Diet Control of Isoleucine Increases Healthspan and Lifespan By Up to 33% in Mice

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Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.

• Isoleucine restriction (IleR) improves metabolic health in both sexes
• IleR reprograms hepatic metabolism in a sex- and age-dependent manner
• IleR reduces frailty and increases lifespan, with stronger effects on male lifespan
• Amino acid restriction begun at 6 months extends healthspan but not lifespan

Restricting dietary isoleucine increased the lifespan and healthspan of the mice, reduced their frailty, and promoted leanness and glycemic control. Male mice had their lifespans increased 33 percent compared to those whose isoleucine was not restricted, and females had a 7 percent increase.

These mice also scored better in 26 measures of health, including muscle strength, endurance, blood sugar levels, tail use, and hair loss.

Restricting protein intake in general, for instance, has detrimental effects on the body, mouse or human. Translating this research for real-world human use is more complicated than just reducing intake of high-protein foods, even though this is the simplest way to limit isoleucine intake.

Narrowing these benefits down to a single amino acid gets us closer to understanding the biological processes and maybe potential interventions for humans, like an isoleucine-blocking drug.

11 thoughts on “Diet Control of Isoleucine Increases Healthspan and Lifespan By Up to 33% in Mice”

  1. So the strategy is to follow low-protein diet and use collagen powder (about 1.6% isoleucine) as supplement?

    • There’s reason to think the association holds in humans. High branched-chain amino acids (BRAA) are associated with diabetes, which clearly reduces lifespan.

    • Vegetable foods are low in Leucine, Isoleucine, and valine. Animal foods are high. Avoid meat, fish, diary, and eggs.

  2. In mice. Typically when we find interventions in mice that dramatically improve lifespan, we discover that our own biology already effectively implements them.

    People do their testing in mice anyway, because it’s fast. But it’s the biological research equivalent to looking for your dropped car keys under the street light.

    • Precisely what I was thinking.
      It would be so much more usefull to learn from the genetics and immune systems of large mammals, such as elephants and whales.
      Possibly also parrots.

      • The problem, I think, is that aging research is being done and funded by people who hope to benefit from it themselves. Which I can entirely understand, but realistically we’re probably looking at a multi-generational effort to solve this problem. Our biology needs some major revisions, not tweaks.

        I’m not at all happy about that, being 65… But I try to be realistic about it anyway.

        Now, there ARE some promising interventions that seem affordable. Nothing that would be a fountain of youth, but well worth doing. And maybe we need some work on making them affordably scale. Dr. Fahy’s research on thymus regeneration seems to be working out well. Turns out that you don’t really need youthful blood transfusions, you just need your old blood diluted. Things like that.

        And maybe cryonics needs some major advances, to save the generation too old to last long enough for the other research.

  3. And what role does Isoleucine plays in complex protein foods? Can it be Eliminated? The medical medium does not include grains and lagume me in his recommended foods because of the complexity of their proteins and the toll they take on the liver digesting them. If the solution is eliminating Isoleucine by creating gmo versions of these foods the answer is that in general the medical medium consider all gmo food unhealthy. his recommended foods are fruits, vegetables and tubers. tubers have a lot of protein also but it’s very light and easy to digest. They’re very easy to replace grains with.

  4. Dr Robert Lustig wrote about how modern agriculture, and I believe Glyphosate in particular via inhibition of the Shikimic acid pathway in plants leads to inhibition of the synthesis of Aromatic AAs: Tyrosine, Phenylalanine, Tryptophan ( Also essential for Serotonin synthesis) in plants which then affects the levels in food animals. Thus conventionally farmed meat is high in branches chain AAs and low in the Aromatic AAs.

    • I would say LEV in the 2030s for the early adopters, otherwise 2040s. As for rejuvenating a 80 years old back to his 20s, probably in 2060-2070. Kurzweil is desesperate because he is old.

      • I can certainly understand that. With his money I’d be investing heavily in cryonics, personally. The odds of anything life extending paying off in time to keep him from dying aren’t great.

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