This article is reproduced from the "China Biotechnology Network" WeChat public account.
Decades of research have shown that limiting calorie intake in the diet has been a cornerstone of the biology of aging. In the absence of malnutrition, reducing caloric intake has been shown to delay the onset of age-related diseases in a variety of animals, thereby prolonging healthy lifespans.
For humans, reducing caloric intake in the context of the obesity pandemic has also been a dietary recommendation recommended by the medical community. However, more evidence is needed to see if this dietary pattern has the same long-term beneficial effects on humans as laboratory animals, translating this dietary strategy into practical applications to help more people improve their health.
On February 11, Beijing time, in a new study published in Science, the research team from Yale University in the United States confirmed through two years of clinical trials that moderate calorie intake reconnected many metabolic and immune responses that can prolong healthy life, so it has a long-term beneficial effect on the human body. The study also identified a key protein that could be used to mimic this effect.
Research Achievements (Source: Science)
To investigate the specific effects of calorie-restricted diets on humans and whether they could have the same long-term beneficial effects as those observed in laboratory animals, the team investigated a two-year clinical trial previously conducted by the National Institutes of Health called "Comprehensive Assessment of the Long-Term Effects of Reducing Energy Intake on the Human Body" (CALERIE). The trial is the first strictly controlled randomized controlled trial with limited caloric intake.
In the trial, the researchers first identified baseline caloric intake in more than 218 adult participants under the age of 50. One group of participants then began following a 14% reduction in caloric intake per day, and another group went on a diet as usual. Two years later, the researchers collected blood, muscle and other samples from the participants to analyze the long-term effects of calorie restriction on human health.
In addition, due to previous studies that limiting caloric intake in mice increases the risk of infection, while chronic low-grade inflammation in humans is a major trigger for many chronic diseases and can negatively impact lifespan. So the researchers also analyzed the relationship between calorie restriction and inflammation and immune response, and how endogenous pathways could be used to mimic their effects on the human body.
In the new study, they started with the thymus gland. The thymus gland is a gland located above the heart that produces T cells and is an important part of the body's immune system. However, the thymus gland ages faster than other organs. In the period of sexual maturity, the thymus gland can reach a maximum of 25-40 grams, while the thymus gland of the elderly has only 10-15 grams left. By the time healthy adults reach the age of 40, 70% of the thymus glands have been replaced by adipose tissue and have lost their function.
As we age, the thymus produces fewer and fewer T cells, and due to the insufficient supply of new T cells, it is difficult for the remaining T cells to fight against new pathogens, which is one of the reasons why the elderly have a higher risk of developing the disease.
The researchers used magnetic resonance imaging (MRI) to determine whether there were differences in the function of the thymus glands of the two groups of participants. They found that participants in the calorie-restricted group had thymus glands that lost fat and increased in volume after two years. This meant they produced more T cells than they did at the start of the study; there was no change in the volume of thymus function in participants in the group without limiting calorie intake.
Changes in thymus fat volume in participants (Source: Science)
Study corresponding author Vishwa Deep Dixit, director of the Yale Center for Aging Research, said: "The fact that the thymus gland can be rejuvenated is shocking because there is very little evidence that this can happen in humans. It's really possible, it's so exciting! ”
Because calorie restriction has such a significant effect on the thymus, the researchers next explored the effects on the thymus that produce immune cells, and they believe that these changes may be the basis for the overall benefits of calorie restriction. However, when they sequenced the genes in these cells, they found that gene expression did not change after two years of calorie restriction.
The researchers took a closer look at this, revealing a surprising finding. It turns out that this beneficial effect is actually in the tissue microenvironment, not in blood T cells.
The researchers studied adipose tissue of participants in the calorie-restricted group at three time points over two years, i.e. at the beginning of the study, one year later, and two years later. Body fat is very important because it carries a strong immune system. Dixit explains that there are several types of immune cells in fat that, when they are abnormally activated, become a source of inflammation.
The researchers found that after a year there was a significant change in gene expression in adipose tissue, and this change lasted until the second year.
Gene expression changes in adipose tissue (Source: Science)
In addition, they also found a number of genes associated with longer lifespans that could serve as targets for mimicring caloric restriction, promising to improve the metabolic and anti-inflammatory responses in humans.
These genes are involved in the platelet activating factor acetyl hydrolase (PLA2G7), one of the genes that are significantly suppressed after calorie restriction, PLA2G7, a protein produced by immune cell macrophages.
Among participants in the calorie restriction group, the researchers observed changes in the expression of the PLA2G7 gene, suggesting that this protein may be related to the effects of calorie restriction.
To better understand whether PLA2G7 caused some of the beneficial effects observed, they tracked in one experiment when PLA2G7 decreased in mice.
They found that the benefits of reducing pla2G7 levels in mice were similar to those of calorie restriction observed in humans. Specifically, the thymus glands of these mice functioned over a longer period of time, protecting them from diet-induced weight gain, as well as age-related inflammation.
The researchers found that these effects occur because PLA2G7 targets a special inflammatory mechanism called NLRP3 inflammasomes. Reducing PLA2G7 protects older mice from inflammation.
Dixit said: "These findings suggest that PLA2G7 is one of the drivers of the effect of heat restriction. Identifying these drivers helps us understand how the metabolic system and immune system communicate with each other, which can point us to potential targets for improving immune function, reducing inflammation, and even extending healthy lifespans. For example, manipulating PLA2G7 has the potential to reap the benefits of calorie restriction without actually restricting calorie intake, as this may not be appropriate for some specific populations. ”
Taken together, the study shows that two years of moderate calorie restriction reprogramming pathways in fat cells that help regulate the way mitochondria produce energy, enhance the body's anti-inflammatory response, and prolong healthy lifespan.
Dixit concludes: "There's a lot of debate about which diet is better, whether it's low-carb, low-fat, or increased protein, intermittent fasting, and so on. I think time will tell. But our research suggests that simply reducing calorie intake, rather than switching to a specific diet, can have biologically significant effects and shift immune metabolic status in the direction of protecting human health. So from a public health perspective, I think that gives us hope. ”
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Resources:
[1] Spadaro O, Youm Y, Shchukina I, et al. Caloric restriction in humans reveals immunometabolic regulators of health span. Science. 2022 Feb 11;375(6581):671-677. doi: 10.1126/science.abg7292. Epub 2022 Feb 10. PMID: 35143297.