The Menu Mystery

The Menu Mystery

Physiology research sheds light on what and how to eat today.
By Christine Yu

“You are what you eat.”

We’ve heard endless iterations of this phrase, often as an admonishment to eat well. But when French politician and lawyer Jean Anthelme Brillat-Savarin first wrote, “Tell me what you eat and I will tell you what you are,” it’s doubtful he would have anticipated that his words would become a guiding tenet in how we think about food, diet and nutrition. 

The idea that good food, good health and good character are inextricably linked has persisted since Brillat-Savarin first inked those words in 1826. In the 1930s, American nutritionist Victor Lindlahr was quoted as saying, “Ninety percent of the diseases known to man are caused by cheap foodstuffs. You are what you eat,” the first appearance of the phrase in the English language. Since then, it has spawned countless food rules—a series of do’s and don’ts that are supposed to illuminate a path toward optimal health. 

Yet, when it comes to making everyday food choices, it’s not always simple. The landscape of nutrition science is constantly changing. It’s hard to parse through the often conflicting and confusing headlines in the news and on social media or even doctor recommendations. Should you eat eggs or strike them from your diet? Is breakfast the most important meal of the day or should you skip it for better metabolic health? 

Beneath the hype, what does physiology research tell us about the best ways to eat and foods to consume for optimal health? Are there certain foods that reduce the underlying contributors to disease? Let’s take a look. 

How We Eat

Most of us hope to age gracefully and live out our years to the fullest. Nutrition is a critical facet of this equation. Not only do we need to eat to survive, Brillat-Savarin and Lindlahr were right—diet is intricately tied to health and longevity. Certain nutrients and patterns of eating are associated with lower rates of age-related disease. 

The reality is that for most Americans, there’s room for improvement. According to the Food and Drug Administration (FDA), 75% of people don’t eat enough fruits, vegetables or dairy. Sixty-three percent exceed the recommended limit for added sugar. Seventy-seven percent consume too much saturated fat. Ninety percent have too much sodium in their diet.

“Most diseases that affect people today are largely due to improper nutrition and, to some extent, lack of physical activity,” says Joseph Brozinick, PhD, senior research adviser at Eli Lilly. “It’s not just obesity and diabetes. To some extent, perhaps kidney disease, heart failure and some cancers do seem to be affected by nutrition.” 

Scientists have long been interested in understanding the connection between nutrition and physiology. “Trying to understand what dietary components regulate these effects and the molecular mechanisms that are engaged may give us insight not only to think about how to eat healthy, but also to develop small molecules that we can use to treat age-related diseases,” says Dudley Lamming, PhD, associate professor of medicine at the University of Wisconsin-Madison. 

One main area of study is calorie restriction. “For almost 100 years, calorie restriction has been the gold standard for interventions that regulate healthy aging in a wide range of species, from yeast to mice and non-human primates,” Lamming says. “When you calorie restrict, limiting the number of calories that an animal consumes, typically 20 to 40%, they live longer and healthier lives.”

“For almost 100 years, calorie restriction has been the gold standard for interventions that regulate healthy aging in a wide range of species, from yeast to mice and non-human primates.”

Dudley Lamming, PhD

Recently, scientists have found that there may need to be a period of fasting to evoke the beneficial metabolic, molecular and anti-aging adaptations of calorie-restricted diets. Heidi Pak, PhD, a former student in Lamming’s lab, teased apart the effects of calorie restriction and fasting together and alone. In her study, mice that ate only one small meal a day not only had better blood sugar control but were also found to be less frail, have better memories and live longer compared to mice that didn’t fast while also eating fewer calories.

“What Heidi discovered was that a lot of the metabolic effects of calorie restriction, particularly those related to insulin sensitivity, require a fasting period,” Lamming says.

The Protein Conundrum

Fasting and calorie restriction aren’t the only ways to induce advantageous metabolic changes. Lamming also noticed that the amount of protein in our diets may also influence health and longevity. And most Americans may be consuming too much protein. 

“Human epidemiological data suggest that people who eat lower protein diets are healthier and have reduced rates of a number of different diseases, particularly diabetes,” he says. “Short-term protein restriction in people tends to make them leaner, have lower fasting blood glucose and increase insulin sensitivity.” Lamming believes these changes may be due to decreased consumption of specific amino acids. He and his colleagues have identified potential culprits. 

One is isoleucine, a branched chain amino acid. In humans, isoleucine levels correlate with body mass index and mortality risk. By restricting only dietary isoleucine in mice, Lamming and his colleagues—including former graduate students Nicole Richardson and Deyang Yu and current graduate student Michaela Trautman—duplicated many of the metabolic effects of protein restriction. The restriction promoted fat loss and improved glucose tolerance and insulin sensitivity, and mice got leaner. What’s more, there was a “beiging” of white adipose tissue.

“It’s burning off a lot of fuel in the form of heat. The animals aren’t hotter; they don’t move more. But their metabolic rate has essentially increased,” Lamming says. Conversely, when isoleucine was added back to a protein-restricted diet, the positive effects of the diet were mitigated.

The other potential culprit is the amino acid histidine. In humans, there’s a correlation with histidine levels in the diet and body mass index, an effect that Lamming says is twice as big as what has been found for isoleucine. When another of Lamming’s former graduate students, Victoria Flores, PhD, restricted histidine in mice, mice similarly got leaner. Metabolic rates increased, and insulin sensitivity improved.

However, protein restriction seems to extend lifespan only in males, not females. While researchers don’t completely understand why, they believe it might have to do with the mTOR signaling pathway, an amino acid- and insulin-responsive protein kinase that’s a key regulator of metabolism and aging. “What we see in our branched chain amino acid-restricted animals is that mTOR signaling goes down, but it only goes down in males, and that correlates with the lifespan extension,” Lamming says.

