Cutting calories linked to gene that may help create a treatment to extend human lifespans

NEW HAVEN, Conn. — Scientists may be on the verge of a treatment that can extend the human lifespan — thanks to a protein tied to how much you eat. This gene appears to have a connection to calorie restriction however, researchers at the Yale School of Medicine believe they can harness its benefits without the need for strict calorie counts by dieters.

The team says decades of experiments in flies, worms, and rodents have revealed that cutting down on food increases lifespan. Now, the new study involving humans and mice has identified that switching off a specific gene stopped diet-induced weight gain and age-related inflammation.

The discovery opens the door to developing medications that target the key protein PLA2G7.

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

Specifically, the animals’ thymus glands, which make immune system T cells, remained functional for longer. They also did not become obese or suffer from illness.

“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,” says senior author Professor Vishwa Dixit, “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?”

The findings, published in the journal Science, offers hope of creating a new “fountain of youth” treatment, focusing on the effects of PLA2G7.

Protecting the thymus gland

The results are based on a first-of-its-kind trial called CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy). Researchers split more than 200 participants into two groups, including one that cut their consumption of calories by 14 percent. Over the next two years, the analysis suggested calorie restriction also has long-term health benefits for humans.

In particular, MRI scans showed the thymus gland had less fat and stayed more productive. There was also no change in the other volunteers who carried on eating as normal. The gland declines faster than any other in the body. By the age of 40, 70 percent of the thymus is fatty and non-functional.

“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,” Dixit explains. “That’s one of the reasons why elderly people are at greater risk for illness.”

“The fact that this organ can be rejuvenated is, in my view, stunning because there is very little evidence of that happening in humans,” the researcher continues. “That this is even possible is very exciting.”

Surprisingly, there were no changes in gene expression because the action took place in the tissue microenvironment, rather than the blood cells. Study authors measured the participants’ body fat, or adipose tissue, at the beginning of the study and then after one and two years.

“We found remarkable changes in the gene expression of adipose tissue after one year that were sustained through year two,” Prof. Dixit says.

“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.”

Getting the benefits of cutting calories without actually doing it?

It turns out that calorie restriction significantly inhibited PLA2G7. Immune cells called macrophages produce this protein, which fuels inflammation. Lowering levels of PLA2G7 protected aging mice.

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

It might be possible to manipulate PLA2G7 and get the benefits without having to actually restrict calories, which can be difficult and even harmful for some people.

“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,” Prof. Dixit concludes.

“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.”

South West News Service writer Mark Waghorn contributed to this report.

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