Key Protein Found That Might Be Used to Increase Human Healthy Lifespan

Years of studies have demonstrated that restricting the number of calories that mice, worms, and flies consume can lengthen their lives in experimental settings. It’s unclear, however, if similar calorie restrictions would have the same effect on people. The health advantages of modest calorie restriction in people have now been shown by a new study headed by Yale researchers. The study also reveals a critical protein that may one day be used to improve human longevity.

On February 10, 2022, the results were published in Science:

The findings were based on the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) clinical trial, which was the first controlled investigation of calorie restriction in healthy individuals. More than 200 study participants were recruited for the investigation, and baseline calorie consumption was initially determined. In the next two years, the researchers examined the long-term health consequences of calorie restriction after asking a portion of those people to cut their calorie consumption by 14% while the others continued to eat normally.

According to Vishwa Dark Dixit, the Waldemar Von Here for Professor of Pathology, Candidates to apply, and Comparative Medicine and senior author of the paper, the ultimate goal of the clinical trial was to determine if calorie restriction is as advantageous for people as it is for laboratory animals. And if it is, he added, scientists needed to know more about how exactly calorie restriction affects the body to promote health.

Dixit also wanted to find out how calorie restriction could be related to inflammation and the immune response because prior studies have indicated that calorie restriction in mice might increase infections.

Dixit, who is also the head of the Yale Center for Research on Aging, stated: “Because we know that persistent low-grade inflammation in humans is a primary driver of many chronic illnesses and, therefore, has a detrimental influence on life duration.” What impact does calorie restriction have on the immunological and metabolic systems, and if it has any positive impacts, how can we use endogenous pathways to imitate such effects in people?

Dixit and his colleagues began their investigation by examining the thymus, a gland that sits above the heart and is responsible for producing T cells, a kind of white blood cell and an important immunological component. The thymus ages more quickly than other organs do. Dixit said that 70% of the thymus is already obese and dysfunctional by the time healthy persons are 40 years old. The thymus also generates fewer T cells as it ages. Because the T cells we still have aren’t very effective at battling fresh viruses, Dixit explained that as we age, we start to notice the absence of new T cells. “That’s one of the causes why older individuals are more susceptible to sickness.”

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The thymus, a gland that lies above the heart and generates T cells, a kind of white blood cell and an important component of the immune system, was the first area Dixit and his colleagues examined. Compared to other organs, the thymus ages more quickly.

According to Dixit, 70% of the thymus is already obese and dysfunctional by the time healthy individuals reach the age of 40. Additionally, the thymus generates fewer T cells as it ages. We start to notice the loss of new T cells as we age because the ones we still have aren’t very effective at fending off emerging diseases, according to Dixit. “That’s one of the reasons older individuals have a higher chance of getting sick.”

“There is very little indication that that occurs in humans, so the notion that this organ can be regenerated is, in my opinion, astounding,” said Dixit. It’s thrilling that this is even a possibility.

Dixit and his colleagues anticipated that, given the thymus’s substantial alteration, they would also see changes in the immune cells the thymus was producing—changes that could be the basis for the overall advantages of calorie restriction. However, after two years of calorie restriction, scientists detected no changes in gene expression when they sequenced the genes in those cells.

The researchers had to investigate more closely because of this observation, which led to the following unexpected result: According to Dixit, “the activity was actually in the tissue microenvironment and not the blood T cells.”

At the start of the trial, after one year, and after two years, Dixit and his team looked at the adipose tissue, or body fat, of individuals who were on a calorie-restricted diet. Body fat is crucial because it houses a strong immune system, according to Dixit. He noted that there are many types of immune cells in fat that, when they are abnormally stimulated, constitute a source of inflammation.

After one year, “we detected dramatic alterations in adipose tissue gene expression that were maintained until year two,” said Dixit. This showed specific calorie restriction-mimicking targets that may enhance metabolic and anti-inflammatory responses in humans as well as genes that were linked to extending life in animals.

In light of this, the researchers decided to investigate whether the genes they had discovered through analysis could be responsible for some of the advantageous effects of calorie restriction. One of the genes that was strongly suppressed after calorie restriction was the gene encoding PLA2G7, also known as group VII A platelet-activating factor acetylhydrolase. A protein called PLA2G7 is generated by immune cells called macrophages.

Participants who were restricting their caloric intake showed a shift in the expression of the PLA2G7 gene, which suggested that the protein may be connected to the consequences of calorie restriction. The researchers also monitored what transpired when the protein was lowered in mice in a lab experiment to better comprehend if PLA2G7 produced some of the impacts noticed with calorie restriction.

According to experts, these changes happened as a result of PLA2G7’s targeting of the NLRP3 inflammasome, a particular inflammatory process. Aged mice were protected against inflammation by lowering PLA2G7.

According to Dixit, “These results show that PLA2G7 is one of the drivers of the effects of calorie restriction.” “Identifying these drivers helps us better understand how the immune system and the metabolic system interact, which can direct us to prospective targets that might boost healthy longevity and improve immune function, decrease inflammation, and possibly even do so.”

For instance, he suggested that by manipulating PLA2G7, it may be feasible to reap the benefits of calorie restriction without really reducing one’s intake of calories, which may be hazardous to some.

There is a great deal of disagreement over the best diet to follow, according to Dixit. “Time will reveal which of them are crucial,” she said. “But CALERIE is a well-controlled trial that demonstrates how a simple caloric decrease, without the use of any particular diet, has a significant impact on biology and changes the immuno-metabolic state in a way that is protective of human health. Therefore, I believe it offers hope from the perspective of public health.

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