (e.g., whey). An opposite pattern has been documented in older individuals. Accordingly, some authors have demonstrated that the intake of whey protein stimulates postprandial muscle protein deposition in older men more efficiently than casein or casein hydrolysate."

There might be a timing aspect to it - eg by boosting mTOR only in the morning (protein rich breakfast etc).

Circadian rhythm of the body timing is quite important.

There is some research pointing towards that most hunger pangs not caused by daily eating schedule are protein related.

I think it’s multifactorial, but yes, protein is definitely an important part. Impaired gluconeogenesis or glycogen production, or insulin resistance could be other factors there. Chromium, vanadium, zinc, copper, selenium, iron, iodine deficiencies can all lead to problems in those areas. Certain (micro)biome pathogens, too, eg acetaldehyde producers.

Interestingly though, the article says mice on the low-isoleucine diet did better on muscle strength.

It's not exactly what it says. They mention "better shape" but I wish it would be more precise how the jugement is made and what factors are at play. If it's not a hard measure I wouldn't trust their judgment much because of confirmation bias.

There are also a lot of people who consider that anything that isn't extra lean is not good even though we have a lot of evidence that it is actually not healthy. You need some amount of body fat for good hormones regulation, storage and protection.

In the paper, past a certain age the difference in fat mass is not very significant but the control group had much better lean mass. So, it's not that they only lost some fat, the starved mouse are also missing out on useful muscle mass that could potentially make their life better and more enjoyable.

The more I read the more it looks like vegan progaganda...

"“Very quickly, we saw the mice on the reduced isoleucine diet lose adiposity — their bodies got leaner, they lost fat,” says Lamming, while the bodies of the mice on the low-amino-acid diet also got leaner to start, but eventually regained weight and fat."

Interesting n=1 experiment of a guy who lowered his fasting blood glucose from pre-diabetic to normal by restricting BCAAs: https://fireinabottle.net/how-i-both-aced-and-failed-my-oral...

Way above my head but less of whatever isoleucine is doesn't sound advisable:

https://aminoacidsguide.com/Ile.html

"Isoleucine participates in hemoglobin synthesis, as well as in the regulation of blood sugar and energy levels. Studies revealed that this amino acid has a very low toxicity at pharmatological levels up to 8% of solution concentration in rats."

"As a matter of fact, the three amino acids (Isoleucine, Leucine, and Valine) constitute nearly 70% of all the amino acids in the body's proteins. That is why their value in human body is so high."

I can't read the article but there's no explanation for why they would be interested in isoleucine in particular. They also seem nonplussed as to the mechanisms of any isoleucine-restriction longevity. As a result it comes across very post hoc.

I suspect I'm missing something though?

How does this square with the fact that isoleucine is important for muscle mass development?

Wild-assed guess: the benefits of increased muscle mass and bone density matter much more to humans than they do to mice. We are large and heavy, while mice are small and light.

It doesn't. And honestly the result should be treated skeptically until someone replicates it.

Mice studies like this have a ton caveats: the animal lives 3 years versus the human 100 years.

Research like this is better for understanding biochemical pathways then whole organism affects, especially since "aging" isn't a well defined phenomenon (it's a grab bag of other things we want to prevent).

Apparently it wasn't an issue? The article says mice on the low-isoleucine diet did better on muscle strength.

That muscle mass development has nothing to do with living healthier or longer?

Well it's correlated, in that the resistance training associated with developing muscle mass also increases bone density and other factors that lead to living longer. Curious what would happen if you did resistance training while simultaneously stunting the development of muscle. Would you still get the same health benefits?

we don't need much muscle

We really do. Especially as we age, maintaining a large amount of lean muscle is essential for metabolic health and preventing disabling injuries.

https://gabriellereece.com/muscle-as-the-cornerstone-of-long...

https://peterattiamd.com/outlive/

"maintaining a large amount of lean muscle is essential" I doubt about this. Maintaining exercise sure, maintaining low fat tissue sure, mintaining essential muscles comes as a result of daily activity: walking, using less devices and more manual processes, taking stairs rather than elevators, this makes more sense than going to gym, because diverse muscles work, in a more natural and physiological way

Look at centarians profiles, they're light, active, and not eating a lot (very little meat, mostly plant based)

This is a great study. And Thanksgiving is a perfect time for a low isoleucine dinner—-turkey is about as low as you can get.

Another point about why meat and milk is good when young, but not so much beyond middle age.

Dunno, (long) covid seems to deplete (iso)leucine and BCAA/HMB is necessary to supplement if one wants to recover from it and not function like a zombie for years...

Since mice are mostly herbivores (they do eat insects and worms and stuff, but apart from that mostly grain, seeds and plants), I wouldn’t really expect them to thrive eating large quantities of an amino acid found mostly (in decently large quantities) in meats anyway… So don’t put too much stock in this being directly applicable to humans.

Why will I live longer and healthier if I eat mice???

Despite common folk wisdom about "nine lives", field data strongly suggests that no individual living on an all-mouse diet has survived beyond age 40.

This reminds me of a cartoon I saw recently: “Every single person that confuses correlation and causation ends up dying!”

New favorite quote

Yes, but what if the mice are living inside houses instead of in a field?

