A new study by researchers from Yale University reveals that calorie restrictions can offer health advantages. Most people know that eating fewer calories than you burn can lead to weight loss and increased stamina. However, the new study highlights other health benefits as well.

Years of research on flies, worms, and mice proved that calorie restrictions could prolong their life span. Researchers also wanted to investigate whether this would have the same result in humans. The latest study led by Yale researchers identified a significant protein that could enhance human health. They published their findings in the journal Science.

Researchers based this study on results from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) clinical trial. This marked the first-ever controlled study of calorie restrictions in healthy humans.

For the trial, the research team gathered information on the baseline calorie intake of over 200 participants. The researchers also asked some participants to reduce their calories by 14% while the rest continued their regular diet. Then, the team studied the long-term health implications of eating a low-calorie diet over two years.

They already knew the benefits of calorie restrictions on lab animals. Vishwa Deep Dixit, the study’s senior author, said their main goal was to observe if humans would be similarly affected. The team wanted to investigate the mechanisms behind calorie restriction in the human body to do this.

Calorie Restrictions Versus Immune System Health

However, one negative observation of calorie restrictions in mice was that it could increase infections. Dixit wanted to know if calorie restriction may increase inflammation and lower immunity.

“Because we know that chronic low-grade inflammation in humans is a major trigger of many chronic diseases and, therefore, has a negative effect on life span,” said Dixit, who is also director of the Yale Center for Research on Aging. “Here we’re asking: What is calorie restriction doing to the immune and metabolic systems, and if it is indeed beneficial, how can we harness the endogenous pathways that mimic its effects in humans?”

Yale Study Explains Why Calorie Restrictions Increase Human Health

Dixit and the team began by investigating the thymus, a gland above the heart that produces T cells for the study. These white blood cells help the immune system function properly. Dixit said this gland ages more quickly than other organs. For instance, 70% of the thymus becomes fatty and unfunctional before a healthy adult turns 40. As this process occurs, the thymus also produces fewer T cells.

“As we get older, we begin to feel the absence of new T cells because the ones we have left aren’t great at fighting new pathogens,” said Dixit. “That’s one of the reasons why elderly people are at greater risk for illness.”

So, because the thymus plays a crucial role in immune system health, the research team wanted to focus their efforts on this gland. They used magnetic resonance imaging (MRI) to investigate differences between the thymus glands of those restricting calories and the control group.

They discovered that the thymus glands of participants undergoing calorie restrictions had less fat and functional volume after two years. This means that their thymus’ produced more T cells than at the beginning of the study. However, participants eating a regular diet showed no changes in functional volume.

Calorie Restrictions Could Open Up Exciting Possibilities

Dixit said that the thymus could regenerate shows promise for human health. Before this study, little evidence existed of this happening in humans, so he asserts the possibility is exciting.

Since calorie restrictions resulted in significant changes in the thymus, the team anticipated finding similar effects in immune cells. However, when they performed gene sequencing on immune cells in the thymus after two years, they observed no changes.

After doing more research, the team made a surprising discovery: “It turns out that the action was really in the tissue microenvironment, not the blood T cells,” Dixit said.

Specific Genes Altered Due to Calorie Restrictions

The team studied the body fat of participants undergoing calorie restrictions at three time points throughout the study. They measured adipose tissue (body fat) at the start of the study, after one year, and at its end.

Dixit said some amount of body fat helps the immune system function properly. Fat hosts several types of immune cells, but when they’re abnormally activated, they can cause inflammation. This might explain why rats undergoing calorie restrictions suffered from more infections.

“We found remarkable changes in the gene expression of adipose tissue after one year that were sustained through year two,” said Dixit. “This revealed some genes that were implicated in extending life in animals but also unique calorie restriction-mimicking targets that may improve metabolic and anti-inflammatory response in humans.”

So, the team wanted to investigate which genes, if any, triggered positive changes from calorie restriction. They discovered that one gene called PLA2G7, or group VII A platelet-activating factor acetylhydrolase, became significantly inhibited during calorie restriction. Immune cells called macrophages produce this protein.

Incredible Outcomes

To understand if PLA2G7 caused some changes observed in those restricting calories, the team investigated what happened when they reduced this protein in laboratory mice.

“We found that reducing PLA2G7 in mice yielded benefits that were similar to what we saw with calorie restriction in humans,” said Olga Spadaro, a former research scientist at the Yale School of Medicine and lead author of the study.

Specifically, the team found that the thymus glands of the mice functioned for much longer. Due to diet, they also had more excellent protection from weight gain and age-related inflammation.

The research team discovered that these positive changes occurred since PLA2G7 triggers a specific mechanism of inflammation called NLRP3 inflammasome. So, reducing the protein in aged mice also lowered inflammation.

Final Thoughts on How Restricting Calories Improves Health

The recent Yale University study highlights the benefits of calorie restrictions and the mechanisms driving these positive changes. Dixit said that the research points to PLA2G7 as one of the critical components of calorie restrictions. By identifying which genes become affected by reducing calories, it helps the team understand how the immune system and metabolism work together.

This data can help scientists uncover potential targets to enhance immune system function, reduce inflammation and perhaps extend human life. For example, manipulating PLA2G7 could result in the same calorie restriction benefits without actually reducing calories. While calorie restriction can lead to a trimmer physique, Dixit said it could also cause adverse health outcomes.

“There’s so much debate about what type of diet is better — low carbohydrates or fat, increased protein, intermittent fasting, etc. — and I think time will tell which of these are important,” said Dixit. “But CALERIE is a very well-controlled study that shows a simple reduction in calories, and no specific diet has a remarkable effect in terms of biology and shifting the immuno-metabolic state in a direction that’s protective of human health. So from a public health standpoint, I think it gives hope.”