25th February 2022

The first controlled study of caloric restriction in humans

Scientists have published the first controlled study of caloric restriction in humans. This has confirmed its anti-aging and other health benefits and also identified a key protein that could be harnessed to extend health in humans.

Decades of research has shown that limits on calorie intake by flies, worms, and mice can enhance lifespan in laboratory conditions. But whether such calorie restriction can do the same for humans has remained unclear. Now a new study led by researchers at Yale University, Connecticut, confirms the health benefits of moderate calorie restrictions in humans – and identifies a key protein that could be harnessed to extend health in humans.

The researchers used data from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) clinical trial, the first controlled study of calorie restriction in healthy humans. For the trial, they established a baseline calorie intake among more than 200 study participants. They then asked a share of those participants to reduce their calorie intake by 14% while the rest continued to eat as usual, and analysed the long-term health effects of calorie restriction over the next two years.

Vishwa Dixit, Professor of Pathology, Immunobiology, and Comparative Medicine, and senior author of the study, said that his team wanted to better understand what calorie restriction does to the body specifically that leads to improved health. Building on previous studies in mice, he and his colleagues set out to determine how it might be linked to inflammation and the immune response.

“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 spans,” explained Professor Dixit, who is also director of the Yale Center for Research on Aging. “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?”

Dixit and his team started by analysing 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 the age of 40, said Dixit, 70% of the thymus is already fatty and non-functional. And as it ages, the thymus produces fewer T cells. “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,” said Dixit. “That’s one of the reasons why elderly people are at greater risk for illness.”

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

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

In addition to stronger immunity, an increase in T cells is associated with an improved ability to burn stores of fatty acids for energy, said Eric Ravussin, PhD, paper co-author. That’s important because if a person doesn’t burn this fuel, the fat may build up in organs such as the muscle and liver – leading to insulin resistance, obesity, type 2 diabetes, and aging.

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

In particular, calorie restriction reduced the levels of a gene encoding for platelet activating factor acetyl hydrolase (PLA2G7). Reducing PLA2G7 produces health benefits that include lowering age-related inflammation and improving metabolic health. PLA2G7 is a protein produced by immune cells known as macrophages.

To better understand if PLA2G7 caused some of the effects observed with calorie restriction, the researchers also tracked what happened when they reduced the protein in mice during a laboratory experiment.

“We found that reducing PLA2G7 in mice yielded benefits that were similar to what we saw with calorie restriction in humans,” said Olga Spadaro, a former research scientist at the Yale School of Medicine and study co-author. Specifically, the thymus glands of these mice were functional for a longer time, 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, according to the team. Lowering PLA2G7 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 talk to each other, which can point us to potential targets that can improve immune function, reduce inflammation, and potentially even enhance healthy lifespan.”

“If researchers can find a way to harness PLA2G7, they could create a treatment to extend a person’s health span, the time an individual experiences good health,” said co-author John Kirwan, PhD.

“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,” said Dixit. “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.”

The study appears this month in the peer-reviewed journal Science.

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