For starters, house mice are ~certain to contain far more microplastics, PFAS, and other pollutants and toxins than free-range field* mice.

*As in "natural, organic field". Not a field of weeds growing atop some old toxic waste dump.

It would be interesting if less isoleucine was responsible for some of the longevity improvements of calorific restriction in mice.

We all know mice are the perfect human model.

Metabolism is pretty conserved across organisms, so it’s not even that bad

Yes but longevity isn't.

Saving you a Wikipedia search: “ Foods that have high amounts of isoleucine include eggs, soy protein, seaweed, turkey, chicken, lamb, cheese, and fish.”

https://en.wikipedia.org/wiki/Isoleucine?wprov=sfti1#Nutriti...

It doesn't make sense to me to focus-fire a single nutrient of a food, find some reason to not maximize it in mice, and then use that to avoid whole foods that contain that nutrient, especially as a human.

A food could have all sorts of individual nutrients that look bad in isolation while the food only improves human health outcomes when put to the test.

Randomized controlled diet experiments over the lifetime of a human are pretty difficult. So they make do with what data they can get.

Putting that data together to form a recommendation is incredibly difficult. If we could just get people not to imagine that it's trivial ("eat no isolucene and live forever"), we'd be several steps ahead of where we are.

Isn't that the food normally linked with the longevity of people of the Mediterranean areas?

Yes, this study comes with the standard “in mice” caveat. We don’t know if this would replicate in humans. It is interesting though if for no other reason than to illustrate that all calorie sources are not equivalent.

Even in mice there is a large sex difference.Most beneficial in males.

This is a really good point. There are a lot of really odd outcomes these mice models consistently produce but we don't know what causes them and/or don't care because it's not within the scope of the primary research question

Some of us care ;-) including Dudley Lamming.

Here is our group’s latest paper in Science. We try to get at genetics of sex differences in lifespan:

https://pubmed.ncbi.nlm.nih.gov/36173858/

In this study we mapped 7 chromosomal regions that modulate lifespan in mice. We are now up to about 35 regions. Of course the goal is to understand the actual processes modulated by each so-called “locus”.

So 100% of my protein sources

You need it to survive. It's an essential amino acid.

It's as if proteins contain a lot of amino acids.

Probably don’t stress about it too much (or really at all), unless you are a mouse.

So everything except beef, pork, nuts and grains in terms of protein sources?

From the summary of the paper

> Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice

So maybe stop using that BCAA supplement?

These days BCAAs have the reputation of being pretty useless anyway, unless your diet is very poor. You get enough BCAAs from complete protein sources.

I just started using it out of curiosity and I have to say it does seem to improve recovery and building. I don't know if I'm hallucinating yet (just about a week in) but something has changed for sure and that's not confirmation bias (measurable on the bioimpedance meter) Putting muscle mass is not my priority as I am mostly a runner, but I do swim too and upper body strength makes a good difference there. So, I would rather not lose whatever I build and make it easier to maintain... My diet isn't very high in animal products most of the time which may be the reason. But between vegan doomerism and the price of quality meat it's not easy to find a balance...

Look up the AXA1125 for non-fatty liver disease and see how BCAA with a bunch of other amino acids (arginine, NAC, glutamine) gets your liver and mitochondria back in shape.

I didn't know about that, to clarify I meant for people using it to build muscle.

Turkey should not be high on this list. This source is comparatively low in isoleucine according to Dudley Lamming—the senior author, sand here is a site to check other meats:

tools.myfooddata.com

My advocatus diaboli asks: Was this study financed by Turkey farmers?

100 years in this society, what more could one want..

Important news for mice everywhere. Maybe we can make engine wiring harnesses out of isoleucine in the future.

All these anti-aging posts make me cringe. Face it, you’re going to die one day. You want to be healthier? Eat a healthy diet and exercise instead of looking for shortcuts

> healthy diet

Easy to say that phrase, much harder to elucidate exactly what it means. And how will we find out what it means without studying it?

Everyone is different. Eat what you want. There is no perfect diet. And we are all going to die [if not tomorrow :-]

That’s anti-science. It’s well established you shouldn’t just “eat what you want,” at least when it comes to living a long/healthy life. Death is a compounding statistical phenomenon, not a discrete one.

Most nutrition science is bunk. We know you shouldn't consume too many calories. We know you need a certain minimum amount of micronutrients and essential amino acids. Nothing else really meets modern evidence based medicine criteria. If there are actual benefits from eating or avoiding certain foods then the effect sizes appear to be much smaller than other lifestyle factors like sleep, exercise, stress, and substance abuse.

As a practical matter a more productive approach is to (mostly) ignore the science and conduct informal n=1 experiments. Try adding or removing certain foods for a few months and see how that impacts your athletic performance and subjective well being.

It's really hard to tell what's science in nutrition and what is some unreplicable crap Nestlé is using to say its cereals are healthy.

Brief reminder we recommended sugar over fats for decades.

It’s all science, reproducibility is a larger crisis within science at the moment not unique to nutrition. But even if it was (and it is) slightly higher in food science, the solution is not “eat whatever you want”, it’s more like that you should understand the fundamentals instead of overfitting to individual studies.

This post is a data point about the definition of “healthy diet”.

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