Decades of research have shown that limiting caloric intake by flies, worms, and mice can extend lifespan in laboratory conditions. However, it remained unclear whether such calorie restriction could do the same for humans.
Currently, a new study led by researchers at Yale University confirms the health benefits of moderate calorie restriction in humans and identifies key proteins that can be used to enhance human health.
This study is based on the results of a comprehensive assessment (CALERIE) clinical trial of the long-term effects of reduced energy intake, the first control study on calorie restriction in healthy humans. In this study, researchers initially established baseline caloric intake among more than 200 study participants. Next, the researchers asked some of the participants to reduce their calorie intake by 14% and the rest to continue eating normally, analyzing the long-term health effects of calorie restriction over the next two years. did.
The overall purpose of the clinical trial was to see if calorie restriction was as beneficial to humans as experimental animals, and was a professor of pathology, immunobiology, and comparative medicine, Waldemar Von Zedtwitz. Vishwa Deep Dixit, senior author of the study, said. If so, he said researchers want to better understand how calorie restriction affects the body, especially for improving health.
Previous studies have shown that calorie restriction in mice can increase infection, so Dixit wants to find out how calorie restriction is associated with inflammation and the immune response. I did.
“Because chronic mild inflammation in humans is known to be a major trigger for many chronic diseases and thus adversely affects longevity,” said Dixit, director of the Yale University Aging Research Center. increase. “Here we are asking: what is calorie restriction doing to the immune and metabolic systems, and if it is really beneficial, an endogenous pathway that mimics its effect in humans. How can I use it? “
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Dixit and his team began by analyzing the thymus, which is located above the heart and produces T cells, a type of white blood cell that is an important part of the immune system. The thymus ages faster than other organs. By the time a healthy adult reaches the age of 40, 70% of the thymus is already fat and non-functional, Dixit said. And as it ages, the thymus produces fewer T cells. “As we get older, we start to feel the lack of new T cells, as what we have left behind is not good at fighting new pathogens,” Dixit said. “That’s one of the reasons why older people are at higher risk of illness.”
In this study, the research team used magnetic resonance imaging (MRI) to determine if there was a functional difference in the thymus between those who restricted calories and those who did not. They found that the thymus of participants with restricted calorie intake was low in fat and high in function after two years of calorie restriction. In other words, it produced more T cells than it did at the beginning of the study. However, participants who did not limit calories had no change in functional activity.
“The fact that this organ can be rejuvenated is surprising in my view, as there is little evidence that it is happening in humans,” Dixit said. “It’s very exciting that even this is possible.”
With such dramatic effects on the thymus, Dixit and his colleagues can also find changes that may underlie the effects on the immune cells that the thymus produces, the overall benefits of calorie restriction. I was expecting it. However, when they sequenced the genes in those cells, they found no change in gene expression after two years of calorie restriction.
This observation required researchers to look into the details and revealed surprising discoveries. “We found that the action was actually in the microenvironment of the tissue, not the blood T cells,” Dixit said.
Dixit and his team studied the adipose tissue, or body fat, of calorie-restricted participants at three points in time: at the beginning of the study, one year later, and two years later. According to Dixit, body fat is very important because it hosts a strong immune system. He explained that there are several types of immune cells in fat, and when they are abnormally activated, they cause inflammation.
“One year later, we saw significant changes in gene expression in adipose tissue that persisted into the second year,” says Dixit. “This reveals not only some genes involved in extending the lifespan of animals, but also unique calorie restriction mimicry targets that may improve human metabolism and anti-inflammatory responses. “
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Recognizing this, researchers then set out to see if any of the genes identified in the analysis could be driving some of the beneficial effects of calorie restriction. .. They polished the gene for PLA2G7 (or Group VII A platelet-activating factor acetylhydrolase), one of the genes that was 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 had restricted caloric intake suggested that protein may be associated with the effects of calorie restriction. To better understand if it is PLA2G7 Caused For some of the effects observed with calorie restriction, researchers also tracked what happened when mouse protein was reduced in laboratory experiments.
“We found that reducing PLA2G7 in mice had the same effect as we saw with human calorie restriction,” said Olga Spadaro, a former research scientist and lead author of the study at Yale School of Medicine. I am. Specifically, the thymus of these mice functioned longer, and the mice were protected from dietary weight gain and from age-related inflammation.
Researchers say these effects were caused by PLA2G7 targeting a specific inflammatory mechanism called the NLRP3 inflammasome. Lowering PLA2G7 protected aged mice from inflammation.
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“These findings show that PLA2G7 is one of the driving forces behind the effects of calorie restriction,” says Dixit. “Identifying these drivers helps us understand how the metabolic and immune systems interact, which improves immune function, reduces inflammation, and has a healthy lifespan. You can identify potential targets that can be extended. “
For example, you might be able to operate PLA2G7 and enjoy the benefits of calorie restriction without actually limiting calories. This can be harmful to some people.
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“There is a lot of debate about which types of diets are good, such as low carbs, fats, increased protein, and intermittent fasting. You’ll see which of these is important over time,” Dixit said. I am. “But CALERIE is a very well-managed study that shows a simple reduction in calories, no specific diet, and shifts biological and immunometabolic status towards protecting human health. It has a significant effect in terms of it, so from a public health perspective, I think it gives hope. “
This study is in the Science Journal.
