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Cutting Back on One Amino Acid Increases Lifespan

Limited intakes of a specific essential amino acid have been found to slow the impacts of aging and even extend lifespan up to 33%.

These findings are prompting scientists to consider potential applications for enhancing human longevity and quality of life.

Isoleucine, one of three branched-chain amino acids necessary for protein synthesis in the body, must be obtained from dietary sources such as eggs, dairy, soy protein, and meats because it cannot be synthesized by cells.

However, an excess of isoleucine might be detrimental. Previous research, analyzing data from a 2016-2017 survey of Wisconsin residents, revealed a correlation between dietary isoleucine levels and metabolic health, noting that individuals with higher BMIs generally consumed greater quantities of this amino acid.

“Different components of the diet have value and impact beyond their function as a calorie. It’s interesting and encouraging to think a dietary change could still make such a big difference in lifespan and what we call ‘healthspan,’ even when it started closer to mid-life.”

Dudley Lamming, a metabolism researcher from the University of Wisconsin, US

The Study

In the study, a genetically diverse group of mice was divided into three diet groups:

  • a control group consuming twenty common amino acids,
  • a group with all amino acids reduced by about two-thirds,
  • a group with only isoleucine reduced by the same amount.

At the study’s onset, the mice were approximately six months old, comparable to a 30-year-old human. They were allowed to eat freely from the specific type of food allocated to their group.

Dietary restriction of isoleucine has shown to increase the lifespan and healthspan of mice, reducing frailty and promoting leanness and glycemic control. Lifespans increased by 33 percent in male mice and by 7 percent in females when isoleucine was restricted.

Improvements were observed in 26 health measures, including muscle strength, endurance, blood sugar levels, tail use, and hair loss.

Male mice on a low-isoleucine diet exhibited less age-related prostate enlargement and a lower likelihood of developing cancerous tumors, common in diverse mouse strains.

Interestingly, despite consuming more calories, these mice maintained leaner body weights by burning more energy, without an increase in activity levels.

Researchers suggest that isoleucine restriction in humans, through diet or pharmaceuticals, could potentially yield similar anti-aging effects. However, conclusive results require human testing, as mouse study findings do not always translate directly to humans.

Controlling diet in humans is challenging due to its complex chemical nature, which may involve other dietary components. General protein restriction can have detrimental effects, making real-world application of this research more complicated than simply reducing high-protein food intake.

The amino acid restriction level remained constant in all experiments, but it is acknowledged that optimal effects may require fine-tuning for different strains and sexes of mice, indicating that a one-size-fits-all approach to diet is impractical.

“We can’t just switch everyone to a low-isoleucine diet. But 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.”

Dudley Lamming


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.

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