Calorie restriction trial reveals key factors in enhancing human health

Decades of research have shown that limits on calorie intake by flies, worms, and mice can improve lifespan under laboratory conditions. But it’s not yet clear whether such calorie restriction can do the same for humans. Now, a new study led by Yale researchers confirms the health benefits of moderate calorie restriction in humans and identifies a key protein that could be harnessed to extend health in humans.

The findings were published on February 10 in Sciences.

The research was based on results from the Comprehensive Evaluation of the Long-Term Effects of Reducing Energy Intake (CALERIE) clinical trial, the first controlled study of calorie restriction in healthy humans. For the trial, researchers first established baseline calorie intake among more than 200 study participants. The researchers then asked a portion of those participants to reduce their calorie intake by 14 percent, while the rest continued to eat as usual, and looked at the long-term health effects of calorie restriction over the next two years.

The overall goal of the clinical trial was to see if calorie restriction is as beneficial to humans as it is to laboratory animals, he said. Vishwa Deep Dixit, the Waldemar Von Zedtwitz Professor of Pathology, Immunobiology and Comparative Medicine, and senior author of the study. And if so, he said, the researchers wanted to better understand what specifically calorie restriction does to the body that leads to better health.

Since previous research has shown that calorie restriction in mice can increase infections, Dixit also wanted to determine how calorie restriction might be related to inflammation and the immune response.

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

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Dixit and his team started by looking at the thymus, a gland that sits above the heart and produces T cells, a type of white blood cell and an essential part of the immune system. The thymus ages at a faster rate than other organs. By the time healthy adults reach age 40, Dixit said, 70% of the thymus is already fatty and nonfunctional. And as you age, your thymus produces fewer T cells. “As we age, we start to feel the absence of new T cells because the ones we have left are not good at fighting new pathogens,” Dixit said. “That’s one of the reasons older people are at higher risk of getting sick.”

For the study, the research team used magnetic resonance imaging (MRI) to determine if there were functional differences between the thymus glands of those who restricted calories and those who did not. They found that the thymus glands in participants with limited caloric intake had less fat and higher functional volume after two years of caloric restriction, meaning they were producing more T cells than at the start of the study. But the participants who didn’t restrict their calories had no change in functional volume.

The fact that this organ can be rejuvenated is, from my point of view, surprising because there is very little evidence that this happens in humans,” said Dixit. “That this is possible is very exciting.”

With such a dramatic effect on the thymus, Dixit and colleagues expected to also find effects on the immune cells that the thymus produced, changes that could underlie the overall benefits of calorie restriction. But when they sequenced the genes in those cells, they found there was no change in gene expression after two years of calorie restriction.

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This observation required the researchers to take a closer look, which revealed a surprising finding: “It turns out that the action was actually in the tissue microenvironment, not in the blood T cells,” Dixit said.

Dixit and his team had studied the adipose tissue, or body fat, of participants undergoing calorie restriction at three points in time: at the beginning of the study, after one year and after two. Body fat is very important, Dixit said, because it harbors a robust immune system. There are several types of immune cells in fat, and when they’re aberrantly activated, they become a source of inflammation, she explained.

We found remarkable changes in adipose tissue gene expression after one year that were maintained through the second year,” said Dixit. “This revealed some genes that were implicated in life extension in animals, but also unique targets that mimic calorie restriction that may enhance metabolic and anti-inflammatory responses in humans.”

Recognizing this, the researchers set out to see if any of the genes they identified in their analysis might be driving some of the beneficial effects of calorie restriction. They zeroed in on the gene for PLA2G7, or group VII A platelet-activating factor acetylhydrolase, which was one of the genes significantly downregulated after calorie restriction. PLA2G7 is a protein produced by immune cells known as macrophages.

This change in PLA2G7 gene expression seen in participants who limited their calorie intake suggested that the protein might be related to the effects of calorie restriction. To better understand if PLA2G7 caused Some of the effects seen with calorie restriction, the researchers also tracked what happened when the protein was reduced in mice in a laboratory experiment.

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We found that reducing PLA2G7 in mice produced benefits similar to what we saw with calorie restriction in humans,” said Olga Spadaro, a former Yale School of Medicine research scientist and lead author of the study. Specifically, the thymus glands of these mice functioned longer, the mice were protected from diet-induced weight gain, and they were protected from age-related inflammation.

These effects occurred because PLA2G7 targets a specific mechanism of inflammation called the NLRP3 inflammasome, the researchers said. PLA2G7 reduction protected aged mice from inflammation.

These findings demonstrate that PLA2G7 is one of the drivers of the effects of calorie restriction,” said Dixit. “Identifying these drivers helps us understand how the metabolic system and the immune system communicate with each other, which can point us to potential targets that can improve immune function, reduce inflammation, and potentially even improve healthy living.”

For example, it might be possible to manipulate PLA2G7 and get the benefits of calorie restriction without actually having to restrict calories, which can be harmful for some people, he said.

There is a lot of debate about which type of diet is better (low carb or fat, higher protein, intermittent fasting, etc.) and I think time will tell which ones are important,” Dixit said. “But CALERIE is a very well-controlled study that shows that a simple reduction in calories, without a specific diet, has a remarkable effect in terms of biology and changes the immunometabolic state in a direction that protects human health. So from a public health standpoint, I think it gives hope.”

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