In 2014, Dudley Lamming came across an intriguing study from Australia that piqued his interest. The study observed how mice responded to various controlled diets, and a surprising revelation stood out – the mice that consumed the least amount of protein appeared to be the healthiest. Lamming, a metabolism researcher at the University of Wisconsin School of Medicine and Public Health, was compelled to delve deeper into this phenomenon and address the fundamental question: Why would low-protein diets contribute to improved animal health?

Since that pivotal moment, Lamming and his team of graduate students have embarked on a journey to unravel the mysteries behind the health benefits associated with low-protein diets. Their investigations have uncovered a compelling yet lesser-known pattern that extends across both animal models and humans. Diets rich in branched-chain amino acids (BCAAs), specifically leucine, isoleucine, and valine, are correlated with metabolic disorders such as diabetes and obesity. Conversely, restricting BCAAs in the diet seems to counteract these metabolic ailments, potentially extending the healthy lifespan of rodents.

The precise mechanisms through which BCAAs influence metabolism remain somewhat elusive, but preliminary findings suggest that limiting these amino acids may lead to faster metabolisms and improved blood sugar control. The complexity of diet-related research in humans makes it challenging to fully understand the ramifications of BCAA restriction, but the emerging data offer a fresh perspective on dietary considerations. Notably, studies indicate that low-protein diets can reprogram metabolism, independent of calorie intake.

Dudley Lamming emphasizes this paradigm shift, stating, "There’s a growing realization that a calorie is not just a calorie, that a calorie has implications beyond just its caloric content. What our research is showing is that protein calories are not the same as other calories."

The concept of calorie restriction for longevity and health benefits has been explored for almost a century, with studies showcasing positive outcomes in various animal models. In 2009, researchers at UW–Madison demonstrated that rhesus monkeys on a long-term calorie-restricted diet exhibited increased lifespans. However, the spotlight on protein-restricted diets has been relatively dim. Nevertheless, evidence suggests that many benefits associated with calorie restriction can be achieved by limiting protein intake, and these benefits persist even when animals are allowed to consume as much as they desire.

Recent studies conducted by Lamming and his team have honed in on the specific role of BCAAs in diet. In one set of experiments, mice were subjected to a diet containing only one-third of the normal amount of BCAAs, without any calorie restriction. The result? Male mice on this diet throughout their lives lived approximately 30% longer on average, roughly extending their lifespan by eight months. Surprisingly, female mice did not exhibit the same benefits, suggesting potential sex-specific nuances in BCAA metabolism that warrant further exploration.

The researchers identified reduced activity in the mTOR biochemical pathway in male mice consuming the low-isoleucine diet. This pathway, activated by BCAAs, has been linked to improved metabolic health and increased longevity. While Lamming acknowledges the counterintuitive nature of these findings, particularly in the context of modern dietary advice advocating for increased protein consumption, he sees an opportunity to rethink dietary recommendations, especially in a population characterized by overweight and sedentary lifestyles.

In a subsequent study, the researchers delved deeper into the individual effects of the three BCAAs – leucine, isoleucine, and valine. The findings revealed that isoleucine restriction had the most potent effect, leading to leaner mice with healthier blood sugar metabolism. Valine restriction exhibited similar but weaker effects, while reducing leucine levels showed no clear benefits and may even be detrimental.

To explore how BCAAs influenced obesity, the researchers introduced mice to a Western diet high in both fat and sugar, a known cause of obesity in rodents. Strikingly, when obese mice transitioned to a Western diet low in isoleucine, they consumed more food but still lost weight. The weight loss was primarily attributed to an accelerated metabolism, where the body burned more calories as heat during periods of rest.

In an effort to extend the relevance of their findings to human health, Lamming's team collaborated with population health professor Kristen Malecki and colleagues. Analyzing data from the Survey of the Health of Wisconsin, a statewide public health study, they found that an increased intake of isoleucine was associated with a higher body mass index (BMI) in participants, aligning with the observations from rodent studies.

Acknowledging the unconventional nature of their research findings, Lamming recognizes that contemporary dietary advice often leans towards increasing protein intake. Protein, known for promoting a sense of fullness, aids in calorie control and is deemed essential for athletes engaged in muscle building and repair. However, with the prevalent issues of obesity and sedentary lifestyles in the majority of the U.S. population, Lamming sees an opportunity to reconsider dietary norms.

"Humans overall are not so good at long-term adherence to calorie-restricted diets," notes Lamming. Yet, evidence from animal models suggests that low-protein diets may facilitate fat loss even with normal caloric intake by reshaping metabolism. While numerous questions remain, particularly regarding the translation of low-protein diets to humans, Lamming and other researchers are working towards conducting small-scale studies to investigate the effects of low-BCAA diets.

Creating a realistic low-BCAA diet presents its own challenges, given that vegan diets are typically low in BCAAs while animal proteins are rich sources. Additionally, considering the prevalent tendency for Americans to consume more protein than necessary, a shift towards a low-BCAA diet may pose cultural and dietary hurdles.

Lamming concludes, "We’ve learned that the dietary composition of what you eat really matters for health span and longevity. And I think we’re on track to find a diet that people could adhere to without restricting calories, that would still enable them to live a long and healthy life."