Cutting Back on One Amino Acid Increased Lifespan of Mice by Up to 33%

In a study in the United States, researchers found that limiting the intake of one particular essential amino acid slowed signs of ageing in mice and even lengthened their lifespan.

The team is now asking whether the same line of evidence might eventually help people live longer - and live better.

What is isoleucine, and why it matters

Isoleucine is one of three branched-chain amino acids used by the body to build proteins. It is essential for survival, yet our cells cannot make it from scratch, so it has to come from foods such as eggs, dairy products, soya protein, and meat.

Even so, more is not always better.

Earlier work, drawing on data from a 2016-2017 survey of Wisconsin residents, linked dietary isoleucine levels with metabolic health. In that analysis, people with higher BMIs were, in general, consuming much larger amounts of the amino acid.

How the study tested isoleucine restriction in mice

In the newest study, scientists used a genetically diverse population of mice and assigned them to one of three diets:

• A control diet containing 20 common amino acids
  
• A diet in which all amino acids were reduced by about two-thirds
  
• A diet in which only isoleucine was reduced by the same amount
  

A video accompanying the research provides a brief overview of the findings.

At the outset, the mice were about six months old - roughly comparable to a 30-year-old person. The animals could eat as much as they wished, but only the specific food assigned to their group.

As endocrinologist Dudley Lamming from the University of Wisconsin, who contributed to both studies, put it in 2023 when the latest results were released: "Different components of your diet have value and impact beyond their function as a calorie, and we've been digging in on one component that many people may be eating too much of,"

He added: "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."

Isoleucine restriction and ageing: lifespan, healthspan, and health measures

Cutting dietary isoleucine increased both lifespan and healthspan in the mice, reduced frailty, and supported leanness and glycaemic control. Compared with mice whose isoleucine intake was not restricted, male mice saw a 33 percent rise in lifespan, while females showed a 7 percent increase.

The mice on low-isoleucine diets also performed better across 26 different indicators of health. These measures included muscle strength, endurance, blood sugar levels, tail use, and hair loss.

Among males, the researchers also observed less age-related prostate enlargement, along with a lower likelihood of developing the cancerous tumours that commonly occur in these diverse mouse strains.

More calories, but less weight

One unexpected finding was that mice eating the low-isoleucine food consumed substantially more calories than the other groups. Instead of putting on weight, however, they expended more energy and kept a leaner body weight, despite showing no differences in activity levels.

What this could (and could not) mean for humans

The researchers suggest that limiting isoleucine in humans - either through dietary changes or pharmaceutical approaches - might plausibly produce comparable anti-ageing effects. As with any mouse study, though, the answer will remain uncertain until clinical testing in people is done.

They also stress that translating the results is not straightforward. While the mice were fed tightly controlled diets, the authors point out that diet involves extremely complex chemistry, and other dietary factors could be contributing to the outcomes.

More broadly, reducing protein intake overall can be harmful in both mice and humans. That means applying these findings in everyday life is not as simple as merely eating fewer high-protein foods, even if that is the most direct way to lower isoleucine intake.

Across the experiments, the degree of amino acid restriction was kept constant. The team notes, however, that additional fine-tuning may be needed to achieve the best effects across different mouse strains and between sexes - when it comes to diet, there is no universal template.

As Lamming said: "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."

The research was published in Cell Metabolism.

An earlier version of this article was published in November 2023.