In a new paper, Yale scientists present encouraging data from an unprecedented human study of caloric restriction, a powerful anti-aging intervention .
Eat less, live more
Despite all the might of today’s science, simple lifestyle choices are still the clearest option for living longer and healthier. These choices include being physically active, eating better, and eating less, as simple calorie count matters a lot. A healthy diet might be able to confer the benefits of caloric restriction (CR).
CR has been doing wonders in extending the lives of animals , but it is not devoid of problems. Results like this require drastic 25%-40% CR, and cutting that many calories involves certain trade-offs. For instance, while being generally healthier and living longer, calorically restricted mice have suffered from an increased severity of viral and parasitic infections . Furthermore, such regimens are just too harsh to be translatable to humans.
In this new paper, scientists from Yale University describe the first controlled CR trial in humans, Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE). Around 200 participants were divided into a study group and a control group. Those in the study group were asked to reduce their calorie intake by about 14% for the two-year duration of the study. This amount of CR was generally well tolerated by the participants. The question is whether such mild CR is good for anything.
CR helps the immune system
Since it is much harder to measure lifespan in humans, who thankfully are pretty long-lived species, researchers have to use various proxies. In this case, the authors started with analyzing thymic function.
The thymus is a small organ where immune T cells are produced and matured. Unlike most organs, the thymus does not continue working for the entire lifespan. Its function peaks during puberty, and then the thymus shuts down its T cell production and turns into fat. This decline in thymic function, called thymic involution, is thought to be a major aspect of aging. One of the most impressive levels of rejuvenation in humans to date was achieved by restoring the thymus .
The two-year-long CR significantly increased thymic mass and volume in the study group, while in the control group, no change was detected. The number of cells that had been recently produced by the thymus was increased as well.
CR lowers glucose utilization and promotes oxidation of fatty acids as the body switches to burning fat for energy. Consequently, CR usually results in weight loss, and CALERIE participants experienced a reduction of fat mass. The researchers then decided to dig deeper by analyzing the impact of CR on gene expression in fat.
They found that CR did alter the adipose tissue transcriptome, with 233 genes upregulated and 131 downregulated compared to the control group. Interestingly, this change happened during the first year of CR, and then the transcriptome stabilized, with no changes during the second half of the study detected. This CR-induced transcriptional reprogramming included pathways that are known to regulate the production of energy by mitochondria, anti-inflammatory responses, and longevity.
The researchers also note that the changes in gene expression resembled the ones that follow bariatric surgery. Similar expression patterns were observed in a study of twins with different levels of physical activity. This hints at similarities in the ways CR and physical activity affect our body.
The CR gene?
One of the genes most drastically inhibited as a result of CR caught the scientists’ attention. It codes for the protein PLA2G7, which is produced by macrophages. The researchers tried deleting this gene in mice to test whether this would recapitulate any effects of CR. The deletion indeed resulted in a decrease in thymic atrophy and provided some protection against diet-induced weight gain and age-related inflammation.
The researchers then discovered that PLA2G7 activates the NLRP3 inflammasome, a protein complex also produced in macrophages that triggers an inflammatory immune response. The NLRP3 inflammasome has been shown to contribute to various age-related diseases via the persistent low-grade inflammation known as inflammaging . All this makes the inhibition of PLA2G7 a therapeutic avenue worth exploring.
The molecular underpinnings of CR are not entirely understood, so the discovery of a protein that may be responsible for some of its effects is major news. Geroscientists have been looking for CR mimetics for quite some time, since taking a pill instead of going on a diet would be an easy way – and for some people, the only way – to benefit from CR. Still, most people can just start enjoying the real thing.
 Spadaro, O., Youm, Y., Shchukina, I., Ryu, S., Sidorov, S., Ravussin, A., … & Dixit, V. D. (2022). Caloric restriction in humans reveals immunometabolic regulators of health span. Science, 375(6581), 671-677.
 Pifferi, F., Terrien, J., Marchal, J., Dal-Pan, A., Djelti, F., Hardy, I., … & Aujard, F. (2018). Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Communications biology, 1(1), 1-8.
 Kristan, D. M. (2007). Chronic calorie restriction increases susceptibility of laboratory mice (Mus musculus) to a primary intestinal parasite infection. Aging cell, 6(6), 817-825.
 Fahy, G. M., Brooke, R. T., Watson, J. P., Good, Z., Vasanawala, S. S., Maecker, H., … & Horvath, S. (2019). Reversal of epigenetic aging and immunosenescent trends in humans. Aging cell, 18(6), e13028.
 Gritsenko, A., Green, J. P., Brough, D., & Lopez-Castejon, G. (2020). Mechanisms of NLRP3 priming in inflammaging and age related diseases. Cytokine & Growth Factor Reviews, 55, 15-25.