Calorie restriction, immune function, and health span

Researchers are making progress in understanding how calorie restriction brings about health benefits.Gorodenkoff / Shutterstock

Calorie restriction involves reducing food intake without causing malnutrition. Animal studies have found health benefits in calorie restriction that include improved metabolism, longer life spans, and delayed onset of age-associated diseases. But extreme caloric restriction—a 40% reduction in calories—is associated with impaired immune function, which can lead to more severe infections. 

Researchers have been studying calorie restriction in both people and animal models to understand how it brings about metabolic benefits. Knowing this could lead to therapies that confer the benefits without the drawbacks.

A team of researchers led by Dr. Vishwa Deep Dixit at Yale University School of Medicine explored the metabolic and immune effects of calorie restriction. NIH’s National Institute on Aging (NIA) and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) partly supported the study. Results appeared in Science on February 11, 2022.

The team used samples from a clinical trial called CALERIE in which participants, aged 25-45, were asked to reduce their calorie intake by 25% over two years. The participants whose samples were used reduced their calorie intake by an average of about 14%.

Magnetic resonance imaging was used to examine the thymus, an organ in the chest that produces immune system T cells. The thymus usually accumulates fat with age and produces fewer T cells. After two years of calorie restriction, participants had larger thymuses than at the beginning of the study. These enlarged thymuses had less fat and produced more T cells. Control participants who did not restrict calories showed no change in thymus size or function.

The team found that calorie restriction led to changes in gene activity in body fat and associated immune cells. Many of these genes hadn’t been previously identified in animal studies. They decided to focus on one gene in particular for further study: the gene for Pla2g7. Pla2g7 regulates inflammation, and caloric restriction inhibited its activity.

To study the effects of this inhibition, the scientists bred mice that lacked the gene for Pla2g7. Mice without Pla2g7 gained less weight from eating a high-fat diet than control mice and were less likely to develop fatty liver disease. They also burned more fat than control mice. In addition, aged mice lacking Pla2g7 had less inflammation and larger, more productive thymuses.

Prolonging the health of the thymus is a particularly notable benefit of calorie restriction. There has been little evidence before that this organ could be rejuvenated in humans.

Together, these findings suggest that caloric restriction improves health, at least in part, by reducing Pla2g7 activity. Therapies that target Pla2g7 may yield benefits similar to calorie restriction without the drawbacks.

“These findings demonstrate that PLA2G7 is one of the drivers of the effects of calorie restriction,” Dixit explains. “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.”

—by Brian Doctrow, Ph.D.