The thymus is responsible for turning thymocytes produced in the bone marrow into T cells of the adaptive immune system, in a complicated process of selection. This system is highly productive in youth, but active thymic tissue atrophies with age. This occurs for reasons that are far from fully explored, but may involve complex systemic issues related to rising inflammation and ongoing exposure to pathogens. As the thymus atrophies, the supply of T cells diminishes, and this loss of reinforcements is one of the major causes of immune aging. The T cell component becomes ever more full of exhausted, damaged, misconfigured, and senescent cells.
In this context, today's research materials are very interesting indeed. The authors report on their demonstration that a couple of years of mild calorie restriction in humans (a 14% reduction in calorie intake) can produce regrowth of the atrophied thymus. A very striking cross-sectional MRI image is provided in the publicity materials. The researchers go into some detail as to which of the countless metabolic changes produced in response to a reduced calorie intake are responsible for these effects. They point to PLA2G7 downregulation, which may be a target for future therapies to mimic this outcome. That PA2G7 downregulation suppresses inflammation is a point of support for inflammation-centric hypotheses of age-related thymic atrophy.
The study includes imaging and metrics for the thymus, but looks to be light on important details regarding the T cell output of the thymus and related immune system parameters. Unfortunately, this is par for the course in studies of thymus regrowth and resulting restoration of more youthful T cell production. Researchers either measure the size and structure of the thymus, or the relevant immune system parameters, and almost never both of these items in the same study.
New research is based on results 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, researchers first established baseline calorie intake among more than 200 study participants. The researchers then asked a share of those participants to reduce their calorie intake by 14% while the rest continued to eat as usual, and analyzed the long-term health effects of calorie restriction over the next two years.
The team started by analyzing 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, 70% of the thymus is already fatty and nonfunctional. And as it ages, the thymus produces fewer T cells.
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 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 participants who weren't restricting their calories had no change in functional volume.
The researchers then honed in on the gene for PLA2G7, was one of the genes significantly inhibited following calorie restriction. PLA2G7 is a protein produced by immune cells known as macrophages. This change in PLA2G7 gene expression observed in participants who were limiting their calorie intake suggested the protein might be linked to the effects of calorie restriction. To better understand if PLA2G7 caused some of the effects observed with calorie restriction, the researchers also tracked what happened when the protein was reduced in mice in a laboratory experiment.
Reducing PLA2G7 in mice yielded benefits that were similar to what we saw with calorie restriction in humans. 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. Lowering PLA2G7 protected aged mice from inflammation.
The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Expression of the gene Pla2g7 is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy, protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be harnessed to lower inflammation and extend the health span.