Uncovering how low-protein diets might reprogram metabolism

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In 2014, Dudley Lamming read a study from Australia that looked at how mice responded to dozens of controlled diets when it came to his attention: the mice given the least amount of protein were the healthiest.

“That was really interesting because it contradicts a lot of the health information people get,” says Lamming, a metabolic researcher at the University of Wisconsin School of Medicine and Public Health.

Since then, Lamming and PhD students have been trying to answer the question raised by the Australian study in his laboratory: Why should a low-protein diet make animals healthier?

They discovered a little-known but robust pattern in both animal models and humans. A diet high in the three branched chain amino acids BCAAs has been linked to diabetes, obesity, and other metabolic disorders. Conversely, a low-BCAA diet can counteract these metabolic diseases and even extend the healthy lifespan of rodents.

It’s not yet entirely clear how BCAAs control metabolism, although restricting them appears to promote faster metabolism and healthier blood sugar control. And because of the immense complexity of nutritional research in humans, the full effects of BCAA restriction in humans are not yet known.

But the research line offers a fascinating new way of thinking about what we eat. Studies show that a low-protein diet reprograms the metabolism, even if animals consume the same – or more – calories.

“There’s a growing awareness that a calorie is not just a calorie, that a calorie has effects beyond its calorie content,” says Lamming. “Our research shows that protein calories are not the same as other calories.”

Less is more

Scientific evidence of the benefits of both calorie and protein restriction goes back nearly a century, and the field has grown in recent years. In 2009, UW Madison researchers showed that rhesus monkeys lived longer on a long-term low-calorie diet. Studies in other animals have shown similar results.

Reduced protein diets have attracted less attention. However, there is evidence that many of the benefits of restricting calories can be achieved by limiting protein intake alone. These benefits persist even when animals eat as much as they want.

In two studies published earlier this year, Lamming and his colleagues, including PhD students Nicole Richardson and Deyang Yu, focused in particular on branched-chain amino acid restriction. BCAAs make up three of the nine essential amino acids that humans cannot produce and have to eat. As the name suggests, their chemical structures contain tree-like branches.

In a series of experiments published in January, Richardson tested a diet on mice that contained only one-third the normal amount of BCAAs. It wasn’t a reduced calorie diet; the animals could eat as much as they wanted.

Male mice that ate the food their entire life lived, on average, about 30% longer – about eight more months. It’s not clear why female mice didn’t benefit, although other research suggests that female mice may need a slightly different diet to see the benefits of reduced BCAA consumption.

The gender differences “were very surprising to us,” says Lamming. “Almost all research to date has been done on male mice. This indicates the importance of these studies in both sexes.”

However, male mice showed reduced activity of a biochemical pathway called mTOR, which is activated by BCAAs. Many experiments have shown that treatments that reduce mTOR activity tend to improve metabolic health and increase lifespan.

In another article published in May, Yu and Richardson went even deeper. They asked if the three individual BCAAs – leucine, isoleucine, and valine – had unique effects in the body or if they all worked similarly.

“We found that isoleucine restriction was by far the most powerful,” says Lamming. Mice fed a diet low in isoleucine were leaner and exhibited healthier blood sugar metabolism. Valine-restricted diets had similar but weaker effects. Reducing leucine levels has been of no benefit and can even be detrimental.

To study how the three BCAAs affected obesity, the researchers provided mice with what is known as a Western diet, which is both high in fat and high in sugar. After a few months of a Western diet, mice become obese.

When Lamming’s group started feeding these obese mice a Western diet low in isoleucine, the mice started eating more food but still lost weight. The weight loss was primarily caused by a faster metabolism, in which the body burns more calories than heat when at rest.

On human health terms, the Lamming Laboratory worked with SMPH Population Health Professor Kristen Malecki and her colleagues to analyze the food diaries and weight of participants in the Wisconsin Health Survey, a statewide public health study conducted by Wisconsin -Partnership program is supported.

By calculating how many amino acids each person ingested, they discovered that an increased intake of isoleucine was linked to a higher body mass index, which they had predicted based on the rodent studies.

Rethink diet

Lamming realizes that the results of his research are not intuitive. Many modern dietary recommendations recommend adding protein without limiting it. Protein promotes satiety, which can help people control their calories. And for athletes who want to build and repair muscle, these essential amino acids are actually essential.

But with the majority of the US population being overweight and sedentary, Lamming sees an opportunity to rethink diet. “Overall, humans are not that good at sticking to a low-calorie diet over the long term,” he says. But evidence from animal models suggests that even with normal caloric intake, a low-protein diet helps you lose fat by reprogramming your metabolism.

Many questions remain unanswered, particularly with regard to a low-protein diet in humans. The types of long-term controlled diet studies lamming can perform in rodents are nearly impossible in humans. But the Lamming Laboratory and other groups are working to test low-BCAA diets in small human studies.

Even developing a realistic, low-BCAA diet is difficult. Vegan diets are usually low in BCAAs and animal proteins are high. However, more nutritional research needs to be done, particularly to create a diet low in isoleucine. And Americans typically eat a lot more protein than they need, so changing that habit could be difficult.

“We learned that the composition of the food you eat is really important to your health and longevity,” says Lamming. “And I think we are well on the way to finding a diet that people can follow without calorie restriction and that will still allow them to live long and healthy lives.”

Eating a diet low in certain amino acids can be the key to weight loss

More information:
Samantha M. Solon-Biet et al., The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging and longevity in ad libitum-fed mice, cell metabolism (2014). DOI: 10.1016 / j.cmet.2014.02.009

Deyang Yu et al., The Adverse Metabolic Effects of Branched Chain Amino Acids Mediated by Isoleucine and Valine, Cell Metabolism (2021). DOI: 10.1016 / j.cmet.2021.03.025

Provided by the University of Wisconsin-Madison

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