“We’ve cured diabetes and obesity a lot in animals but never in humans. It’s hard to translate some of the findings in preclinical models to clinical models or to people. That’s where a lot of things fall apart.”

Joseph Brozinick, PhD

While some researchers are bullish on low-protein diets, others believe muscle mass and function are critical for health and well-being. “Muscle mass has a significant impact on energy balance, which impacts energy metabolism, and improved muscle function reduces risk for chronic disease. There is also a relationship between skeletal muscle mass and outcomes of well-being such as depression and sleep quality,” says Jamie Baum, PhD, director for the Center of Human Nutrition and associate professor at the University of Arkansas, who got her start studying higher protein diets during the heyday of the South Beach and Atkins diets. 

“Muscle is also essential for disposing of nutrients,” Baum says. But to preserve muscle mass, you need dietary protein. Baum recommends a higher intake of lean protein, roughly 30% of daily calorie intake.

“Muscle is a protein storage organ in the body, and losing a lot of protein is detrimental to your health,” Brozinick says. “The biggest predictor of survival from profound injury and disease—like cancer, chronic kidney disease, sepsis and traumatic injury—is your ability to hang on to lean muscle mass.” And that extends to people who are obese or have type 2 diabetes. It’s particularly true for older adults who are at risk of sarcopenia—an age-related involuntary loss of skeletal muscle mass and strength that is associated with a higher risk of mortality.

Brozinick thinks muscle’s role in overall health, aside from exercise and physical activity, may have to do with mitochondria. Because mitochondria are symbionts, they have their own DNA. When mitochondria in the muscle become unhealthy and break apart, their DNA is released into the cell and is considered a toxic substance. 

“[Mitochondrial DNA] can communicate with other cells in the body and induce inflammation among other things,” Brozinick says. This can have adverse effects on other organ systems. He says there’s some indication that the ability of muscle to oxidize fat and other substrates may be an important factor in health, aside from just quantity of muscle. 

From Bench to Kitchen Counter

Every scientist knows that translating laboratory findings into real-world, practical applications isn’t seamless. “We’ve cured diabetes and obesity a lot in animals but never in humans. It’s hard to translate some of the findings in preclinical models to clinical models or to people. That’s where a lot of things fall apart,” Brozinick says. 

“One thing I always note is that our mice are sedentary and probably not good models for athletes or people who are very physically active. They may well benefit from a higher protein diet,” Lamming says. “Our results also may not apply in the same way to people who are over the age of 65 and suffer from age-related muscle loss. These people are often prescribed to eat more protein.”

Instead, Lamming says his mice may be better models for the general population, which tends to be sedentary and overweight or obese. Even still, differences between individuals may also influence expected results.

The debate between low-protein versus higher-protein diets also illustrates that science is often anything but black and white. “That’s the beauty of science; it can contradict itself,” Baum says. “There are people that would argue with me that high levels of branched chain amino acids are bad for chronic disease. But why is that? Is it because your muscles aren’t functioning and can’t clear them? Is it because, just like with diabetes and you become unresponsive to insulin, you become unresponsive to branched chain amino acids? I don’t know.”

In some cases, researchers may need to pull back the lens and consider the larger context. For Baum, her frustration lies with the overemphasis on specific molecules. “Our bodies don’t work like that, but I feel like a lot of this research is geared toward a pharmacological approach,” she says. “But is that the right approach for aging, nutrition and chronic disease?” 

Even working within industry, Brozinick tries to maintain a holistic perspective, one he’s had since he first became interested in physiology as a collegiate student-athlete and wanted to understand how the body’s different systems worked together. “All these organ systems talk to one another. They communicate with other tissue beds. If all you care about is liver metabolism or adipose, you lose touch with that,” he says. 

The debate between low-protein versus higher-protein diets also illus­trates that science is often anything but black and white. “That’s the beauty of science; it can contradict itself.”

Jamie Baum, PhD

While research may point to the benefits of intermittent fasting or diets with a specific amount of protein, the reality of people’s lives and systemic barriers can make dietary advice difficult to implement. Most people have a hard time sticking with a traditional diet or other restrictive way of eating over the long term. Plus, healthy foods such as fresh produce and lean protein may not be available in every neighborhood or fit into every household’s budget or food culture. They may also require more time to prep. With long work hours and caretaking responsibilities, not everyone has the available resources. Over 10% of households in the U.S. were food insecure at some point in 2021.

Is Personalized Nutrition the Answer?

The answer to the question “What should I eat?” isn’t clear-cut. It can vary depending on age, genetics, activity level, body type, food environment, socioeconomic status and even the microbiome environment. Increasingly, scientists are looking into these individualized patterns.

“We’re very interested in trying to explore how your genetics might influence your response to different diets,” Lamming says. “There is definitely variation, and it would be really nice to be able to prescribe a specific diet to a specific person.”

The current research on the molecular and mechanistic level could pave the way toward more personalized diet and nutrition advice. In its Strategic Plan for National Institutes of Health (NIH) Nutrition Research, NIH has targeted precision nutrition as a key strategy. It’s a way to customize what’s traditionally been a one-size-fits-all approach to eating and to drive the field forward. But there’s more work to do. 

Until then, rather than trying a specific diet such as Keto or Paleo, Brozinick says to focus on common sense recommendations: Eat a mix of fruits and vegetables for their antioxidant capacity. Include healthy fats such as mono- and polyunsaturated fats found in nuts and olive oil. Consume a moderate amount of protein. Meet your fiber intake. Don’t go overboard on any one thing. And exercise. 

This article was originally published in the January 2023 issue of The Physiologist Magazine.