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Diet and lifestyle

An intermittent low-protein diet improves health

Protein bars, drinks and powders take up increasing shelf space in shops. The goal is to stay slim and build up muscle mass. However, research shows that calorie restriction is necessary to sustain a long and healthy life. New research on animals reveals that an intermittent low-protein diet might be able to replace lifelong calorie restriction and the accompanying hunger. The research shows that this intermittent low-protein diet improves metabolism and extends lifespan.

Everything in moderation, as they say. Researchers have known for many years that moderately reducing energy intake improves health, and experiments in animal models have even shown that this can extend life. Lifelong dieting, however, represents an ascetic lifestyle that most people find very difficult to maintain in practice, which is why researchers continue to investigate health-promoting eating habits that can be more easily applied in practice.

“Recent studies have shown that giving rodents unlimited access to a very-low-protein diet produces significant health benefits, although they actually eat more than they did on a normal-protein diet. This indicates that reducing the protein content of the diet can improve health without the need to reduce energy intake and thus starve,” says Thomas E. Jensen, Associate Professor, Department of Nutrition, Exercise and Sports, University of Copenhagen.

Intermittent dieting might be the answer

Another effective alternative to lifelong dieting that is becoming increasingly popular is to intermittently reduce energy intake: for example, every other day or a few days a week. Danish researchers have now tried to combine these two types of dieting by providing a calorie-unrestricted intermittent low-protein diet to determine whether this can still improve health.

“Our experiments show that alternating between a normal-protein diet and a low-protein diet can achieve virtually the same health improvements as a permanent low-protein diet. This intermittent diet triggers the same molecular mechanisms in the body as those on a permanent low-protein diet, although the total calorie intake is actually higher. These experiments involved mice, but there are many indications that intermittent dieting can also positively affect people’s metabolism and health,” explains Thomas E. Jensen.

The idea for the study came from a desire to better understand some noteworthy results from 2014, when researchers found that mice fed a low-protein diet had far better health and lived longer than mice who ate a high-protein diet. One theory for this effect is that a high-protein diet can change the composition of intestinal bacteria, and it probably also reduces insulin sensitivity.

“The experiments showed that eating a lot of protein and a little carbohydrate probably makes mice eat less and become leaner, but their metabolism deteriorates and their lifespan decreases. Conversely, a diet high in carbohydrates and low in protein led to moderate overweight, but the mice were healthier and lived longer. We were trying to confirm this seemingly paradoxical phenomenon and then change it to a more practically applicable alternative,” says Thomas E. Jensen.

Improving the ability to control glucose

The researchers put mice on a 14-day diet with different compositions of protein, fat and carbohydrate to investigate how dietary variation affects the mice’s gut. A special group of mice received a low-protein and high-carbohydrate diet for 14 days and then a standard diet for 14 days. Meanwhile, the researchers measured the mice’s weight, metabolism and composition of intestinal bacteria and the liver’s secretion of fibroblast growth factor 21 (FGF21), a hormone that increases basal metabolism and improves glucose metabolism.

“Our theory was that the intermittent low-protein diet would improve the mice’s metabolic health and ability to maintain weight, and we found significant changes along the way. Each time the mice ate a low-protein diet, they increased their basal metabolism and lost weight within a few days despite consuming more calories overall than the mice on a standard diet,” explains Thomas E. Jensen.

The mice also improved their ability to manage glucose – a crucial factor in avoiding type 2 diabetes – and changed the composition of their intestinal bacteria in a healthier direction.

“Overall, the positive effects of being on an intermittent low-protein diet were very similar to the positive effects of being on a permanent low-protein diet,” says Thomas E. Jensen.

The liver seems to remember a low-protein diet

Many of the benefits of low-protein diets are attributed to increased secretion of FGF21 from the liver. An unexpected finding in this study was that considerably more FGF21 was secreted each time the mice ate a low-protein diet, even though they returned to the standard diet for 14-day periods.

“We would expect that a 14-day normal-protein diet would reset the system, but the liver seems to remember that it has been on a low-protein diet and is prepared for this to happen again. We do not yet know the mechanism behind this memory phenomenon and what the physiological function is, but this is exciting – both for physiological understanding and for developing medicine. This also has an immediate practical implication, since the increased response may enable the periods on a low-protein diet to be shortened even more over time while still achieving the same health benefits,” says Thomas E. Jensen.

In addition to experimenting with the diet, the researchers also tried to measure how exercise affected the mice in the different dietary groups. These results were also surprising. In fact, exercise seemed to suppress some of the positive effects of the intermittent low-protein diet. However, it is too early to conclude anything definite about mechanisms and effects.

“Exercise has previously been shown to increase FGF21 secretion in mice, so our hypothesis was that combining low-protein diets and exercise would increase FGF21 levels even more. However, we found that exercise actually reduced the ability of the low-protein diet to increase FGF21. Since exercise and diet often accompany one another when people change lifestyle, this is important to examine further. Should we train differently? Should we exercise more during normal-diet periods? What are the mechanisms behind this?” asks Thomas E. Jensen.

The study thus leaves many unanswered questions to be investigated in the future.

“This is currently a mouse study and should be followed up by studies involving people. The few published studies on people eating low-protein diets also indicate that this can increase FGF21 secretion and benefit metabolism. However, we have a ways to go before we can make actual dietary recommendations,” says Thomas E. Jensen.

Periodized low protein–high carbohydrate diet confers potent, but transient, metabolic improvements” has been published in Molecular Metabolism and “The gut microbiome on a periodized low-protein diet is associated with improved metabolic health” has been published in Frontiers in Microbiology. In 2015, the Novo Nordisk Foundation awarded a grant to Thomas E. Jensen for the project Understanding Skeletal Muscle Plasticity in Health and Disease. In 2019, Thomas E. Jensen received grants from Independent Research Fund Denmark, the Danish Diabetes Academy, the Novo Nordisk Foundation and the Lundbeck Foundation to continue his research.

Thomas Elbenhardt Jensen
Associate Professor
Skeletal muscle is a plastic tissue that responds and adapts to external stimuli during physical activity and inactivity. Increased knowledge of the molecular signaling mechanisms that control this adaptation is not only important for understanding how the muscle reacts to work and training, but also lifestyle and aging-related diseases such as diabetes, obesity and cancer. Inactivity and aging are associated with reduction of skeletal muscle mass and metabolic health, and exercise is effective in prevention of these adverse phenotypic changes. Molecularly, mechanistic Target of Rapamycin Complex 1 (mTORC1) is a key regulator of muscle size, the cellular renovation process known as autophagy and metabolism, but the molecular regulation of mTORC1 remains incompletely understood, particularly in the context of muscle and exercise. The overall goal of my current research is to: a) improve the understanding of mTORC1 regulation and function in active and inactive muscle, specifically its regulation by mechanical stress during exercise and the role of subcellular organization, b) identify novel drug targets to modulate muscle phenotype and mTORC1 signaling. In a major international research effort, made possible to a large part by a Novo Nordisk Foundation Excellence grant from 2015-2020, my research team will engage in a combination of powerful omics-based discovery tools (phosphoproteomics, membrane proteomics) and hypothesis-driven studies using state-of-the-art molecular cell biology and advanced microscopy techniques in muscle cells, rodent and human muscle. The results of this research are expected to have a major scientific impact on our basic knowledge of mTORC1 regulation and function in muscle and possibly drug development targeting human disease.