Restricting calorie intake extends lifespan and decreases disease burden in animals. In humans, a 14 percent reduction in calorie intake could allow us to harness these beneficial effects, especially on the thymus, a crucial organ for the immune system, according to a study published February 10 in Science. The study also identifies a key protein, PLA2G7, that underlies these effects of calorie restriction, and, the authors say, may point the way toward a means of reaping those benefits with no hunger required.

“By combining human with mice studies, the authors have identified a promising targetable protein. Interfering with this protein can improve metabolic and immune health,” María Mittelbrunn, a researcher in immunometabolism and inflammation at the Severo Ochoa Centre for Molecular Biology in Madrid, Spain, who was not involved in the research, writes in an email to The Scientist. “This study will open a new avenue to investigate whether interfering with PLA2G7 could be a novel intervention to improve the quality of life of the elderly.”

There’s long been evidence that limiting calorie intake can lengthen the lives of lab animals, and some people tout measures such as intermittent fasting to try to achieve a similar end. Yet Vishwa Deep Dixit, an immunobiologist at the Yale School of Medicine and coauthor on the new study, points out that “we have very little idea whether caloric restriction is even relevant to human physiology.” To remedy this, several years ago the multicenter CALERIE study, in which Dixit was one of the investigators, had participants live in normal conditions for two years and follow any diet they chose, but restrict their calorie intake. While participants were told to reduce their calorie intake by 25 percent, they managed to achieve an average reduction of 14 percent. In the new study, the research team analyzed data and specimens from the CALERIE trial, including blood and adipose tissue samples, and showed that even this reduction affected the immune system. 

“One of the most striking and very positive effects of that was on the thymus,” Dixit says. That gland produces T cells, but by the time healthy humans are 45 years old, “about 75 percent of the thymus is made up of fat,” Dixit says, and is no longer very good at producing the immune cells, which is why aging blunts the immune response. In a subset of CALERIE participants who had restricted their calorie intake, the thymus was “rejuvenated,” Dixit says: MRI scans showed that its mass and volume increased, and CD8 T cell production was increased compared to the start of the study. “The study challenges the notion that the organ, once it has degenerated, cannot be reversed back to function,” says Dixit. 

He and his team further drilled down on how calorie restriction affects the body. To do so, they profiled adipose tissue biopsies from eight CALERIE participants, as the tissue contains many immune cells, and analyzed the impact of calorie restriction on the transcriptome. The levels of a range of mRNA transcripts, including those coding for proteins involved in metabolism and inflammation, changed over the course of the trial. 

One gene that was expressed at lower levels in response to calorie restriction was PLA2G7—specifically in immune cells called macrophages, which are critical for maintaining the function of adipose tissue but can also cause inflammation. In humans, PLA2G7 encodes platelet-activating factor acetylhydrolase (PLA2G7), an enzyme also called lipoprotein-associated phospholipase A2, which is used as a biomarker for cardiovascular risk

To find out the nature of the connection between the gene and the effects of calorie restriction, the researchers knocked out PLA2G7 in mice. The animals showed no dysfunction, but “aged in a healthier way compared to littermates,” as Dixit describes it. When given a high-fat diet, the PLA2G7-knockout mice were partially protected from weight gain and the negative effects of adiposity compared to wildtype mice on the same diet, and showed less inflammation with age and larger thymuses. The knockout mice “have several features that were reminiscent of what was happening in human beings, so we think that PLA2G7 is indeed one of the endogenous mechanisms that is inhibited by calorie restriction,” concludes Dixit. 

“Excitingly, this new work of Dixit et al using CALERIE samples and MRI scans, showed that the thymus . . . maintained its functional integrity and it increased in mass and volume with [calorie restriction] over 2 years compared to the control group,” Leanne Redman, a physiologist at the Pennington Biomedical Research Center in Louisiana who was a coauthor on the CALERIE study but was not involved in the new work, writes in an email to The Scientist. The study, she adds, demonstrates how reducing calorie intake rewires processes that control metabolic and immune function in adipose tissue.

Mittelbrunn says she’d like to see further investigation into PLA2G7 as a regulator of the length of time mice remain alive and healthy. The study authors “demonstrate that the mice depleted for PLA2G7 have lower inflammation and improve metabolic health but ideally, to demonstrate improvement of healthspan, the author should also investigate whether these mice are free from other serious diseases, such as cardiovascular diseases, neurodegeneration or sarcopenia,” she writes. “A more extensive characterization of the protection of interfering with PLA2G7 will be very interesting.”

Calorie reduction likely mediates its effects through other molecular players as well, Dixit says, and his team is investigating several candidates. If further research confirms that reducing PLA2G7 levels leads to effects similar to calorie restriction, but without reducing food intake, PLA2G7 “could potentially in [the] future be targeted to enhance health and reduce inflammation.”