Identified a key protein that can be used to prolong a person’s healthy life

Decades of research have shown that restricting calorie intake by flies, worms and mice can increase life expectancy in the laboratory. But whether such a calorie restriction can do the same for humans remains unclear. Now, a new study led by Yale researchers confirms the health benefits of moderate calorie restriction for humans – and identifies a key protein that can be used to maintain human health.

The results were published on February 10, 2022 Science.

The study was based on the results of a clinical study, the Comprehensive Assessment of the Long-Term Effects of Reducing Intake of Energy (CALERIE), the first controlled study of calorie restriction in healthy people. For the test, the researchers first established baseline calorie intake among more than 200 study participants. The researchers then asked some of these participants to reduce their calorie intake by 14%, while the rest continued to eat normally and analyzed the long-term health effects of calorie restriction over the next two years.

The overall goal of the clinical study was to see if calorie restriction was as beneficial to humans as it was to laboratory animals, said Vishwa Deep Dixit, professor of pathology, immunobiology and comparative medicine Waldemar von Zedtwitz and senior author of the study. . And if so, he said, the researchers wanted to better understand what calorie restriction does to the body, leading to better health.

Because previous studies have shown that calorie restriction in mice can increase infection, Dixit also wanted to determine how calorie restriction may 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 thus negatively affects life expectancy,” said Dixit, who is also director of the Yale Center for Aging Research. “Here we ask: what does calorie restriction do with the immune and metabolic systems, and if it is really beneficial, how can we use endogenous pathways that mimic its effects on humans?”

Dixit and his team began by analyzing the thymus gland, the gland that is above the heart and produces T cells, the type of white blood cells and an important part of the immune system. The thymus ages faster than other organs. By the time healthy adults reach the age of 40, Dixit said, 70% of the thymus is already sebaceous and dysfunctional. And as you age, the thymus produces fewer T cells. “As we grow older, we begin to feel the lack of new T cells because the ones we have left are unable to fight the new pathogens,” Dixit said. “This is one of the reasons why older people are at greater risk of disease.”

For the study, the research team used magnetic resonance imaging (MRI) to determine if there are functional differences between the thymus of those who restricted calories and those who did not. They found that the thymus in participants with limited calorie intake had less fat and more functional volume after two years of calorie restriction, meaning they produced more T cells than at the start of the study. But participants who did not limit their calories did not change in functional volume.

“The fact that this organ can be rejuvenated is, in my opinion, staggering because there is very little evidence of what is happening in humans,” Dixit said. “The fact that it’s even possible is very interesting.”

Thymus calorie restriction

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

This observation required researchers to take a closer look, which revealed a surprising conclusion: “It turns out that the effect was indeed in the microenvironment of tissues, not in blood T cells,” – said Dixit.

Dixit and his team studied the adipose tissue or fat deposits of participants who were calorie restricted at three points: at the start of the study, a year later, and two years later. Body fat is very important, Dixit said, because it has a strong immune system. There are several types of immune cells in fat, and when they are aberrantly activated, they become a source of inflammation, he explained.

“We found significant changes in adipose tissue gene expression a year later that persisted for two years,” Dixit said. “It has revealed some genes that have been involved in prolonging the lives of animals, but also unique targets that mimic calorie restriction that can improve the metabolic and anti-inflammatory response in humans.”

Recognizing this, the researchers then decided to test whether any of the genes they identified in their analysis could stimulate some of the beneficial effects of calorie restriction. They refined the gene for PLA2G7 – or the platelet-activating factor acetylhydrolase group VII A – which was one of the genes significantly inhibited after calorie restriction. PLA2G7 is a protein produced by immune cells known as macrophages.

This change in PLA2G7 gene expression observed in participants who restricted calorie intake suggested that the protein may be related to calorie restriction effects. To better understand when PLA2G7 caused some of the effects observed with calorie restriction, the researchers also tracked what happened when protein was reduced in mice in a laboratory experiment.

“We found that reducing PLA2G7 in mice had benefits similar to those we saw in calorie restriction in humans,” said Olga Spadaro, a former researcher at the Yale School of Medicine and lead author of the study. In particular, the thymus glands of these mice worked longer, the mice were protected from weight gain caused by diet, and they were protected from age-related inflammation.

These effects occurred because PLA2G7 targets a specific inflammatory mechanism called the inflammatory mass NLRP3, the researchers said. Decreased PLA2G7 protected older mice from inflammation.

“These findings suggest that PLA2G7 is a factor in calorie restriction effects,” Dixit said. “Identifying these factors helps us understand how the metabolic system and the immune system communicate with each other, which can show us potential goals that can improve immune function, reduce inflammation and possibly even increase healthy life expectancy.”

For example, one could manipulate PLA2G7 and reap the benefits of calorie restriction without the need for actual calorie restriction, which could be detrimental to some people, he said.

“There’s a lot of controversy about which type of diet is better – low in carbs or fats, increased protein, intermittent starvation, etc. – and I think time will tell what’s important,” Dixit said. “But CALERIE is a very well-controlled study that shows a simple reduction in calories and lack of a specific diet, has a great effect in terms of biology and shifts the immune-metabolic state in a direction that protects human health. So in terms of public health, I think it gives hope. “

For more on this study, see Moderate calorie restriction alters metabolism, immunity for longer health.

Help: “A new player has appeared in calorie restriction” Timothy W. Rhodes and Rosalyn M. Anderson, February 10, 2022, Science.
DOI: 10.1126 / science.abn6576 Identified a key protein that can be used to prolong a person’s healthy life

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